AwSclB regulates a network for Aspergillus westerdijkiae asexual sporulation and secondary metabolism independent of the fungal light control.

As a prevalent pathogenic fungus, Aspergillus westerdijkiae poses a threat to both food safety and human health. The fungal growth, conidia production and ochratoxin A (OTA) in A. weterdijkiae are regulated by many factors especially transcription factors. In this study, a transcription factor AwSclB in A. westerdijkiae was identified and its function in asexual sporulation and OTA biosynthesis was investigated. In addition, the effect of light control on AwSclB regulation was also tested. The deletion of AwSclB gene could reduce conidia production by down-regulation of conidia genes and increase OTA biosynthesis by up-regulation of cluster genes, regardless under light or dark conditions. It is worth to note that the inhibitory effect of light on OTA biosynthesis was reversed by the knockout of AwSclB gene. The yeast one-hybrid assay indicated that AwSclB could interact with the promoters of BrlA, ConJ and OtaR1 genes. This result suggests that AwSclB in A. westerdijkiae can directly regulate asexual conidia formation by activating the central developmental pathway BrlA-AbaA-WetA through up-regulating the expression of AwBrlA, and promote the light response of the strain by activating ConJ. However, AwSclB itself is unable to respond to light regulation. This finding will deepen our understanding of the molecular regulation of A. westerdijkiae development and secondary metabolism, and provide potential targets for the development of new fungicides.

Diastereoselective Synthesis of Dihydrobenzofuran Spirooxindoles and Their Transformation into Benzofuroquinolinones by Ring Expansion of Oxindole Core.

A mild and efficient approach for the diastereoselective synthesis of dihydrobenzofuran spirooxindoles using 3-chlorooxindoles and imines is presented. This process involves a formal [4 + 1] annulation, yielding the product with excellent diastereoselectivity. Furthermore, a novel method for constructing benzofuroquinolinone scaffolds through the ring expansion of oxindoles has been established. This method involves a lactam ring expansion to the quinolinone skeleton. Besides, a one-pot procedure for creating benzofuroquinolinone scaffolds from 3-chlorooxindoles and imines is also provided.

The potential bidirectional association between Helicobacter pylori infection and gallstone disease in adults: A two-cohort study.

BACKGROUND: Previous studies have suggested that Helicobacter pylori (H. pylori) may act as a precipitating factor in gallstone formation, and the potential association between H. pylori infection and gallstone disease (GD) is still unclear and controversial. This study aimed to clarify the potential bidirectional relationship between H. pylori infection and GD. METHODS: This retrospective cohort study was performed in a population that underwent health checkups at the hospital between 2013 and 2018. H. pylori infection status was evaluated by urea breath test (UBT), and GD was diagnosed via ultrasound. Cox regression and propensity score matching (PSM) were used. RESULTS: Among 1011 participants without H. pylori infection at baseline, 134 participants were infected with H. pylori. Among 1192 participants without gallstones or cholecystectomy at baseline, 60 participants developed gallstones or cholecystectomy. The hazard ratio (HR) (95% CI) for incident H. pylori infection comparing the GD versus the no GD group was 1.84 (1.19, 2.85). The age- and sex-adjusted HR (95% CI) for incident GD comparing H. pylori-positive subjects to H. pylori-negative subjects was 1.74 (1.01, 2.98). Consistent results were also found with PSM and multivariate analysis. CONCLUSIONS: This cohort study demonstrated a potential bidirectional association between H. pylori infection and GD, which provides a basis for indicating the risk of GD and implementing the clinical strategies for GD. For the prevention and treatment of GD, H. pylori infection should be carefully considered and evaluated.

Expression of NEAT1 can be used as a predictor for Dex resistance in multiple myeloma patients.

