Atomization efficacy of a novel micro-dose mesh nebulizer (CVS-100) versus the traditional mesh nebulizer (M102) in adults with chronic obstructive pulmonary disease: A randomized non-inferiority clinical trial.

OBJECTIVE: To compare the atomization efficacy of a novel micro-dose mesh nebulizer (CVS-100) versus the traditional mesh nebulizer (M102) in nebulizing a combination of ipratropium bromide and salbutamol for treatment of stable moderate-to-severe chronic obstructive pulmonary disease (COPD). METHODS: A randomized, parallel, non-inferiority study was conducted. A total of 64 stable COPD patients were randomly assigned to either the experimental group or the control group in a 1:1 ratio. Each the experimental group received nebulized Combivent (Compound Ipratropium Bromide Solution) with CVS-100, while the control group received Combivent with M102. Lung ventilation function was measured before and 30 min after nebulization, and the difference in percentage of forced expiratory volume in the first second (FEV1) of predicted value (FEV1%pred), the forced expiratory flow at 50% (FEF50%), the forced expiratory flow at 75% (FEF75%), the mid-expiratory flow (FEF25-75%), and maximal voluntary ventilation (MVV) was evaluated. The non-inferiority margin for the lower 95% confidence limit was set at 3.5%. RESULTS: The lower limit of the 95% confidence interval for the difference in FEV1%pred between the two groups was -1.83357, which was greater than -3.5. No significant differences were found in FEF50%, FEF75%, FEF25∼75%, MVV before and after nebulization between the two groups. CONCLUSION: The novel micro-dose mesh nebulizer (CVS-100) was found to be non-inferior to the traditional mesh nebulizer (M102) in terms of the change in FEV1%pred from baseline after nebulization. Similar results were observed for all other measures of efficacy.

Effects of multi-frequency ultrasonic assisted sodium hypochlorite on the cleaning effect and quality of fresh-cut scallion stems.

This study aimed to evaluate the feasibility of multi-frequency ultrasound-assisted sodium hypochlorite (NaClO) on fresh-cut scallion stem (FCS) cleaning. Ultrasonic cleaning parameters (frequency mode, frequency amplitude, and the sample to water ratios) were optimized against cleanliness and microbial biomass as evaluation indexes. Under the optimum conditions, the free chlorine residues and quality attributes of FCS were also investigated. The results showed that the cleanliness of FCS improved significantly (p < 0.05) and the total number of microorganisms, especially Escherichia coli, decreased dramatically under the optimized cleaning condition with the simultaneous ultrasound (US) at the sweep frequency (SF) combination of 20 + 28 kHz, the ultrasonic density of 60 W/L, pulse time of 10 s, which indicated that the shelf life of FCS would be extended. Compared to FCS after the 250 ppm NaClO cleaning, the retention of ascorbic acid (AA), color, and texture structure of FCS had no significant difference after ultrasound-assisted NaClO treatment. Meanwhile, the content of allicin increased by 52.5% under ultrasound-assisted cleaning. The integration of US into the cleaning process resulted in a notably reduction of 68% in NaClO concentration, as well as the weight loss and respiration rate (RR) of the scallion stems. Therefore, ultrasound-assisted NaClO cleaning was regarded as a promising and effective approach for cleaning fresh-cut vegetables.

Inhibition of Arid1a increases stem/progenitor cell-like properties of liver cancer.

ARID1A, a key subunit of the SWI/SNF chromatin remodeling complex, exhibits recurrent mutations in various types of human cancers, including liver cancer. However, the function of ARID1A in the pathogenesis of liver cancer remains controversial. Here, we demonstrate that Arid1a knockout may result in states of different cell differentiation, as indicated by single-cell RNA sequencing (scRNA-seq) analysis. Bulk RNA-seq also revealed that Arid1a deficiency upregulated these genes related to cell stemness and differentiation, but downregulated genes related to the hepatic functions. Furthermore, we confirmed that deficiency of Arid1a increased the expression of hepatic stem/progenitor cell markers, such as Cd133 and Epcam, and enhanced the self-renewal ability of cells. Mechanistic studies revealed that Arid1a loss remodeled the chromatin accessibility of some genes related to liver functions. Thus, Arid1a deficiency might contribute to cancer development by increasing the number of stem/progenitor-like cells through dysregulating the expression of these genes related to cell stemness, differentiation and liver functions.

Dectin-2 promotes house dust mite-skewed Th2 response through the activation of cDC2s.

