S100A8/9 modulates perturbation and glycolysis of macrophages in allergic asthma mice.

Background: Allergic asthma is the most prevalent asthma phenotype and is associated with the disorders of immune cells and glycolysis. Macrophages are the most common type of immune cells in the lungs. Calprotectin (S100A8 and S100A9) are two pro-inflammatory molecules that target the Toll-like receptor 4 (TLR4) and are substantially increased in the serum of patients with severe asthma. This study aimed to determine the effects of S100A8/A9 on macrophage polarization and glycolysis associated with allergic asthma. Methods: To better understand the roles of S100A8 and S100A9 in the pathogenesis of allergic asthma, we used ovalbumin (OVA)-induced MH-S cells, and OVA-sensitized and challenged mouse models (wild-type male BALB/c mice). Enzyme-linked immunosorbent assay, quantitative real-time polymerase chain reaction, flow cytometry, hematoxylin-eosin staining, and western blotting were performed. The glycolysis inhibitor 3-bromopyruvate (3-BP) was used to observe changes in glycolysis in mice. Results: We found knockdown of S100A8 or S100A9 in OVA-induced MH-S cells inhibited inflammatory cytokines, macrophage polarization biomarker expression, and pyroptosis cell proportion, but increased anti-inflammatory cytokine interleukin (IL)-10 mRNA; also, glycolysis was inhibited, as evidenced by decreased lactate and key enzyme expression; especially, knockdown of S100A8 or S100A9 inhibited the activity of TLR4/myeloid differentiation primary response gene 88 (MyD88)/Nuclear factor kappa-B (NF-κB) signaling pathway. Intervention with lipopolysaccharides (LPS) abolished the beneficial effects of S100A8 and S100A9 knockdown. The observation of OVA-sensitized and challenged mice showed that S100A8 or S100A9 knockdown promoted respiratory function, improved lung injury, and inhibited inflammation; knockdown of S100A8 or S100A9 also suppressed macrophage polarization, glycolysis levels, and activation of the TLR4/MyD88/NF-κB signaling pathway in the lung. Conversely, S100A9 overexpression exacerbated lung injury and inflammation, promoting macrophage polarization and glycolysis, which were antagonized by the glycolysis inhibitor 3-BP. Conclusion: S100A8 and S100A9 play critical roles in allergic asthma pathogenesis by promoting macrophage perturbation and glycolysis through the TLR4/MyD88/NF-κB signaling pathway. Inhibition of S100A8 and S100A9 may be a potential therapeutic strategy for allergic asthma.

Formulating and Representing Multiagent Systems With Hypergraphs.

Graph-learning methods, especially graph neural networks (GNNs), have shown remarkable effectiveness in handling non-Euclidean data and have achieved great success in various scenarios. Existing GNNs are primarily based on message-passing schemes, that is, aggregating information from neighboring nodes. However, the diversity and complexity of complex systems from real-world circumstances are not sufficiently taken into account. In these cases, the individual should be treated as an agent, with the ability to perceive their surroundings and interact with other individuals, rather than just be viewed as nodes in existing graph approaches. Additionally, the pairwise interactions used in existing methods also lack the expressiveness for the higher-order complex relations among multiple agents, thus limiting the performance in various tasks. In this work, we propose a Multiagent Hypergraph Force-learning method dubbed MHGForce. First, we formalize the multiagent system (MAS) and illustrate its connection to graph learning. Then, we propose a generalized multiagent hypergraph-learning framework. In this framework, we integrate message-passing and force-based interactions to devise a pluggable method. The method empowers graph approaches to excel in downstream tasks while effectively maintaining structural information in the representations. Experimental results on the Cora, Citeseer, Cora-CA, Zoo, and NTU2012 datasets in node classification demonstrate the effectiveness and generality of our proposed method. We also discuss the characteristics of the MHGForce and explore its role through parametric analysis and visualization. Finally, we give a discussion, conclude our work, and propose future directions.

Combined exposure to PM2.5 and PM10 in reductions of physiological development among preterm birth: a retrospective study from 2014 to 2017 in China.