OBJECTIVE: Multiple myeloma is a heterogeneous disorder and the intratumor genetic heterogeneity contributes to emergency of drug resistance. Dexamethasone has been used clinically for decades for MM. Nevertheless, their use is severely hampered by the risk of developing side effects and the occurrence of Dex resistance. LncRNA NEAT1 plays a oncogenic role and participates in drug resistance in many solid tumors. Therefore, we investigated a potential usefulness of this molecular as a biomarker for diagnosis of MM and possible correlations of NEAT1 expression with drug resistance and prognosis. METHODS: Bone marrow and peripheral blood mononuclear cells samples were collected from 60 newly diagnosed MM patients. The expression of NEAT1expression level were detected by quantitative real-time PCR analyses. The relationship about the expression levels of lncRNA with other clinical and cytogenetic features was analyzed. In addition, we measured to analysis the correlation between the expression of NEAT1 and Dex resistance in MM patients. RESULTS: It was found that the expression of NEAT1 is significantly higher in multiple myeloma patients compared to controls and does not change with other clinical features and cytogenetic features. We further discovered that overexpression of NEAT1 was associated with Dex resistance and a poor prognosis in MM patients. CONCLUSION: LncRNA NEAT1 has a significant value that might act as a promoting factor in the development of MM and may be severed as a diagnostic factor in MM. NEAT1 invovled in Dex resistance, which provide a new interpretation during the chemotherapy for MM.

Competitive evolved sub-clonal BCR::ABL1 and novel MSI2::PC fusion genes in myelodysplastic syndrome with isolated del(5q).

Myelodysplastic syndrome (MDS) represents a group of neoplasms with extensive heterogeneity. Recurrent mutations in dozens of driver genes have been identified in over 90% of MDS cases, although fusion genes are rarely seen. We first report the competitive evolved sub-clonal breakpoint cluster region (BCR)::ABL1 and novel MSI2::PC fusion gene in MDS with del(5q) in initial diagnosis that underwent dismal progression. However, the BCR::ABL1 clone vanished while the MSI2::PC clone rose to the major one with disease progression. A novel MSI2::PC fusion transcript was identified in initial diagnosis and disease progression of the patient through transcriptome sequencing (RNA-seq) and Quantitative reverse transcription polymerase Chain Reaction (PCR) showed MSI2::PC/ABL1 expression at initial diagnosis and disease progression. In addition, mutation screening of 300 leukemia driver genes identified ARID2 c.5046del/p.F1682Lfs*19 and ZNF292 c.4565A > G/p.Q1522R mutation in bone marrow sample at initial diagnosis and disease progression. In conclusion, the dynamic process of the two fusion and phenotype manifestations may help to understand further the molecular significance of the anomalies of BCR::ABL1, MSI2, and PC in oncogenesis.

Biglycan promotes hepatic fibrosis through activating heat shock protein 47.

BACKGROUND: Biglycan (BGN) is a small leucine-rich proteoglycan that participates in the production of excess extracellular matrix (ECM) and is related to fibrosis in many organs. However, the role of BGN in liver fibrosis remains poorly understood. This study aimed to investigate the role and mechanism of BGN in liver fibrosis. METHODS: Human liver samples, Bgn-/0 (BGN KO) mice and a human LX-2 hepatic stellate cells (HSCs) model were applied for the study of experimental fibrosis. GEO data and single-cell RNA-seq data of human liver tissue were analysed as a bioinformatic approach. Coimmunoprecipitation, immunofluorescence staining, western blotting and qRT-PCR were conducted to identify the regulatory effects of BGN on heat shock protein 47 (HSP47) expression and liver fibrosis. RESULTS: We observed that hepatic BGN expression was significantly increased in patients with fibrosis and in a mouse model of liver fibrosis. Genetic deletion of BGN disrupted TGF-ß1 pathway signalling and alleviated liver fibrosis in mice administered carbon tetrachloride (CCl4 ). siRNA-mediated knockdown of BGN significantly reduced TGF-ß1-induced ECM deposition and fibroblastic activation in LX-2 cells. Mechanistically, BGN directly interacted with and positively regulated the collagen synthesis chaperon protein HSP47. Rescue experiments showed that BGN promoted hepatic fibrosis by regulating ECM deposition and HSC activation by positively regulating HSP47. CONCLUSION: Our data indicate that BGN promotes hepatic fibrosis by regulating ECM deposition and HSC activation through an HSP47-dependent mechanism. BGN may be a new biomarker of hepatic fibrosis and a novel target for disease prevention and treatment.

Enhancing the Molecular Order and Vertical Component Distribution of the P3HT/O-IDTBR System during Layer-by-Layer Processing.