The role of Dectin-2 (gene symbol, Clec4n) in house dust mite (HDM) induced Th2 immune response and the exact mechanism remains controversial. In this study, we illustrated that, Clec4n-/- mice had decreased Th2 immune response following HDM challenge, which may ascribe to dramatically reduced type 2 conventional dendritic cells (cDC2s) in lung of Clec4n-/- mice, as cDC2s from lung of Clec4n-/- mice after challenging had less ability to induce Th2 response with decreased production of IL-4/IL-13. Further in vitro experiments showed the activation of Clec4n-/--BMDCs significantly decreased after HDM stimulation accompanied with decreased activation of Syk-NF-κB and Syk-JNK signal pathway. Importantly, Dectin-2 expression in PBMCs from asthmatic patients was significantly higher than that in healthy controls. Taken together, these results demonstrated that Dectin-2 could promote cDC2s activation in lung, which polarizes Th2 immune response outlining a novel mechanism of asthma development.

ARID1A deficiency weakens BRG1-RAD21 interaction that jeopardizes chromatin compactness and drives liver cancer cell metastasis.

ARID1A, encoding a subunit of SWI/SNF chromatin remodeling complex, is widely recognized as a tumor suppressor gene in multiple tumor types including liver cancer. Previous studies have demonstrated that ARID1A deficiency can cause liver cancer metastasis, possibly due to the altered chromatin organization, however the underlying mechanisms remain poorly understood. To address the effect of Arid1a deficiency on chromatin organization, we generated chromatin interaction matrices, and exploited the conformation changes upon Arid1a depletion in hepatocytes. Our results demonstrated that Arid1a deficiency induced A/B compartment switching, topologically associated domain (TAD) remodeling, and decrease of chromatin loops. Further mechanism studies revealed that ATPase BRG1 of SWI/SNF complex could physically interact with RAD21, a structural subunit of chromatin architectural element cohesin; whereas ARID1A deficiency significantly diminished the coupled BRG1-RAD21. Interestingly, the tumor-associated genes within the switched compartments were differentially expressed depending upon Arid1a depletion or not. As a consequence of ARID1A deficiency-induced conformational alteration, the dysregulation of some genes such as PMP22 and GSC, promoted the invasion capacity of liver cancer cells. This study provides an insight into liver cancer tumorigenesis and progression related to ARID1A mutations.

LZP is required for hepatic triacylglycerol transportation through maintaining apolipoprotein B stability.

The conserved zona pellucida (ZP) domain is found in hundreds of extracellular proteins that are expressed in various organs and play a variety of roles as structural components, receptors and tumor suppressors. A liver-specific zona pellucida domain-containing protein (LZP), also named OIT3, has been shown to be mainly expressed in human and mouse hepatocytes; however, the physiological function of LZP in the liver remains unclear. Here, we show that Lzp deletion inhibited very low-density lipoprotein (VLDL) secretion, leading to hepatic TG accumulation and lower serum TG levels in mice. The apolipoprotein B (apoB) levels were significantly decreased in the liver, serum, and VLDL particles of LZP-deficient mice. In the presence of LZP, which is localized to the endoplasmic reticulum (ER) and Golgi apparatus, the ER-associated degradation (ERAD) of apoB was attenuated; in contrast, in the absence of LZP, apoB was ubiquitinated by AMFR, a known E3 ubiquitin ligase specific for apoB, and was subsequently degraded, leading to lower hepatic apoB levels and inhibited VLDL secretion. Interestingly, hepatic LZP levels were elevated in mice challenged with a high-fat diet and humans with simple hepatic steatosis, suggesting that LZP contributes to the physiological regulation of hepatic TG homeostasis. In general, our data establish an essential role for LZP in hepatic TG transportation and VLDL secretion by preventing the AMFR-mediated ubiquitination and degradation of apoB and therefore provide insight into the molecular function of LZP in hepatic lipid metabolism.

Arid1a regulates insulin sensitivity and lipid metabolism.

