Activated Clec4nhi Neutrophils Aggravate Lung Injury in an Endothelial IGFBP7-Dependent Manner.

The role of endothelial cells in acute lung injury (ALI) has been widely elaborated, but little is known about the role of different subtypes of endothelial cells in ALI. ALI models were established by lipopolysaccharide. Single-cell RNA sequencing was used to identify differential molecules in endothelial subtypes and the heterogeneity of lung immune cells. Specific antibodies were used to block insulin-like growth factor binding protein 7 (IGFBP7), and AAVshIGP7 was used to specifically knock down IGFBP7. Here, we found that IGFBP7 was the most differentially expressed molecule in diverse subsets of endothelial cells and that IGFBP7 was strongly associated with inflammatory responses. Elevated IGFBP7 significantly exacerbated barrier dysfunction in ALI, whereas blockade of IGFBP7 partially reversed barrier damage. General capillary cells are the primary source of elevated serum IGFBP7 after ALI. Using single-cell RNA sequencing, we identified significantly increased Clec4nhi neutrophils in mice with ALI, whereas IGFBP7 knockdown significantly reduced infiltration of Clec4nhi cells and mitigated barrier dysfunction in ALI. In addition, we found that IGFBP7 activated the NF-κB signaling axis by promoting phosphorylation and ubiquitination degradation of F-box/WD repeat-containing protein 2 (FBXW2), thereby exacerbating barrier dysfunction in ALI. Taken together, our data indicate that blockade of serum IGFBP7 or IGFBP7 depletion in general capillary cells reversed barrier damage in ALI. Therefore, targeting IGFBP7 depletion could be a novel strategy for treating ALI.

Circulating microvesicles miR139-3p from bronchopulmonary dysplasia aggravates pulmonary vascular simplification by targeting 4E binding protein 1.

BACKGROUND: Microvesicles (MVs) play a crucial role in bronchopulmonary dysplasia (BPD). There are many MVs in circulating plasma, and they are in direct contact with lung endothelial cells. However, the molecular mechanism and causative effect of circulating MVs on BPD remain unclear. METHODS: Clinical plasma samples were collected, circulating MVs were isolated, and microRNA (miRNA) sequencing was performed. The BPD model was established, and different MVs were administered. Alveoli and pulmonary vessels were examined by hematoxylin-eosin staining, and body weight and length were measured. In vitro, gene expression was disrupted by miRNA mimics, miRNA inhibitors or plasmid transfection. Cell proliferation and protein expression were detected by cell scratch assay, accurate 5-ethynyl-2-deoxyuridine test, western blotting, or immunofluorescence assay. RESULTS: BPD-derived MVs further aggravated pulmonary vascular simplification, while circulating MVs from control mice mitigated pulmonary vascular simplification. Micro-RNA sequencing and independent sample verification revealed that miR139-3p, but not miR6125 or miR193b-3p, was the most critical effector molecule in MVs. Mechanism studies showed that eukaryotic translation initiation factor 4E binding protein 1 was the target gene for miR139-3p. In addition, we found that supplementation of miR139-3p inhibitor partially alleviated pulmonary vascular simplification. CONCLUSIONS: These results indicate that circulating MVs are involved in forming BPD by carrying miR139-3p molecules and support miR139-3p inhibitors as a potential therapeutic strategy for alleviating pulmonary vascular simplification in BPD.

IGFBP7 promotes endothelial cell repair in the recovery phase of acute lung injury.

IGFBP7 has been found to play an important role in inflammatory diseases, such as acute lung injury (ALI). However, the role of IGFBP7 in different stages of inflammation remains unclear. Transcriptome sequencing was used to identify the regulatory genes of IGFBP7, and endothelial IGFBP7 expression was knocked down using Aplnr-Dre mice to evaluate the endothelial proliferation capacity. The expression of proliferation-related genes was detected by Western blotting and RT-PCR assays. In the present study, we found that knockdown of IGFBP7 in endothelial cells significantly decreases the expression of endothelial cell proliferation-related genes and cell number in the recovery phase but not in the acute phase of ALI. Mechanistically, using bulk-RNA sequencing and CO-IP, we found that IGFBP7 promotes phosphorylation of FOS and subsequently up-regulates YAP1 molecules, thereby promoting endothelial cell proliferation. This study indicated that IGFBP7 has diverse roles in different stages of ALI, which extends the understanding of IGFBP7 in different stages of ALI and suggests that IGFBP7 as a potential therapeutic target in ALI needs to take into account the period specificity of ALI.