The molecular order and vertical component distribution are critical to enhance the charge transport in layer-by-layer (LbL) processed active layer. However, the excessive inter-diffusion between donor and acceptor layers during LbL processing irrepressibly reduces their ordered packing. Herein, a novel tactic to optimize the molecular order and vertical morphology of the active layer through suppressing the deep penetration of (5Z,5'Z)-5,5'-((7,7'-(4,4,9,9-tetraoctyl-4,9-dihydro-s-indaceno[1,2-b:5,6 -b']dithiophene-2,7-diyl)bis(benzo[c][1,2,5]thiadiazole-7,4-diyl))bis(methanylylidene)) bis(3-ethyl-2-thioxothiazolidin-4-one) (O-IDTBR) to poly(3-hexylthiophene) (P3HT) film during LbL processing is proposed. This is enabled by inducing the formation of P3HT nanofibers through ultraviolet (UV) irradiation and solution aging. During the LbL processing, these nanofibers with high crystallinity reduce the damage of O-IDTBR solution to P3HT film and restrict the penetration of O-IDTBR into P3HT matrix. As a result, the P3HT nanofibers are preserved and the degree of vertical phase separation is enlarged in the LbL-processed film. Meanwhile, the molecular order of both components is enhanced. The resulting morphology that featured as intertwined P3HT nanofibers/O-IDTBR network efficiently promotes charge transport and extraction, boosting the power conversion efficiency (PCE) of the devices from 6.70 ± 0.12% to 7.71 ± 0.10%.

Celastrol pretreatment attenuates concanavalin A-induced hepatitis in mice by suppressing interleukin-6/STAT3-interleukin-17 signaling.

BACKGROUND AND AIM: Celastrol is extracted from Tripterygium wilfordii Hook F. It has been reported to have protective effects against various liver diseases and immune regulation of autoimmune diseases. However, little is known about whether celastrol protects against immune-mediated hepatitis. This study aimed to investigate the effect of celastrol on liver injury induced by concanavalin A (ConA) and the potential mechanisms. METHODS: Intravenous administration of ConA was applied to induce acute liver injury in mice with or without pretreatment of celastrol. The effects of celastrol on ConA-induced liver injury were further demonstrated by biochemical and histopathological assessments, immunoblotting, and flow cytometry analysis. RESULTS: Both biochemical and histopathological observations showed that pretreatment of celastrol significantly ameliorated liver injury induced by ConA. Moreover, the hepatocyte apoptosis and inflammatory responses induced by ConA were also improved in celastrol-pretreated mice. Further studies revealed that these improvements were characterized as the celastrol-mediated suppression of total interleukin (IL)-17 from liver mononuclear cells in ConA-treated mice. Flow cytometry analysis suggested that celastrol specifically decreased IL-17 production by CD4+ T cells but not by CD8+ T cells. Fundamentally, pretreatment with celastrol inhibited both the IL-6 produced by F4/80+ macrophages and the IL-6 receptor on Th17 cells in the liver, which further led to the downregulated activation of STAT3, thus accounting for blocked Th17 signaling. CONCLUSIONS: Celastrol may exhibit immune regulatory effects by regulating IL-6/STAT3-IL-17 signaling in ConA-induced hepatitis, which suggested new potentials for celastrol to be applied in treating immune-mediated liver diseases.

Statistically and visually analyzing the latest advancements and future trends of uranium removal.

Uranium contamination and remediation is a very important environmental research area. Removing radioactive and toxic uranium from contaminated media requires fundamental knowledge of targets and materials. To explore the-State-of-the-Art in uranium contamination control, we employed a statistical tool called CiteSpace to visualize and statistically analyze 4203 peer-reviewed papers on uranium treatment published between 2008 and 2022. The primary content presentations of visual analysis were co-authorships, co-citations, keyword co-occurrence analysis with cluster analysis, which could offer purposeful information of research hots and trends in the field of uranium removal. The statistical analysis results indicated that studies on uranium removal have focused on adsorption of uranium from aqueous solution. From 2008 to 2022, biochar and biological treatment were firstly used to sequester uranium, then adsorption for uranium removal dominates with adsorbents of graphene oxide, primary nanofiber magnetic polymers and metal-organic frameworks (MOFs). In recent years, photocatalysts and metal-organic frameworks are expected to be two of the most popular research topics. In addition, we further highlighted the characteristics and applications of MOFs and GOs in uranium removal. Overall, a statistical review was proposed to visualize and summarize the knowledge and research trends regarding uranium treatment.

