Interleukin-36 is overexpressed in human sepsis and IL-36 receptor deletion aggravates lung injury and mortality through epithelial cells and fibroblasts in experimental murine sepsis.

BACKGROUND: Sepsis is defined as a life-threatening syndrome caused by an unbalanced host response to infection. The role of interleukin (IL)-36 cytokines binding to the IL-36 receptor (IL-36R) in host response during sepsis remains unknown. METHODS: Serum IL-36 level was measured in 47 septic patients sampled on the day of intensive care unit (ICU) and emergency department admission, 21 non-septic ICU patient controls, and 21 healthy volunteers. In addition, the effects of IL-36R deletion on host inflammatory response in cecal ligation and puncture (CLP)-induced polymicrobial sepsis was determined. RESULTS: On the day of ICU and emergency department admission, the patients with sepsis showed a significant increase in serum IL-36 levels compared with ICU patient controls and healthy volunteers, and the serum IL-36 levels were related to the severity of sepsis. Non-survivors of septic patients displayed significantly lower serum IL-36 levels compared with survivors. A high serum IL-36 level in ICU and emergency department admission was associated with 28-day mortality, and IL-36 was found to be an independent predictor of 28-day mortality in septic patients by logistic regression analysis. Furthermore, IL-36R deletion increased lethality in CLP-induced polymicrobial sepsis. Septic mice with IL-36R deletion had higher bacterial load and demonstrated more severe multiple organ injury (including lung, liver, and kidney) as indicated by clinical chemistry and histopathology. Mechanistically, IL-36R ligands released upon lung damage activated IL-36R+lung fibroblasts thereby inducing expression of the antimicrobial protein lipocalin 2. Moreover, they induced the apoptosis of lung epithelial cells. CONCLUSIONS: Septic patients had elevated serum IL-36 levels, which may correlate with disease severity and mortality. In experimental sepsis, we demonstrated a previously unrecognized role of IL-36R deletion in increasing lethality.

Manganese induces tumor cell ferroptosis through type-I IFN dependent inhibition of mitochondrial dihydroorotate dehydrogenase.

Ferroptosis is a novel form of regulated cell death characterized by the iron-dependent accumulation of lipid peroxides to lethal levels, which is morphologically, biochemically, and genetically distinct from apoptosis, necroptosis, autophagy, and pyroptosis. Manganese play an important role in innate immunity and antitumor immunity. Many manganese-based nanomaterials induce tumor cell death by catalyzing the production of reactive oxygen species (ROS) within the tumor. However, the exact underlying mechanisms remain unclear. As research on ferroptosis advances and its regulatory mechanisms in tumors continue to be refined, more evidence has suggested that triggering ferroptosis in tumor cells is an effective strategy for tumor treatment. In this study, we found that administration of MnCl2 to tumor cells resulted in lipid peroxidation and increased the levels of mitochondrial ROS, consequently leading to ferroptosis. Dihydroorotate dehydrogenase (DHODH)-mediated ferroptosis defence is a targetable vulnerability in cancer. We show that MnCl2 downregulated DHODH expression in tumor cells, resulting in increased mitochondrial ROS and lipid peroxidation to induce ferroptosis. In addition, MnCl2 enhanced the phosphorylation levels of STING, TBK1, and IRF3 and upregulated the expression of type-I interferon (IFN), produced by the cGAS-STING signaling pathway. When inhibiting the cGAS-STING signaling pathway or type-I IFN, DHODH expression was restored, reversing lipid peroxidation and ROS production and rescuing MnCl2-induced ferroptosis.. Knockout of IFNAR1 or overexpression of DHODH weakens the antitumor effect of MnCl2. Mechanistically, these results revealed that Manganese treatment-activated cGAS-STING signaling promote mitochondrial lipid peroxidation and ROS production by releasing type-I IFNs that reduce DHODH function and thereby inducing ferroptosis in tumor cells. This may provide a new strategy to complement existing antitumor treatment regimens.

In-situ removal of odorous NH3 and H2S by loess modified with biologically stabilized leachate.