Butyrate, but not propionate, reverses maternal diet-induced neurocognitive deficits in offspring.

BACKGROUND: Maternal diet plays a beneficial role in the health, including the neurodevelopment, of offspring. Insufficient fibre consumption among the general population has increased concern about neurocognitive diseases. However, the association between maternal low-fibre diet (MLFD) and neurocognitive function in offspring is still unclear. METHODS: Mice were fed diets containing diverse levels of fibre or administered short-chain fatty acids (SCFAs) during gestation. The neurocognitive functions of the offspring and synaptic plasticity-related protein levels were measured. Gene expression was disrupted by siRNA interference. Samples from pregnant women and paired umbilical cord blood (UCB) samples were analysed by the general linear model. RESULTS: We found that MLFD impaired cognitive function and synaptic plasticity in offspring and that the impairments were reversed by butyrate intake but not propionate intake. Mechanistic studies showed that histone deacetylase (HDAC)-4 is the most likely mediator of butyrate-dependent neurocognitive improvement. In addition, using human maternal serum and paired UCB samples, we demonstrated that SCFA levels in offspring were positively correlated with levels in the maternal serum. CONCLUSION: These results provide solid evidence that fibre in the maternal diet regulates neurocognitive functions in offspring through altering SCFA levels and supports the use of SCFA-dependent perinatal intervention for improving offspring health in the clinic.

Observation of non-superconducting phase changes in nitrogen doped lutetium hydrides.

The recent report of near-ambient superconductivity and associated color changes in pressurized nitrogen doped lutetium hydride has triggered worldwide interest and raised major questions about the nature and underlying physics of these latest claims. Here we report synthesis and characterization of high-purity nitrogen doped lutetium hydride LuH2±xNy. We find that pressure conditions have notable effects on Lu-N and Lu-NH chemical bonding and the color changes likely stem from pressure-induced electron redistribution of nitrogen/vacancies and interaction with the LuH2 framework. No superconducting transition is found in all the phases at temperatures 1.8-300 K and pressures 0-38 GPa. Instead, we identify a notable temperature-induced resistance anomaly of electronic origin in LuH2±xNy, which is most pronounced in the pink phase and may have been erroneously interpreted as a sign of superconducting transition. This work establishes key benchmarks for nitrogen doped lutetium hydrides, allowing an in-depth understanding of its novel pressure-induced phase changes.

Changes in Vitamin A Levels and the Effect of Early Vitamin A Supplementation on Vitamin A Levels in Infants Throughout the First 6 Months of Life: A Prospective Cohort Study in Chongqing, China.

Objectives: This study aimed to explore the changes in infant vitamin A (VA) status and the effect of early VA supplementation on VA level throughout the first 6 months of life. Methods: A prospective cohort study was conducted in Chongqing, China. A total of 1,016 healthy infants were enrolled at birth. Then, 930, 882, 854 and 822 healthy infants were followed up at postnatal day 7 and postnatal months 1, 3, and 6, respectively. Blood samples and dietary survey and physical development data were collected. Serum VA was measured by chromatography tandem-mass spectrometry and was classified according to the VA deficiency (VAD) criteria for older children aged 6-70 months (<0.70, 0.70-1.05, ≥1.05 µmol/L). Normally distributed continuous variables are presented as the mean ± standard deviation. The categorical variables are described by the frequency and percentage (%). The reference interval for the VA level was the 2.5th-97.5th percentile. Changes in VA status with age and the relationship of VA supplementation with VA level were investigated by generalized estimating equations followed by Bonferroni post hoc test, controlling for the effects of feeding pattern and sex. Results: Infant VA levels increased significantly from 0.499 ± 0.146 to 1.061 ± 0.414 µmol/L with age at 6 months, even without VA supplementation (P < 0.05). From birth to 6 months, the percentage of infants with a VA level <0.70 µmol/L decreased from 88.6 to 19.5%. During follow-up, no infant demonstrated clinical VAD conditions, such as night blindness, conjunctival xerosis or Bitot's spots. Less than 7.0% of infants were underdeveloped in terms of weight, length and head circumference. The VA status of infants with VA≥0.588 µmol/L at birth gradually increased to adequate VA (VA ≥ 1.05 µmol/L) at 6 months. For these infants, there was no significant difference in VA level between the VA supplementation and non-supplementation groups (P > 0.05). Infants with VA <0.430 µmol/L at birth still had VA <0.70 µmol/L at 6 months; in this group, VA levels increased by 0.08 µmol/L more among supplemented infants than among non-supplemented infants (P < 0.05). Conclusions: A low VA level among neonates at birth may be a normal physiological state and may increase with age; thus, not all neonates may need early VA supplementation. More multicenter studies are needed to determine a new cutoff point for the diagnosis of neonatal VAD and the administration of nutritional intervention.