Genome-Wide Analysis of the DC1 Domain Protein Gene Family in Tomatoes under Abiotic Stress.

DC1 (Divergent C1) domain proteins are a new class of proteins that have been discovered in recent years, which play an important role in plant growth, development, and stress response. In order to better study the distribution and function of DC1 domain proteins in tomatoes, a genome-wide identification was conducted. It was found that there are twenty-one DC1 domain protein genes distributed on nine chromosomes of tomatoes, named SlCHP1-21. Phylogenetic analysis shows that twenty-one SlCHP genes are divided into six subfamilies. Most of the SlCHP genes in tomatoes have no or very short introns. All SlCHP proteins, with the exception of SlCHP8 and SlCHP17, contain variable amounts of C1 domain. Analysis of the SlCHP gene promoter sequence revealed multiple cis-elements responsive to plant stress. qRT-CR analysis showed that most members of SlCHP gene expressed in the roots. The SlCHP11, 13, 16, 17, and SlCHP20 genes showed specific responses to high temperature, low temperature, salt, and drought stress. In addition, the subcellular localization and interaction proteins of SlCHP were analyzed and predicted. Together, these results provides a theoretical basis for further exploration of the function and mechanism of the SlCHP gene in tomatoes.

Vitamin D receptor inhibits EMT via regulation of the epithelial mitochondrial function in intestinal fibrosis.

We previously showed that the vitamin D receptor (VDR) plays a crucial role in acute inflammatory bowel disease and that intestinal fibrosis is a common complication of Crohn's disease (CD). Epithelial-mesenchymal transition (EMT) is an important hallmark of fibrogenesis through which epithelial cells lose their epithelial phenotype and transform into mesenchymal cells. It is known that the VDR plays an essential role in epithelial integrity and mitochondrial function, but its role in intestinal fibrosis remains unknown. Here, we investigated whether the VDR is involved in epithelial mitochondrial dysfunction that results in EMT in intestinal fibrosis. Using human CD samples, intestine-specific VDR-KO mice, and fibroblast cellular models, we showed that the expression of the VDR was significantly lower in intestinal stenotic areas than in nonstenotic areas in patients with chronic CD. Genetic deletion of the VDR in the intestinal epithelium exacerbated intestinal fibrosis in mice administered with dextran sulfate sodium or 2,4,6-trinitrobenzene sulfonic acid, two experimental colitis inducers. In addition, we found that vitamin D dietary intervention regulated intestinal fibrosis by modulating the intestinal expression of the VDR. Mechanistically, knocking down the VDR in both CCD-18Co cells and human primary colonic fibroblasts promoted fibroblast activation, whereas VDR overexpression or VDR agonist administration inhibited fibroblast activation. Further analysis illustrated that the VDR inhibited EMT in the HT29 cell model and that mitochondrial dysfunction mediated epithelial integrity and barrier function in VDR-deficient epithelial cells. Together, our data for the first time demonstrate that VDR activation alleviates intestinal fibrosis by inhibiting fibroblast activation and epithelial mitochondria-mediated EMT.

The safety and efficacy of peroral endoscopic cardial constriction in gastroesophageal reflux disease.

BACKGROUND AND AIM: Gastroesophageal reflux disease (GERD) is one of the most common digestive disorders, which seriously affects the quality of life and brings a heavy burden to the medical care. Peroral endoscopic cardial constriction (PECC) can narrow the cardia through mucosal ligation to alleviate acid reflux symptoms. This study aims to assess the clinical efficacy of PECC. METHODS: This was a retrospective case series including patients diagnosed with GERD and undergoing PECC from September 2019 to July 2021. GERD-Q questionnaire and GERD-QOL questionnaire were applied to evaluate the symptom severity and the impact of life because of GERD. RESULTS: A total of 16 patients were included in our study. The mean GERD-Q score was 10.94 ± 2.11 before PECC, while 5.38 ± 3.90 after PECC. The mean GERD-QOL score was 43.60 ± 16.94 before PECC, while 73.65 ± 22.08 after PECC. 62.5% of patients were satisfied with the symptom control and no serious complications were reported in our study. CONCLUSIONS: PECC is an efficient and safe minimally invasive endoscopic intervention for GERD. It can significantly improve GERD-related symptoms and quality of life.