BACKGROUND: Although significant progress has been made in understanding the mechanisms of steatosis and insulin resistance, the physiological functions of the epigenetic regulators in these processes remain largely elusive. METHODS: Hepatocyte-specific Arid1a knockout mice were administrated with high-fat diet (HFD) for 12 weeks, then insulin sensitivity was assessed by glucose tolerance test (GTT) and insulin tolerance test (ITT). The metabolism-related indicators were determined by employing a variety of biological methods, including histology, real-time PCR, enzyme-linked immunosorbent assay (ELISA), Western blotting assay, Chromatin immunoprecipitation (ChIP), RNA-seq and assay for Transposase-Accessible Chromatin with high-throughput sequencing (ATAC-seq). FINDINGS: Hepatocyte-specific Arid1a deletion significantly increases susceptibility to develop hepatic steatosis, insulin resistance and inflammation in mice fed a HFD. In vitro, Arid1a deletion in isolated hepatocytes directly leads to free fatty acid-induced lipid accumulation and insulin resistance. Mechanically, Arid1a deficiency impairs fatty acid oxidation by downregulating PPARα and altering the epigenetic landscape of some metabolism genes. INTERPRETATION: These findings reveal that targeting Arid1a might be a promising therapeutic strategy for liver steatosis and insulin resistance. FUND: This work was supported by National Natural Science Foundation of China (81672772 and 81472621), China National Science and Technology Major Project for Prevention and Treatment of Infectious Diseases (No.2017ZX 10203207) and National Program on Key Research Project of China (grant no. 2016YFC0902701).

Bibliometric analysis of scientific publications in respiratory journals from China and other top-ranking countries between 2007 and 2017.

INTRODUCTION: Respiratory disease remains one of the leading causes of mortality and morbidity worldwide. OBJECTIVES: In this study, we aimed to compare the quantity and quality of scientific publications in the field of respirology from the United States, the United Kingdom, Germany, Canada and China. METHODS: Articles published in 58 respiratory journals from 2007 to 2017 were screened with Science Citation Index Expanded database. The number of total and annual articles, article types, impact factor (IF), h-index, citations and articles in the high-impact journals from the corresponding country were collected for quantity and quality comparisons. The correlation of socioeconomic factors and annual publications was also analysed. RESULTS: A total of 93078 articles were published worldwide in respiratory journals from 2007 to 2017. The United States contributed the largest proportion (34399 (37.0%)), followed by the United Kingdom (9494 (10.2%)), Germany (6918 (7.4%)) and Canada (6574 (7.1%)). Publications from China represented the 6th, but this quantity is rapidly increasing. The United States occupies the dominant place in all kinds of article types under investigation in the study, except in the category of meta-analysis. For total and average citations, China still lags behind the other 4 countries in the study. The annual numbers of articles from China, Canada and the United States were positively correlated with gross domestic product (P < 0.05). CONCLUSIONS: The United States has played predominant role in respiratory research for the last 11 years. Although China has made great progress in the number of published articles over the past decade, the quality of these publications needs further improvement.

The 100 most influential publications in asthma from 1960 to 2017: A bibliometric analysis.

BACKGROUND: The area of asthma medicine has produced a large volume of important clinical and scientific papers that can be found in those most influential journals. The purpose of our study was to identify the 100 most cited papers in asthma research and to analyze their characteristics. METHODS: We used the Institute for Scientific Information Web of Knowledge Database to identify the most frequently cited articles published from 1960 to December 2017. Original articles and reviews were included in the study. The 100 top-cited articles were then analyzed with regard to number of citations, publication year, journals, institution, research type and field, authors and countries of authors of publications. RESULTS: The 100 top-cited articles in asthma were published between 1960 and 2011 with a median of 933 citations per article (range, 701-2947). The number of citations per article was greatest for articles published in the 1990s. The United States of America contributed most of the classic articles, followed by England. The leading institutions were Imperial College London, McMaster University, Erasmus University Rotterdam. The 100 top-cited articles were published in twenty-five journals, led by The New England Journal of Medicine (21 articles), followed by American Journal of Respiratory and Critical Care Medicine (19 articles), Lancet (11 articles), respectively. Among the 100 classics, 50% articles were clinical research articles. CONCLUSIONS: Our study provides a historical perspective on the progress of research on asthma. Studies conducted in well-developed European countries and North America, published in high-impact journals had the highest citations.

A laboratory exercise for detecting microbial contaminants.

The development and evaluation of a 6-hours laboratory class, based on capillary electrophoresis (CE) and the detection of microbial contaminants, is described. It can be easily scaled up or down, to suit class sizes up to 188 and completed in a shorter time scale. CE uses narrow-bore fused-silica capillaries to separate a complex array of large and small molecules. A laboratory exercise has been devised to illustrate how CE-based genetic analysis system processes DNA fragment analysis to detect three microbial contaminants. The protocol is relatively inexpensive and uses standard molecular biology reagents and equipment. © 2018 by The International Union of Biochemistry and Molecular Biology, 46(3):279-284, 2018.

IL4 (interleukin 4) induces autophagy in B cells leading to exacerbated asthma.

