MICB0106 gene polymorphism is associated with ulcerative colitis in central China

Background: The highly polymorphic nonclassical MHC class I chain-related genes A and B (MICA and MICB) encode stress-inducible glycoproteins expressed on various epithelial cells including intestinal epithelial cells. MICA and MICB gene polymorphisms and expressions are associated with autoimmune diseases but not known in ulcerative colitis (UC). Aims: To investigate the association of MICB exon 2-4 polymorphisms and soluble MICA (sMICA) expression with the susceptibility of UC in central China. Materials and methods: Genomic DNA was isolated from peripheral blood. The allele frequencies of MICB exon 2-4 were genotyped in 105 UC patients and 213 healthy controls by PCR single-stranded conformation polymorphism method. Thirty-two patients and 32 controls were selected for determining serum sMICA expression by ELISA. Results: Allele frequency of MICB0106 was significantly higher in UC patients than in healthy controls (19.0% vs. 8.9%, corrected P (Pc)=0.0006), especially in patients with extensive colitis (24.4% vs. 8.9%, Pc=0.0006), moderate and severe disease (24.1% vs. 8.9%, Pc=0.0006), extraintestinal manifestations (20.5% vs. 8.9%, Pc=0.012), male patients (22.1% vs. 8.0%, Pc=0.006), and patients over the age of 40 years (28.8% vs. 8.3%, Pc=0.0006). The sMICA level was significantly higher in UC than in healthy controls (604.41±480.43 pg/ml vs. 175.37±28.31 pg/ml, P=0.0001) but not associated with the MICB0106 genotypes. Conclusions: Overall, MICB0106 allele was positively associated with UC in the Han Chinese in central China. sMICA was highly expressed in UC but not associated with the MICB0106 genotype

Sirtuin2 suppresses the polarization of regulatory T cells toward T helper 17 cells through repressing the expression of signal transducer and activator of transcription 3 in a mouse colitis model

Abstract Introduction Regulatory T cells (Tregs) play an important role in inflammatory bowel diseases (IBDs) through modulating intestinal inflammation. However, the factors affecting Treg function and plasticity during IBD progression are not thoroughly disclosed. The current study aims to reveal new molecular mechanisms affecting Treg plasticity. Methods A mouse strain, in which tdTomato and enhanced green fluorescent protein were under the control of the Foxp3 promoter and Il17a promoter, was established and subjected to colitis induction with dextran sulfate sodium. The existence of Tregs and IL‐17‐expressing Tregs (i.e., Treg/T helper 17 [Th17] cells) were observed and sorted from the spleen, mesenteric lymph nodes, and lamina propria by flow cytometry, followed by measuring Sirtuin2 (Sirt2) expression using quantitative reverse transcription polymerase chain reaction and Immunoblotting. Lentivirus‐induced Sirt2 silencing was applied to determine the impact of Sirt2 on Treg polarization to Treg/Th17 cells and even Th17 cells. The effect of Sirt2 on Stat3 was analyzed by flow cytometry and immunoblotting. Results Sirt2 was highly expressed in lamina propria Tregs and it moderately suppressed Foxp3 expression as well as the immunosuppressive function of Tregs. Surprisingly, lentivirus‐mediated Sirt2 silencing promoted the generation of Treg/Th17 cells out of Tregs. Sirt2 silencing also enhanced the generation of Th17 cells out of Tregs under the Th17 induction condition. Furthermore, Sirt2 inhibited Th17 induction by suppressing the protein level of the signal transducer and activator of transcription 3. Conclusion Sirt2 suppresses Treg function but also inhibits Treg polarization toward Treg/Th17 cells and Th17 cells. The ultimate effect of Sirt2 on colitis might depend on the balance among Tregs, Treg/Th17 cells, and Th17 cells

Risk Factors for Patient–Ventilator Asynchrony and Its Impact on Clinical Outcomes: Analytics Based on Deep Learning Algorithm