The loess regions distribute widely in Northwestern China, North America and Eastern Europe. For these regions, landfill is a suitable technology for solid waste treatment. However, as a landfill cover material, loess is not very effective in controlling the emission of malodorous gases. The present study modified loess with biologically stabilized leachate, and investigated the capacities and mechanisms of the modified loess to remove odorous NH3 and H2S. The removal rates of NH3 and H2S at different acclimation time, targeted gas concentrations and temperatures were measured. It was found that the NH3 removal rate of the modified loess was up to 0.08 µmol/(g·hr), which was 1.8 times that of the virgin loess. The H2S removal rate of the modified loess was up to 1.74 µmol/(g·hr), which was 1.25 times that of the virgin loess. The half-meter loess layer modified by biologically stabilized leachate achieved nearly 100% removal of H2S. The improvement of NH3 and H2S removal ability was mainly due to the enrichment of relevant microorganisms. This work proposed a novel method for in-situ control of malodorous pollutants in landfills in the loess regions, and proved that the in-situ removal of NH3 and H2S using the loess modified with biologically stabilized leachate is feasible and cost-effective.

Immune profiles in mouse brain and testes infected by Zika virus with variable pathogenicity.

The Zika virus is responsible for neurological diseases such as microcephaly, Guillain-Barré syndrome, neuropathy, and myelitis in human adults and children. Previous studies have shown that the Zika virus can infect nerve progenitor cells and interfere with neural development. However, it is unclear how the immune system responds to infection with Zika viruses with variable pathogenicity. Here, we used two Zika strains with relatively different pathogenicity, the Asian ancestral strain CAM/2010 and the America pandemic strain GZ01/2016, to infect the brains of mice. We found that both strains elicited a strong immune response. Notably, the strain with relatively high pathogenicity, GZ01/2016, caused more intense immune regulation, with stronger CD8+ T cell and macrophage activation at 14 days post infection (dpi), as well as a greater immune gene disturbance. Notably, several TNF family genes were upregulated at 14 dpi, including Tnfrsf9, Tnfsf13, Tnfrsf8, Cd40, and Tnfsf10. It was notable that GZ01/2016 could maintain the survival of nerve cells at 7dpi but caused neurological disorders at 14dpi. These results indicate that Zika viruses with high pathogenicity may induce sustained activation of the immune system leading to nerve tissue damage.

The Effect of Commuting Time on Job Stress in Obese Men With Different Exercise Frequency in China.

Previous studies have mainly focused on the independent impact of commuting time, exercise, and stress on people. There are few studies regarding the impact of the combined effect of multiple factors on special populations such as obese people. As obesity has become increasingly widespread in China, we studied the impact of commuting time on work stress on Chinese obese men (who exercise regularly vs. who exercise irregularly). We performed a secondary retrospective analysis of the cross-sectional data from the 2014 China Labor Force Dynamics Survey. We found that long commute times and less exercise have a positive effect on the increase in stress, but the effect is less evident for people who exercise regularly. Commuters traveling on foot are more stressed than those traveling by car. This study also found that commuting time had a significant impact on the perceived work stress of obese men who exercised irregularly. But the relationship between commuting time and work stress was different among groups with different commuting styles. For obese men who commuted on foot or motorcycle, commuting time had a significant impact on their job stress. However, for obese men who commuted by bicycle, bus, or car, commuting time had no significant effect on job stress. Additionally, active and passive commuting have different effects on stress. Active commuters tend to be more stressed, while passive commuters do not show a significant impact.

Exploring the Relationship between Walking and Emotional Health in China.

Walking has a positive impact on people's emotional health. However, in the case of serious air pollution, it is controversial whether walking exercise can still improve individuals' emotional health. Using data from the 2014 wave of the China Labor-Force Dynamics Survey, this study explored the relationship between walking and emotional health with different levels of environmental pollution. The results indicated that respondents who took regular walks had better emotional health than those who did not walk regularly. For those whose main mode of physical exercise was walking, the average number of walks per week was significantly and positively correlated with their emotional health; however, the average duration of the walk had no significant impact on their emotional health. Moreover, for those whose main mode of physical exercise was walking and who lived in neighborhoods with a polluted environment, regular walking still had a positive impact on their emotional health. This suggests that even if environmental pollution is serious, walking still plays an important role in regulating individuals' mental health. We propose that in order to promote the emotional health of residents, it is necessary to create more public spaces for outdoor activities and simultaneously increase efforts to control environmental pollution.

A feature-supervised generative adversarial network for environmental monitoring during hazy days.

The adverse haze weather condition has brought considerable difficulties in vision-based environmental applications. While, until now, most of the existing environmental monitoring studies are under ordinary conditions, and the studies of complex haze weather conditions have been ignored. Thence, this paper proposes a feature-supervised learning network based on generative adversarial networks (GAN) for environmental monitoring during hazy days. Its main idea is to train the model under the supervision of feature maps from the ground truth. Four key technical contributions are made in the paper. First, pairs of hazy and clean images are used as inputs to supervise the encoding process and obtain high-quality feature maps. Second, the basic GAN formulation is modified by introducing perception loss, style loss, and feature regularization loss to generate better results. Third, multi-scale images are applied as the input to enhance the performance of discriminator. Finally, a hazy remote sensing dataset is created for testing our dehazing method and environmental detection. Extensive experimental results show that the proposed method has achieved better performance than current state-of-the-art methods on both synthetic datasets and real-world remote sensing images.