A meta-analysis on the diagnostic performance of magnetic resonance imaging and transient elastography in nonalcoholic fatty liver disease.

BACKGROUND: Noninvasive methods have been used for the assessment of hepatic steatosis in patients with nonalcoholic fatty liver disease (NAFLD). The aim was to assess the efficacy and accuracy of both magnetic resonance imaging(MRI) and transient elastography(TE) for the evaluation of hepatic steatosis. MATERIALS AND METHODS: The PubMed, Cochrane Library, Embase, MEDLINE and Web of Science databases were searched to retrieve studies examining the accuracy of MRI-proton density fat fraction(PDFF) and TE-controlled attenuation parameter(CAP) for evaluating the grading of steatosis(S0-S3) diagnosed by liver biopsy in NAFLD. We compared the sensitivity, specificity, hierarchical summary receiver operating characteristic curves(HSROC) and clinical utility of these methods. RESULTS: Twenty-four articles with a total of 2979 patients with NAFLD were included. The steatosis distribution was 8.1%/35.1%/32.2%/24.6% for S0/S1/S2/S3. For the diagnostic accuracy of MRI-PDFF, the HSROCs were 0.97 for ≥S1, 0.91 for ≥S2 and 0.90 for ≥S3. For the diagnostic accuracy of TE-based CAP, the HSROCs were 0.85 for ≥S1, 0.83 for ≥S2 and 0.79 for ≥S3. Following a 'positive' measurement (over the threshold value) for ≥S1, the corresponding post-test probabilities of PDFF and CAP for the presence of steatosis were 82% and 61%, respectively, when the pretest probability was 24%. If the values were below these thresholds ('negative' results), the post-test probabilities were 3% and 7%. CONCLUSION: MRI-PDFF and TE-CAP both provide highly accurate noninvasive approaches for quantifying and staging hepatic steatosis in NAFLD. Compared with TE-CAP, MRI-PDFF is significantly more accurate for evaluating dichotomized grades of steatosis.

Insulin-like growth factor binding protein 1 ameliorates lipid accumulation and inflammation in nonalcoholic fatty liver disease.

BACKGROUND AND AIMS: Insulin-like growth factor binding protein 1 (IGFBP1) is recently proved to be associated with glucose regulation and insulin resistance. However, little is known about its direct impact on nonalcoholic fatty liver disease (NAFLD). This study aims to investigate the effect and potential mechanism of IGFBP1 in NAFLD. METHODS: We first measured the expression level of IGFBP1 in NAFLD patients, mice, and cells. Then in in vivo study, C57BL/6 mice were fed with a methionine/choline-deficient (MCD) diet for 4 weeks to establish the model of NAFLD. And for the last 2 weeks, the mice were injected intraperitoneally with vehicle or recombinant mouse IGFBP1 0.015 mg/kg/d. The L02 cells were treated with free fatty acids (FFA) or palmitate acids (PA) and recombinant IGFBP1 for 48 h. Integrin-linked kinase (ILK) inhibitor and small interfering RNA were used to explore the potential interactions between IGFBP1 and integrin ß1 (ITGB1). RESULTS: The expression of IGFBP1 was increased in NAFLD patients, mice, and cells. IGFBP1 treatment significantly ameliorated lipid accumulation and hepatic injury in MCD-fed mice. IGFBP1 downregulated hepatic lipogenesis and upregulated lipid ß-oxidation. In addition, IGFBP1 attenuated the nuclear factor-kappa B (NF-κB) and extracellular regulated protein kinases (ERK) signaling pathways. In vitro, we proved that IGFBP1 relieved FFA-induced lipid accumulation via interacting with ITGB1 and alleviated inflammation by inhibiting NF-κB and ERK signaling pathways. CONCLUSIONS: IGFBP1 treatment significantly ameliorated hepatic steatosis by interacting with ITGB1 and suppressed inflammation by inhibiting NF-κB and ERK signaling pathways. Therefore, IGFBP1 might be a potential therapeutic target for NAFLD.

A novel missense mutation of RPGR identified from retinitis pigmentosa affects splicing of the ORF15 region and causes loss of transcript heterogeneity.