Intranasal IL-4 Administration Alleviates Functional Deficits of Periventricular Leukomalacia in Neonatal Mice.

Background: Periventricular leukomalacia (PVL) is the major form of brain injury in premature infants. Currently, there are no therapies to treat PVL. Several studies suggested that polarization of microglia, a resident macrophage-like immune cell in the central nervous system, plays a vital role in brain injury and recovery. As an important mediator of immunity, interleukin-4 (IL-4) has critical effects on many immune cells, such as astrocytes and microglia. Increasing evidence shows that IL-4 plays a well-established role in attenuating inflammation in neurological disorders. Additionally, as a noninvasive and highly effective method, intranasal drug administration is gaining increasing attention. Therefore, in our study, we hypothesized that intranasal IL-4 administration is a promising strategy for PVL treatment. Methods: The therapeutic effects of IL-4 on neuroprotection were evaluated using a Control group, Hypoxia group, and Hypoxia + IL-4 treatment group. The PVL mouse model was established by a severe acute hypoxia (SAH) protocol. Exogenous IL-4 was intranasally administered to investigate its neuroprotective effects. A functional study was used to investigate neurological deficits, immunohistochemical technology and Western blotting were used to detect protein levels, and electron microscopy was used to evaluate myelination. Results: The results suggested that hypoxia stimulated Iba1+ microglial activation, downregulated myelin-related gene (NG2, MAG, and MBP) expression, reduced MBP protein levels, and caused neurological deficits. However, the intranasal administration of exogenous IL-4 partially inhibited Iba1+ microglial activation, improved myelination, and alleviated neurological deficits. The mechanistic study showed that IL-4 improved myelination possibly through the IL-4Ra-mediated polarization of microglia from the M1 phenotype to the M2 phenotype. Conclusion: In summary, our findings demonstrated that the intranasal administration of exogenous IL-4 improves myelination and attenuates functional deficits in a hypoxia-induced PVL model. Intranasal IL-4 administration may be a promising strategy for PVL treatment, for which further mechanistic studies are urgent.

Corrigendum: Risk Factors in Predicting Prognosis of Neonatal Bacterial Meningitis-A Systematic Review.

[This corrects the article DOI: 10.3389/fneur.2018.00929.].

Risk Factors in Predicting Prognosis of Neonatal Bacterial Meningitis-A Systematic Review.

Background: Neonatal bacterial meningitis is a severe infection with high mortality and morbidity. It is necessary to identify factors associated with a high risk of a poor prognosis so that we can prevent them with more appropriate treatments. This study was performed to summarize the prognostic factors known to predict adverse outcomes in neonatal bacterial meningitis. Methods: The Medline/PubMed, Cochrane Library and Embase databases were searched for studies of prognostic risk factors in neonates with bacterial meningitis. Studies published from the initiation of the database to April 30th, 2017 were included. The quality of cohort studies was assessed by the Newcastle-Ottawa Scale (NOS). The quality of cross-section studies was assessed by the Agency for Healthcare Research and Quality (AHRQ) scale. Each prognostic factor known to cause adverse outcomes is summarized. Results: Sixteen studies were identified, including 7 cohort studies and 9 cross section studies. Seizure and high protein levels in the cerebrospinal fluid (CSF) predict a poor prognosis in this disease. Coma, the need for ventilation support, and leukopenia also had some value for predicting poor prognoses. A bulging anterior fontanelle was valuable for predicting mortality. Low CSF glucose levels, thrombocytopenia, gestational age (GA) < 37 weeks and an altered sensorium were correlated with a poor prognosis. A birth weight < 2500 g, early onset meningitis and positive CSF cultures were correlated with mortality. Conclusions: This study provides a preliminary exploration of prognostic factors in neonatal bacterial meningitis and thereby fills some of the gaps in the study of prognoses in this disease. These prognostic factors can be used to predict and estimate outcomes in neonatal bacterial meningitis. Without a meta-analysis, the reliability of these factors cannot be assured. In addition, these results emphasize that there is an urgent need for a standardized protocol for follow-up and well-designed prognostic studies in neonatal bacterial meningitis.