The adaptability and challenges of autonomous vehicles to pedestrians in urban China.

China is the world's largest automotive market and is ambitious for autonomous vehicles (AVs) development. As one of the key goals of AVs, pedestrian safety is an important issue in China. Despite the rapid development of driverless technologies in recent years, there is a lack of researches on the adaptability of AVs to pedestrians. To fill the gap, this study would discuss the adaptability of current driverless technologies to China urban pedestrians by reviewing the latest researches. The paper firstly analyzed typical Chinese pedestrian behaviors and summarized the safety demands of pedestrians for AVs through articles and open database data, which are worked as the evaluation criteria. Then, corresponding driverless technologies are carefully reviewed. Finally, the adaptability would be given combining the above analyses. Our review found that autonomous vehicles have trouble in the occluded pedestrian environment and Chinese pedestrians do not accept AVs well. And more explorations should be conducted on standard human-machine interaction, interaction information overload avoidance, occluded pedestrians detection and nation-based receptivity research. The conclusions are very useful for motor corporations and driverless car researchers to place more attention on the complexity of the Chinese pedestrian environment, for transportation experts to protect pedestrian safety in the context of AVs, and for governors to think about making new pedestrians policies to welcome the upcoming driverless cars.

Neutrophils, as "Trojan horses", participate in the delivery of therapeutical PLGA nanoparticles into a tumor based on the chemotactic effect.

Inspired by the fact that leukocytes have innate phagocytic functions and oriented migration capabilities in response to chemoattractants, we have unveiled that endogenous neutrophils as "Trojan horses", participate in the delivery of nanoparticles in an "in vivo self-armed assembly" manner. Neutrophils were the main population to preferentially sequester the intravenous administrated nanoparticles with an average size of 260 nm. The pre-implantation of CXCL1-laden hydrogels could trigger and induce a targeted signal to attract an influx of neutrophils carrying the therapeutic goods to the desired position. In mouse models of melanoma, the combinatorial regimen of using the PLGA nanoparticles with the CXCL1 hydrogels exhibited superior tumor inhibition capability. This work leveraged the natural phagocytosis of neutrophile and the chemotactic effect of chemokines for targeted delivery. We believe this strategy will improve the therapeutic efficiency of nanoparticle-based delivery systems, especially when the chemokines are implanted at sites of surgical tumor removal, during cancer treatment at the clinic.

UPLC Orbitrap MS/MS-based fingerprints of dissolved organic matter in waste leachate driven by waste age.

Waste leachate is a pool of complicated metabolites from waste treatment and disposal as a global environmental problem. The recognition of dissolved organic matter (DOM) in leachate is crucial to improve leachate treatment efficiency and comprehend waste stabilization process. The present study acquired the molecular information for DOM in 22 waste leachate samples using ultra-performance liquid chromatography coupled with hybrid quadrupole Orbitrap mass spectrometry (UPLC Orbitrap MS/MS) based on two dimensions of retention time and mass-to-charge ratio. Unique mass peaks occupied more than 20% of the detected mass peaks in each leachate, implying that the molecular information for DOM could be the fingerprint of waste landfills and storage pits. Waste age and composition predominately accounted for this unique DOM. The double-bond equivalent increased and the H/C decreased with waste age. We further found that 57 precursor ion peaks and artificial matter (confirmed as N-butylbenzenesulfonamide) were significantly correlated with waste age by multiple test and non-target screening. These molecular characteristics of raw leachate were first determined to compensate for the evolution of leachate with waste age. The fingerprints of waste leachate can be further applied in environmental monitoring scenarios, e.g., tracing landfill leakage.

Identification of FimH derivatives as adjuvant vaccinated with PAc that enhance protection against Streptcoccus mutans colonization.