Mutations in the retinitis pigmentosa GTPase regulator (RPGR) gene, are the major cause of X-linked retinitis pigmentosa (RP), in which exon open reading frame 15 (ORF15) of RPGR has been implicated to play a substantial role. We identified a novel hemizygous missense mutation E585K of RPGR from whole-exome sequencing of RP. RNA-Seq analysis and functional study were conducted to investigate the underlying pathogenic mechanism of the mutation. Our results showed that the mutation actually affected RPGR ORF15 splicing. RNA-Seq analysis of the human retina followed by validation in cells revealed a complex splicing pattern near the 3' boundary of RPGR exon 14 in the ORF15 region, resulting from a variety of alternative splicing events (ASEs). The wildtype RPGR mini-gene expressed in human 293T cells confirmed these ASEs in vitro. In contrast, without new RNA species detected, the mutant mini-gene disrupted the splicing pattern of the ORF15 region, and caused loss of RPGR transcript heterogeneity. The RNA species derived from the mutant mini-gene were predominated by a minor out-of-frame transcript that was also observed in wildtype RPGR, resulting from an upstream alternative 5' splice site in exon 14. Our findings therefore provide insights into the influence of RPGR exonic mutations on alternative splicing of the ORF15 region, and the underlying molecular mechanism of RP.

Folic acid-conjugated nitrogen-doped graphene quantum dots as a fluorescent diagnostic material for MCF-7 cells.

This paper reports the preparation and application of folic acid-conjugated nitrogen-doped graphene quantum dots (N-GQDs) as a fluorescent diagnostic material for MCF-7 cells of breast cancer. N-GQDs were prepared by a hydrothermal method using citric acid as the carbon source and diethylamine as the nitrogen source. The doping of different amounts of nitrogen content was effectively controlled by diethylamine. As the amount of nitrogen increased, more binding sites on the N-GQDs were supplied to the folic acid. Laser confocal scanning microscopy showed that increased folic acid binding facilitated the recognition of and entry to cancer cells, which made the labeled cells emit a stronger fluorescence and thus the cancer cells could be better detected. Cytotoxicity tests showed that the material was of low cytotoxicity, making it a promising prospect for fluorescent probes.

FPGA-Based Implementation of Stochastic Configuration Networks for Regression Prediction.

The implementation of neural network regression prediction based on digital circuits is one of the challenging problems in the field of machine learning and cognitive recognition, and it is also an effective way to relieve the pressure of the Internet in the era of intelligence. As a nonlinear network, the stochastic configuration network (SCN) is considered to be an effective method for regression prediction due to its good performance in learning and generalization. Therefore, in this paper, we adapt the SCN to regression analysis, and design and verify the field programmable gate array (FPGA) framework to implement SCN model for the first time. In addition, in order to improve the performance of the SCN model based on the FPGA, the implementation of the nonlinear activation function on the FPGA is optimized, which effectively improves the prediction accuracy while considering the utilization rate of hardware resources. Experimental results based on the simulation data set and the real data set prove that the proposed FPGA framework successfully implements the SCN regression prediction model, and the improved SCN model has higher accuracy and a more stable performance. Compared with the extreme learning machine (ELM), the prediction performance of the proposed SCN implementation model based on the FPGA for the simulation data set and the real data set is improved by 56.37% and 17.35%, respectively.

Alcohol Consumption and the Risk of Gastroesophageal Reflux Disease: A Systematic Review and Meta-analysis.