Background: Preterm birth (PTB) has been linked with ambient particulate matter (PM) exposure. However, data are limited between physiological development of PTB and PM exposure. Methods: Trimester and season-specific PM exposure including PM2.5 and PM10 was collected from Jiaxing between January 2014 and December 2017. Information about parents and 3,054 PTB (gestational age < 37 weeks) outcomes such as weight (g), head circumference (cm), chest circumference (cm), height (cm) and Apgar 5 score were obtained from birth records. We used generalized linear models to assess the relationship between PTB physiological developmental indices and PM2.5, PM10 and their combined exposures. A binary logistic regression model was performed to assess the association between exposures and low birth weight (LBW, < 2,500 g). Results: Results showed that there were 75.5% of low birth weight (LBW) infants in PTB. Decreased PM2.5 and PM10 levels were found in Jiaxing from 2014 to 2017, with a higher PM10 level than PM2.5 each year. During the entire pregnancy, the highest median concentration of PM2.5 and PM10 was in winter (61.65 ± 0.24 vs. 91.65 ± 0.29 µg/m3) followed by autumn, spring and summer, with statistical differences in trimester-specific stages. After adjusting for several potential factors, we found a 10 µg/m3 increase in joint exposure of PM2.5 and PM10 during the entire pregnancy associated with reduced 0.02 week (95%CI: -0.05, -0.01) in gestational age, 7.9 g (95%CI: -13.71, -2.28) in birth weight, 0.8 cm in height (95%CI: -0.16, -0.02), 0.05 cm (95%CI: -0.08, - 0.01) in head circumference, and 0.3 (95%CI: -0.04, -0.02) in Apgar 5 score, except for the chest circumference. Trimester-specific exposure of PM2.5 and PM10 sometimes showed an opposite effect on Additionally, PM2.5 (OR = 1.37, 95%CI: 1.11, 1.68) was correlated with LBW. Conclusion: Findings in this study suggest a combined impact of fine particulate matter exposure on neonatal development, which adds to the current understanding of PTB risk and health.

The Application of Next-Generation Sequencing (NGS) in Neonatal-Onset Urea Cycle Disorders (UCDs): Clinical Course, Metabolomic Profiling, and Genetic Findings in Nine Chinese Hyperammonemia Patients.

During Jan. 2016-Dec. 2019, nine Chinese patients from eight unrelated families were diagnosed with neonatal-onset UCDs by targeted panel sequencing or whole-exome sequencing (WES). Their clinical manifestations, biochemical features, 180-day-age outcomes, and molecular genetic characteristics were reviewed retrospectively. NGS-based tests revealed 7 patients diagnosed with ornithine transcarbamylase deficiency (OTCD) and 2 with carbamoylphosphate synthetase I deficiency (CPS1D). The spectrum of the clinical presentation of nine affected individuals progressed from unspecific symptoms like poor feeding to somnolence, coma, and death. All patients presented with an acute hyperammonemia. The most robust metabolic pattern in OTCD was hyperglutaminemic hyperammonemia with high concentration of urine orotic acid, and it was reported in six patients. Of ten variants found on the OTC gene and CPS1 gene, 3 were novel: (c.176T>C (p.L59P)) in the OTC gene, c.2938G>A (p.G980S) and c.3734T>A (p.L1245H) in the CPS1 gene. There was a high mortality rate of 77.78% (7/9) for all the defects combined. An OTC-deficient male and a CPS1-deficient female survived from episodes of hyperammonemia. Although prompt recognition of UCD and the use of alternative pathway therapy in addition to provision of appropriate nutrition and dialysis improved survival, the overall outcomes for the neonatal-onset type are poor in China.

Less invasive surfactant administration versus endotracheal surfactant instillation followed by limited peak pressure ventilation in preterm infants with respiratory distress syndrome in China: study protocol for a randomized controlled trial.

BACKGROUND: Less invasive surfactant administration (LISA) is a way of giving surfactant without endotracheal intubation and has shown to be promising in reducing the incidence of bronchopulmonary dysplasia (BPD) in preterm infants. However, the mechanism underlying its beneficial effect and variations in the technique of administration may prevent its widespread use. This trial aims to evaluate the effects of two methods of surfactant administration, LISA or endotracheal surfactant administration followed by low peak pressure (LPPSA) ventilation, in preterm infants with respiratory distress syndrome (RDS). METHODS: The LISA Or Low Peak Pressure trial is to be conducted in 14 tertiary neonatal intensive care units in China. A total of 600 preterm infants born with gestational age between 250/7 and 316/7 weeks and with a primary diagnosis of RDS will be involved in the study. Infants will be randomized to the LISA or LPPSA group when surfactant therapy is indicated. Primary outcomes include mortality, severity of bronchopulmonary dysplasia at 36 weeks of postmenstrual age (PMA), and mechanical ventilation (MV) in the first 72 h of life. Secondary outcomes include the days of MV, duration of all sorts of non-invasive respiratory support, fraction of inspired oxygen, oxygen saturation before and after surfactant administration, and time required to perform the procedure for surfactant administration. The incidence of comorbidities, including retinopathy of prematurity (ROP), necrotizing enterocolitis (NEC), intraventricular hemorrhage (IVH), hemodynamically significant patent ductus arteriosus (hsPDA), pneumothorax, and massive pulmonary hemorrhage within 48 h of surfactant administration, and the failure rates of each technique will be determined. DISCUSSION: Data from recent systematic review and meta-analysis have suggested a possible improvement in outcomes of preterm infants with RDS by the LISA technique. However, robust evidence is lacking. Why LISA plays a potential role in reducing respiratory morbidity, mainly BPD in preterm infants, remains unclear. The possible explanations are the active and uninterrupted delivery of continuous positive airway pressure during the LISA procedure and the avoidance of complications caused by intubation and relatively high pressure/volume ventilation following surfactant administration. We hypothesized that LISA's effectiveness lies mainly in avoiding relatively high-pressure positive ventilation immediately following surfactant administration. Thus, this multicenter randomized controlled trial will focus on issues of endotracheal intubation and the pressure/volume used during conventional surfactant administration. The effectiveness, safety and comorbidities of preterm infants following LISA or LPPSA will be evaluated. TRIAL REGISTRATION: Chinese Clinical Trial Registry: ChiCTR1900020970. Registered on 23 January 2019.