Allergic asthma is a common airway inflammatory disease in which B cells play important roles through IgE production and antigen presentation. SNP (single nucleotide polymorphism) analysis showed that Atg (autophagy-related) allele mutations are involved in asthma. It has been demonstrated that macroautophagy/autophagy is essential for B cell survival, plasma cell differentiation and immunological memory maintenance. However, whether B cell autophagy participates in asthma pathogenesis remains to be investigated. In this report, we found that autophagy was enhanced in pulmonary B cells from asthma-prone mice. Autophagy deficiency in B cells led to attenuated immunopathological symptoms in asthma-prone mice. Further investigation showed that IL4 (interleukin 4), a key effector Th2 cytokine in allergic asthma, was critical for autophagy induction in B cells both in vivo and in vitro, which further sustained B cell survival and enhanced antigen presentation by B cells. Moreover, IL4-induced autophagy depended on JAK signaling via an MTOR-independent, PtdIns3K-dependent pathway. Together, our data indicate that B cell autophagy aggravates experimental asthma through multiple mechanisms.

Validity of a Chinese version of the Mini Asthma Quality of Life Questionnaire (MiniAQLQ) and a comparison of completion by patients and relatives.

OBJECTIVE: To test the psychometric properties of the Chinese version of the Mini Asthma Quality of Life Questionnaire (MiniAQLQ) and to investigate the differences between the MiniAQLQ completed by patients (p-MiniAQLQ) and by their relatives (r-MiniAQLQ). METHODS: One hundred and two asthmatic patients and 45 relatives were recruited. The reliability was evaluated using Cronbach's alpha and intraclass correlation coefficient (ICC). The validity of the MiniAQLQ was assessed by comparing it with the Sydney Asthma Quality of Life Questionnaire (AQLQ-S) and lung function measurements. The mean quality of life scores were compared by gender and smoking history, and the p-MiniAQLQ scores were then compared with the r-MiniAQLQ scores. RESULTS: The MiniAQLQ showed high internal consistency (Cronbach's alpha = 0.901) and a high two-week reproducibility (ICC = 0.863). The cross-sectional correlations between the MiniAQLQ and the AQLQ-S were strong. Correlations between the MiniAQLQ and lung function (predicted FEV1% and PEF) ranged from poor to weak at the total or domain levels. The MiniAQLQ scores were not significantly associated with gender or smoking history. There was poor agreement between the p-MiniAQLQ and r-MiniAQLQ scores at the total or domain levels. CONCLUSIONS: The Chinese version of the MiniAQLQ showed good reliability and validity. It is reliable for evaluating the impact of asthma on patients' quality of life. Relatives of the patients did not have a comprehensive grasp of the patients' conditions. Physicians should be cautious when patients' relatives come to the hospital to seek a modified treatment when the patients are not present.

Single-cell RNA-Seq analysis reveals dynamic trajectories during mouse liver development.

BACKGROUND: The differentiation and maturation trajectories of fetal liver stem/progenitor cells (LSPCs) are not fully understood at single-cell resolution, and a priori knowledge of limited biomarkers could restrict trajectory tracking. RESULTS: We employed marker-free single-cell RNA-Seq to characterize comprehensive transcriptional profiles of 507 cells randomly selected from seven stages between embryonic day 11.5 and postnatal day 2.5 during mouse liver development, and also 52 Epcam-positive cholangiocytes from postnatal day 3.25 mouse livers. LSPCs in developing mouse livers were identified via marker-free transcriptomic profiling. Single-cell resolution dynamic developmental trajectories of LSPCs exhibited contiguous but discrete genetic control through transcription factors and signaling pathways. The gene expression profiles of cholangiocytes were more close to that of embryonic day 11.5 rather than other later staged LSPCs, cuing the fate decision stage of LSPCs. Our marker-free approach also allows systematic assessment and prediction of isolation biomarkers for LSPCs. CONCLUSIONS: Our data provide not only a valuable resource but also novel insights into the fate decision and transcriptional control of self-renewal, differentiation and maturation of LSPCs.

Association between Genetic Variants of Transforming Growth Factor-ß1 and Susceptibility of Pneumoconiosis: A Meta-analysis.