AIMS: Epidemiologic evidence on alcohol consumption increasing the risk of gastroesophageal reflux disease (GERD) is contradictory. This study aimed to investigate the correlation between alcohol consumption and GERD by a meta-analysis of observational studies. SHORT SUMMARY: Gastroesophageal reflux disease (GERD) is a prevalent disease, and the incidence is rising. We conducted a meta-analysis of observational studies, indicating that there was a significant association between alcohol consumption and the risk of GERD. This finding provides important implications for the prevention and control of GERD. METHODS: Two investigators retrieved relevant studies on PubMed, Cochrane and EMBASE, respectively. The summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by random effects model to assess the association. Heterogeneity was quantified using the Q statistic and I2. Subgroup analysis, publication bias and sensitivity analysis were also conducted. RESULTS: Twenty-six cross-sectional studies and three case-control studies were included in the meta-analysis. The pooled random effects OR was 1.48 (95%CI, 1.31-1.67; I2 = 88.8%), in comparison between drinkers and non-/occasional drinkers. For reflux esophagitis and non-erosive reflux disease, two subtypes of GERD, the ORs were 1.78 (95%CI, 1.56-2.03; I2 = 87.5%) and 1.15 (95%CI, 1.04-1.28; I2 = 0.3%), respectively. In addition, the pooled OR for drinkers who drank <3-5 times or days per week was 1.29 (95%CI, 1.14-1.46; I2 = 35.5%), while for those who drank more frequently, the OR was 2.12 (95%CI, 1.63-2.75; I2 = 55.1%). Dose-response analysis showed a linear association between alcohol consumption and GERD (Pfornonlinearity=0.235). The pooled OR for a 12.5 g/day increment of alcohol was 1.16 (95%CI, 1.07-1.27; P = 0.001). CONCLUSIONS: This meta-analysis provides evidence for a potential association between alcohol drinking and the risk of GERD. The increase in alcohol consumption and frequency showed a stronger association with GERD.

The effect of continuous blood purification on P38MAPK signaling pathway in patients with multiple organ dysfunction syndrome.

OBJECTIVE: The aim of the study was to investigate the role of p38MAPK signaling pathway in patients with multiple organ dysfunction syndrome treated with continuous blood purification. METHODS: Blood samples were obtained to analyze the protein level of inflammatory factors (IL-1, IL-8, IL-10, and TNF-α) and phosphorylated p38MAPK by utilizing ELISA assay and Western blotting, respectively. The relative mRNA level of iNOS was detected by using RT-PCR. In vitro study was conducted in Caco-2 cells, which were treated with serum from patients subjected to continuous blood purification. Serum-induced inflammatory factors and phosphorylated p38MAPK were also analyzed in Caco-2 cells. RESULTS: The protein levels of IL-1, IL-8, IL-10, and TNF-α were significantly decreased in Caco-2 cells treated with serum obtained from patients who were subjected to continuous blood purification therapy at the time course of 12 and 24 hours. A drastic decrease (P < 0.05) was observed in the level of IL-8 and TNF-α after continuous blood purification therapy in the patients treated with continuous blood purification therapy compared with control group. CONCLUSION: Our study conducted in vivo and in vitro demonstrated that the continuous blood purification therapy could ameliorate the inflammatory response via activating the p38MAPK signaling pathway.

Orai1 and Stim1 Mediate the Majority of Store-Operated Calcium Entry in Multiple Myeloma and Have Strong Implications for Adverse Prognosis.

BACKGROUND/AIMS: Multiple myeloma (MM) is a plasma cell neoplasm which constitutes about 10% of all hematologic malignancies. Despite the development and application of novel agents, MM still undergoes an aggressive and incurable course in the vast majority of patients. Ca2+ is one of the critical regulators of cell migration. Ca2+ influx is essential for the migration of various types of cells including tumor cells. However, the role of store-operated calcium entry (SOC) channels, the only Ca2+ channels of non-excitable cells, has not yet been reported in MM cell survival. METHODS: We evaluated the expression of Stim1 and Orai1 (two key regulators of SOC) in MM tissues and cell lines by immunohistochemical assay, quantitative real-time PCR assay and western blot. MM cell lines were pretreated with pharmacological blockers and siRNAs, and then MM cell proliferation, cell cycle arrest, and apoptosis were examined by FACS (flow cytometry) assay, and Annexin V-FITC/PI staining. The correlation between the expression of Stim1 (or Orai1) level and outcome in MM were assessed by using Progress Free Survival (PFS). RESULTS: Stim1 and Orai1 were both abundantly expressed in MM tissue and MM cell lines. Inhibition of SOCE reduced MM cell viability, and induced cell cycle arrest and apoptosis. Stim1 or Orai1 silencing also reduced cell viability, caused cell apoptosis and cell cycle arrest in MM cell lines. Over-expression of Stim1/Orai1 in MM patients was closely associated with the clinical outcome of MM. CONCLUSION: The Stim1/Orai1-mediated signaling participates in the pathogenesis of MM, which represents an attractive target for future therapeutic intervention.