Background and objectives: Patient–ventilator asynchronies (PVAs) are common in mechanically ventilated patients. However, the epidemiology of PVAs and its impact on clinical outcome remains controversial. The current study aims to evaluate the epidemiology and risk factors of PVAs and their impact on clinical outcomes using big data analytics. Methods: The study was conducted in a tertiary care hospital; all patients with mechanical ventilation from June to December 2019 were included for analysis. Negative binomial regression and distributed lag non-linear models (DLNM) were used to explore risk factors for PVAs. PVAs were included as a time-varying covariate into Cox regression models to investigate its influence on the hazard of mortality and ventilator-associated events (VAEs). Results: A total of 146 patients involving 50,124 h and 51,451,138 respiratory cycles were analyzed. The overall mortality rate was 15.6%. Double triggering was less likely to occur during day hours (RR: 0.88; 95% CI: 0.85–0.90; p < 0.001) and occurred most frequently in pressure control ventilation (PCV) mode (median: 3; IQR: 1–9 per hour). Ineffective effort was more likely to occur during day time (RR: 1.09; 95% CI: 1.05–1.13; p < 0.001), and occurred most frequently in PSV mode (median: 8; IQR: 2–29 per hour). The effect of sedatives and analgesics showed temporal patterns in DLNM. PVAs were not associated mortality and VAE in Cox regression models with time-varying covariates. Conclusions: Our study showed that counts of PVAs were significantly influenced by time of the day, ventilation mode, ventilation settings (e.g., tidal volume and plateau pressure), and sedatives and analgesics. However, PVAs were not associated with the hazard of VAE or mortality after adjusting for protective ventilation strategies such as tidal volume, plateau pressure, and positive end expiratory pressure (PEEP)

Table_1_Metabolic remodeling of glycerophospholipids acts as a signature of dulaglutide and liraglutide treatment in recent-onset type 2 diabetes mellitus.docx

AimsAs metabolic remodeling is a pathological characteristic in type 2 diabetes (T2D), we investigate the roles of newly developed long-acting glucagon-like peptide-1 receptor agonists (GLP-1RAs) such as dulaglutide and liraglutide on metabolic remodeling in patients with recent-onset T2D.MethodsWe recruited 52 cases of T2D and 28 control cases in this study. In the patient with T2D, 39 cases received treatment with dulaglutide and 13 cases received treatment with liraglutide. Using untargeted metabolomics analysis with broad-spectrum LC-MS, we tracked serum metabolic changes of the patients from the beginning to the end of follow-up (12th week).ResultsWe identified 198 metabolites that were differentially expressed in the patients with T2D, compared to the control group, in which 23 metabolites were significantly associated with fasting plasma glucose. Compared to pre-treatment, a total of 46 and 45 differentially regulated metabolites were identified after treatments with dulaglutide and liraglutide, respectively, in which the most differentially regulated metabolites belong to glycerophospholipids. Furthermore, a longitudinal integration analysis concurrent with diabetes case-control status revealed that metabolic pathways, such as the insulin resistance pathway and type 2 diabetes mellitus, were enriched after dulaglutide and liraglutide treatments. Proteins such as GLP-1R, GNAS, and GCG were speculated as potential targets of dulaglutide and liraglutide.ConclusionsIn total, a metabolic change in lipids existed in the early stage of T2D was ameliorated after the treatments of GLP-1RAs. In addition to similar effects on improving glycemic control, remodeling of glycerophospholipid metabolism was identified as a signature of dulaglutide and liraglutide treatments.</p

Electron Cryo-microscopy Structure of Ebola Virus Nucleoprotein Reveals a Mechanism for Nucleocapsid-like Assembly

Ebola virus nucleoprotein (eNP) assembles into higher-ordered structures that form the viral nucleocapsid (NC) and serve as the scaffold for viral RNA synthesis. However, molecular insights into the NC&nbsp;assembly process are lacking. Using a hybrid approach, we characterized the NC-like assembly of eNP, identified novel regulatory elements, and described how these elements impact function. We generated a three-dimensional structure of the eNP NC-like assembly at 5.8&nbsp;Å using electron cryo-microscopy and identified a new regulatory role for&nbsp;eNP helices α22-α23. Biochemical, biophysical, and mutational analyses revealed that inter-eNP contacts within α22-α23 are critical for viral NC assembly and regulate viral RNA synthesis. These observations suggest that the N terminus and α22-α23 of eNP function as context-dependent regulatory modules (CDRMs). Our current study provides a framework for a structural mechanism for NC-like assembly and a new therapeutic target