Integrated Single Cell and Bulk RNA-Seq Analysis Revealed Immunomodulatory Effects of Ulinastatin in Sepsis: A Multicenter Cohort Study.

Sepsis is a leading cause of morbidity and mortality in the intensive care unit, which is caused by unregulated inflammatory response leading to organ injuries. Ulinastatin (UTI), an immunomodulatory agent, is widely used in clinical practice and is associated with improved outcomes in sepsis. But its underlying mechanisms are largely unknown. Our study integrated bulk and single cell RNA-seq data to systematically explore the potential mechanisms of the effects of UTI in sepsis. After adjusting for potential confounders in the negative binomial regression model, there were more genes being downregulated than being upregulated in the UTI group. These down-regulated genes were enriched in the neutrophil involved immunity such as neutrophil activation and degranulation, indicating the immunomodulatory effects of UTI is mediated via regulation of neutrophil activity. By deconvoluting the bulk RNA-seq samples to obtain fractions of cell types, the Myeloid-derived suppressor cells (MDSC) were significantly expanded in the UTI treated samples. Further cell-cell communication analysis revealed some signaling pathways such as ANEEXIN, GRN and RESISTIN that might be involved in the immunomodulatory effects of UTI. The study provides a comprehensive reference map of transcriptional states of sepsis treated with UTI, as well as a general framework for studying UTI-related mechanisms.

NRF2 Inhibits Cardiomyocyte Pyroptosis Via Regulating CTRP1 in Sepsis-Induced Myocardial Injury.

ABSTRACT: C1q/tumor necrosis factor-related protein 1 (CTRP1) has been demonstrated as a crucial regulator in myocardial injury (MI). The present study aims to evaluate the mechanism of CTRP1 in sepsis-induced MI. The septic mouse model was established via cecal ligation and puncture and the in vitro cell model was established via lipopolysaccharide treatment. The mouse survival rate within 96 h was recorded. Morphologic changes of cardiomyocytes were observed and cell viability and cardiac functions were detected. CTRP1 and nuclear factor erythroid 2-related factor (Nrf2) expressions, creatine troponin-T, and creatine phosphokinase isoenzyme levels, and expressions of pyroptotic markers were determined. The binding relationship between Nrf2 and the CTRP1 promotor was predicted and verified. Rescue experiments were designed to confirm the role of CTRP1. CTRP1 was poorly expressed in septic mice. CTRP1 overexpression inhibited cardiomyocyte pyroptosis and improved cardiac functions, MI, and survival rate in septic mice. Nrf2was decreased in cecal ligation and puncture -treated mice. Nrf2 overexpression promoted CTRP1 expression via binding to the CTRP1 promotor and suppressed cardiomyocyte pyroptosis. CTRP1 downregulation abolished the inhibitory effect of Nrf2 overexpression on cardiomyocyte pyroptosis. Overall, Nrf2 promoted CTRP1 expression via binding to the CTRP1 promotor to inhibit cardiomyocyte pyroptosis, thereby alleviating MI in septic mice.

Uncertainty Modeling of Fatigue Crack Growth and Probabilistic Life Prediction for Welded Joints of Nuclear Stainless Steel.

Welded joints are widely used in the pipeline connection of nuclear power plants. Defects in these joints are an important factor leading to the failure of welded joints. It is critical to study the fatigue crack growth and life prediction methods for the welded joints with defects, to reduce their likelihood. In this paper, we present our study of the uncertainty of fatigue crack propagation and probabilistic life prediction for welded joints of nuclear stainless steel. The standard compact tension (CT) specimens were fabricated according to the American Society for Testing and Materials (ASTM) standard. Fatigue crack propagation tests with different stress ratios were performed on CT specimens, using the Mei Te Si (MTS) fatigue test system. A fatigue crack propagation rate model considering the uncertainty of material parameters, and based on the Paris formula and crack propagation experimental data, was established. A probabilistic life prediction method based on Monte Carlo simulation was developed. The fatigue crack propagation prediction result of a CT specimen was compared with the actual tested result, to verify the effectiveness of the proposed method. Finally, the method was applied to an embedded elliptical crack in welded joints of nuclear stainless steel, to predict the fatigue crack growth life and evaluate the reliability.

Association of genetic loci for migraine susceptibility in the she people of China.

BACKGROUND: The purpose of this study was to investigate the association of the genotype and allele frequencies of the polymorphisms rs4379368, rs10504861, rs10915437, rs12134493 and rs13208321 in She people of China with migraine headache susceptibility. The five alleles were previously identified as being associated with migraine in a Western population, but it was not known if this association would hold in a She population. rs4379368 is in the succinic HMG coenzyme A transferase (C7orf10) gene; rs10504861 is near the matrix metallopeptidase 16 (MMP16) gene; rs10915437 is near the adherens junctions associated protein 1 (AJAP1) gene; rs12134493 is upstream of the tetraspanin 2 (TSPAN2) gene; and rs13208321 is within the four and a half LIM domains protein 5 (FHL5) gene. METHODS: This was a case-controlled study conducted in She people of Fujian province in China. Polymerase chain reaction-restriction fragment length polymorphism and direct sequencing were performed. Univariate and multivariate analyses were used to assess the association of the different genotypes of each SNP with migraine. RESULTS: The rs4379368 T allele was not in Hardy-Weinberg equilibrium and was more common than the C allele in subjects with migraine (58.7 %; P = 0.049), possibly suggesting a selection bias for T allele in this population. In support of this, the CT and TT genotypes were more frequent in the migraine compared with the control groups (54.0 % and 31.7 % vs. 48.0 % and 28.7 %, respectively; P = 0.019). These genotypes were also more common in females with migraines than females without migraines (53.8 % and 30.9 % vs. 46.7 % and 27.6 %; P = 0.026). Univariate and multivariate analyses found the CC genotype of rs4379368 and AA or AG genotype of rs13208321 were associated with a reduced risk of migraine (P values ≤0.039). CONCLUSIONS: Our findings suggest that rs4379368 and rs13208321 are potential genetic markers for migraine in this She population. The findings of this study and others indicate important differences between ethnic populations in regard to genetic markers of migraine susceptibility.

Epidemiology of migraine in the She ethnic minority group in Fujian province, China.

OBJECTIVES: We examined the prevalence and risk factors of migraine among the She population. The prevalence of migraine among She Chinese in Fujian province is high. METHODS: This study is a cross-sectional survey. Subjects completed a questionnaire that collected demographic and clinical data related to migraine. Physical examination and clinical laboratory tests were performed. Data were analyzed by regression analysis. RESULTS: Of the 5519 subjects enrolled, 2377 were male (43·1%) and 3142 female (56·9%). Of these, 581 (10·53%) experienced migraine annually, including 6·18% of males and 13·82% of females. Highest prevalence rate was among those aged 40-49 years (11·28%). The 141 (24·3%) subjects who had migraine with aura had higher incidence of family history of headache than those without aura (38·5% vs 19·9%, P < 0·0001). CONCLUSION: Female gender and insomnia are possible risk factors for migraine in the She population.