BACKGROUND: Transforming growth factor-beta 1 (TGF-ß1) and gene variants have been extensively studied in various human diseases. For example, TGF-ß1 polymorphisms were associated with fibrosis and pneumoconiosis, but the data remained controversial. The aim of this meta-analysis was to assess the association between TGF-ß1 -509 C>T [rs1800469], +869 T>C [rs1800470], and +915 G>C [rs1800471] polymorphisms and pneumoconiosis. METHODS: A comprehensive literature search was conducted through searching in PubMed, Embase, the Chinese Biomedical Database, and the Wei Pu (Chinese) Database by the end of April 2016. Eleven publications with 21 studies were included in this meta-analysis, covering a total of 4333 patients with pneumoconiosis and 3478 controls. Study quality was assessed, and heterogeneity and publication bias were measured. All statistical analyses were performed using STATA version 12.0 (StataCorp, College Station, TX, USA) software. RESULTS: The data showed significant associations between TGF-ß1 -509 C>T polymorphism and the risk of pneumoconiosis development (T vs. C, odds ratio [OR] = 1.35, 95% confidence interval [CI]: 1.00-1.81, P = 0.046); between TGF-ß1 +915 G>C polymorphism and the pneumoconiosis risk (C vs. G, OR = 1.69, 95% CI: 1.19-2.40, P = 0.004; CG vs. GG, OR = 1.79, 95% CI: 1.23-2.60, P = 0.002; CC+CG vs. GG, OR = 1.80, 95% CI: 1.24-2.61, P = 0.002). In addition, the subgroup analysis of ethnicity versus pneumoconiosis types indicated a significant association of silicosis among Asian populations but not that of coal workers' pneumoconiosis in Caucasian populations. In contrast, no significant association was exhibited between TGF-ß1 +869 T>C polymorphism and risk of pneumoconiosis. CONCLUSION: The polymorphisms of both TGF-ß1 -509 C>T and +915 G>C are associated with increased risk of pneumoconiosis.

Growth arrest and DNA damage 45G down-regulation contributes to Janus kinase/signal transducer and activator of transcription 3 activation and cellular senescence evasion in hepatocellular carcinoma.

UNLABELLED: Growth arrest and DNA damage 45G (GADD45G), a stress sensor with multiple implications in various biological processes, is down-regulated in a broad spectrum of cancers. However, little is known about the biological effects of GADD45G on hepatocellular carcinoma (HCC) cells and the related mechanisms. In the present study, we found that GADD45G was commonly down-regulated in oncogene-transformed mouse liver cells and in human and mouse HCC. Ectopic expression of GADD45G robustly elicited senescence in HCC cells and suppressed tumor growth in vivo. Furthermore, GADD45G-induced senescence occurred in HCC cells independently of p53, p16(INK4a) (p16), and retinoblastoma (Rb). Instead, the prompt inhibition of Janus kinase 2 (Jak2), tyrosine kinase 2 (Tyk2), and signal transducer and activator of transcription 3 (Stat3) activation was observed in cells undergoing senescence. Impairment of Jak-Stat3 activation caused by GADD45G expression was associated with activation of SH2 domain-containing protein tyrosine phosphatase-2 (Shp2). Expression of constitutively activated Stat3 or human telomerase reverse transcriptase (hTERT), as well as knockdown of Shp2f, efficiently counteracted GADD45G-induced senescence. More important, in clinical HCC specimens, we found that GADD45G expression was inversely correlated with phosphorylated Stat3 expression in tumor cells and disease progression. CONCLUSION: GADD45G functions as a negative regulator of the Jak-Stat3 pathway and inhibits HCC by inducing cellular senescence. The decrease or absence of GADD45G expression may be a key event for tumor cells or premalignant liver cells to bypass cellular senescence.

c-MYC overexpression overrides TAK1 dependency in efficient tumorigenicity of AKT-transformed cells.

Transforming growth factor activated kinase 1 (TAK1) provides prosurvival signals in various types of cells, and emerging evidence indicates that targeting TAK1 is a promising means to eliminate certain types of cancer cells. Here, we show that TAK1 is required for efficient tumorigenicity of AKT-transformed cells. TAK1 inhibition accelerates cell apoptosis of AKT-transformed cells in anchorage-independent cell growth accompanying by the downregulation of Mcl-1 and Bcl-2 expression. On the contrary, the tumorigenicity of c-Myc-transformed cells is not significantly affected by TAK1 inhibition. Moreover, AKT-transformed cells with c-Myc overexpression tolerate TAK1 inhibition in anchorage-independent growth and tumorigenicity in vivo. Together, our results provide evidence that TAK1-dependency in the tumorigenicity of AKT-transformed cells can be alleviated by c-Myc overexpression. These findings suggest that dual-targeting TAK1 and c-Myc might be a rational therapeutic strategy for treatment of certain types of cancer.