Long noncoding RNA MALAT1 sponges miR-129-5p to regulate the development of bronchopulmonary dysplasia by increasing the expression of HMGB1.

OBJECTIVE: To explore the function and mechanism of long noncoding RNA (lncRNA) metastasis associated lung adenocarcinoma transcript 1 (MALAT1) in bronchopulmonary dysplasia. METHODS: Alveolar epithelial cell line BEAS-2B was used as the cell model. The role of MALAT1 and microRNA miR-129-5p in regulating cellular viability and migration were examined by using the CCK-8 and Transwell assays, respectively, in vitro. The luciferase reporter assay and real-time (RT)-PCR were performed to confirm that miR-129-5p was a target of MALAT1. ELISA was conducted to validate MALAT1 and show that miR-129-5p regulated the gene encoding high-mobility group protein 1 (HMGB1). RESULTS: Overexpression of MALAT1 significantly promoted cellular viability, whereas miR-129-5p had the opposite effect. miR-129-5p was shown to be a target of MALAT1, and HMGB1 could be upregulated by MALAT1 overexpression or miR-129-5p inhibition. CONCLUSION: MALAT1 reduced the expression of miR-129-5p, promoting the viability of cells and blocking the development of bronchopulmonary dysplasia. In addition, MALAT1 increased the expression of HMGB1, which contributed to inflammation as the disease progressed.

Ethylenediaminetetraacetic Acid Inhibits Vibrio Vulnificus-Induced Dendritic Cell Apoptosis by Lowering [Ca2+]i.

BACKGROUND/AIMS: Vibrio vulnificus (V. vulnificus) is a Gram-negative marine bacterium that can cause life-threatening primary septicemia, especially in the innate immune system. But how V. vulnificus affects and acts on dendritic cells (DC) is not well understood. The aim of the present study is to investigate [Ca2+]i change and the expression of the mTor-STAT3-Bcl-2 signaling pathway in V. vulnificus B2-induced DC apoptosis, and explore the protective effect of ethylenediaminetetraacetic acid (EDTA) against DC apoptosis in a V. vulnificus B2 and DC2.4 cell coculture infection model, using EDTA as an intervenient. METHODS: The apoptosis rate, [Ca2+]i, and the expression of STAT3, m-Tor and Bcl-2 were detected by cytometry, Fluo-8-AM and Western blotting respectively. RESULTS: The results demonstrated that EDTA inhibited the increase of [Ca2+]i, upregulated the expression of m-Tor-STAT3-Bcl-2 signaling pathway, and protected DC against V. vulnificus B2-induced apoptosis. CONCLUSIONS: EDTA inhibits V. Vulnificus-induced DC apoptosis by lowering [Ca2+]i via m-Tor-STAT3-Bcl-2 signaling pathway.

Factors related to retinal haemorrhage in infants born at high risk.

PURPOSE: This study aims to determine risk factors for retinal haemorrhage (RH) in high-risk infants. METHODS: A total of 3123 cases with high-risk pregnancy and/or neonatal asphyxia 72 hr after delivery were enrolled into this study. Fundus examinations were performed on newborns utilizing a wide-angle imaging system (RetCam III). Retinal haemorrhage (RH) was classified into three grades. Maternal, obstetric and neonatal parameters from high-risk infants with RH were compared with parameters from infants without RH. RESULTS: Retinal haemorrhage (RH) was found in 550 (18%) of 3123 high-risk infants. Retinal haemorrhage (RH) was classified as grade I (39%), grade II (24%) and grade III (37%). Monocular RH occurred in 37% of cases, while the remaining cases were binocular. Moreover, six cases had vitreous haemorrhage. The following parameters correlated (p < 0.05) with RH in this study: delivery mode (χ2  = 469), gestational age (χ2  = 35), birth weight (χ2  = 18), asphyxia (χ2  = 73), scalp hematoma (χ2  = 55), maternal age (χ2  = 8.9), precipitate labour (χ2  = 120) and delivery times (χ2  = 6.1). Logistic regression analysis indicated that delivery mode and asphyxia were risk factors for RH in high-risk infants, with odds ratios of 0.827 and 2.5, respectively. Gender, intracranial haemorrhage and foetal distress were not correlated with RH in high-risk infants. CONCLUSION: The incidence of RH in high-risk infants was 18%, and delivery mode, and neonatal asphyxia were major risk factors for RH in high-risk infants.