FimH is the adhesin of type I fimbriae expressed on Escherichia coli that can mediate specific adherence to host cells. High binding mutations in FimH are related to the adaptive evolution of bacteria. However, additional roles that these allelic variations may play remain elusive. To investigate novel biological functions of the mutations in FimH, we introduced four different variants of FimH by incorporating single amino acid substitutions at specific sites, namely A25P, G73R, A106, and T158P, respectively. In this study, adjuvant potential of FimH variants was evaluated by investigating their ability to trigger innate immune response to DC2.4 and adaptive immunity to improve immunological characteristics. The data revealed that purified A106 and T158P up-regulated the expression of co-stimulatory molecules critically involved in DC2.4 activation by interaction with TLR4, whereas A25P and G73R did not induce the phenotypic maturation of DC2.4. Besides, the culture of DC2.4 with A106 and T158P enhanced the release of cytokines and protein phagocytosis. When formulated with PAc, T158P elicited more robust PAc-specific IgG and IgA antibody responses compared to PBS, PAc and PAc+K12 groups and inhibited bacteria colonization. Collectively, the results confirmed that the T158P mutation located around the inter-domain interface of the protein induced a specific enhancement effect on adjuvant characteristics.

FimH as a mucosal adjuvant enhances persistent antibody response and protective efficacy of the anti-caries vaccine.

OBJECTIVE: To investigate whether the recombinant FimH-S.T protein could modulate immune response to anti-caries vaccine in vitro and in vivo. DESIGN: Recombinant FimH protein derived from Salmonella was constructed and purified. The expression of dendritic cell maturation markers and cytokines release were performed by flow cytometry, Real-time PCR and ELISA. In addition, BALB/c mice were administered with anti-caries PAc vaccine plus FimH-S.T, antibody responses were evaluated by ELISA. Splenocytes of immunized mice were detected for their proliferative ability in response to in vitro retreatment with PAc antigen by flow cytometry. Caries protection against dental caries formation was also investigated. RESULTS: The purified FimH-S.T induced phenotypic maturation of DC2.4 by up-regulating the expression of costimulatory molecules and MHC II, provoked the production and secretion of cytokines via TLR4-dependent signaling pathway in vitro. Furthermore, the mice immunized with the mixture of FimH-S.T and PAc significantly enhanced the PAc-specific antibodies in the serum along with saliva and promoted splenocyte proliferation. Our results also confirmed that PAc+FimH-S.T decreased the caries lesions formation which provided high protective efficacy against dental caries. CONCLUSION: Our study demonstrates that recombinant FimH-S.T could enhance specific IgA responses and protection of anti-caries vaccine, possessing mucosal adjuvant ability by activating DC2.4 via TLR4 signaling pathway.

Hsa_circRNA_33287 promotes the osteogenic differentiation of maxillary sinus membrane stem cells via miR-214-3p/Runx3.

BACKGROUND: Circular RNAs (circRNAs) comprise a novel class of noncoding RNAs that play important roles in a variety of diseases. However, the mechanism by which circRNAs regulate the osteogenic differentiation of maxillary sinus membrane stem cells (MSMSCs) remains largely unclear. METHODS: Microarray analysis was used to explore the expression profiles of circRNAs during the osteogenic differentiation of normal and BMP2 induced-MSMSCs. CircRNA_33287 was identified by agarose electrophoresis, quantitative real-time PCR (qRT-PCR), and western blotting. The function of circRNA_33287 was assessed by loss- and gain-of-function techniques and Alizarin red staining. Potential miRNA binding sites for circRNA_33287, and the target genes of miR-214-3p, were predicted by using online bioinformatics analysis tools. The relationships among the regulatory roles played by circRNA_33287, miR-214-3p, and Runt-related transcription factor 3 (Runx3), during the osteogenic differentiation of MSMSCs were verified by use of the dual luciferase reporter assay, qRT-PCR, and western blotting techniques, respectively. In addition, the molecular sponge potential of circRNA_33287 for miRNA was assessed via in vivo ectopic bone formation and a histological analysis performed after hematoxylin and eosin staining. RESULTS: Expression of circRNA_33287 was confirmed to be up-regulated during the osteogenic differentiation of MSMSCS. Overexpression and silencing of circRNA_33287 increased and decreased the expression levels of key markers of osteogenesis, respectively, including Runx2, OSX, and ALP. Furthermore, circRNA_33287 acted as a molecular sponge for miR-214-3p, which regulated Runx3 expression by targeting its 3'UTR. Moreover, circRNA_33287 protected Runx3 from miR-214-3p-mediated suppression. In addition, circRNA_33287 was shown to increase ectopic bone formation in vivo and displayed the strongest ability to stimulate bone formation when co-transfected with a miR-214-3p inhibitor. CONCLUSION: The novel pathway circRNA_33287/miR-214-3p/Runx3 was found to play a role in regulating the osteoblastic differentiation of MSMSCs in the posterior maxilla.

Conversion of calibration curves for accurate estimation of molecular weight averages and distributions of polyether polyols by conventional size exclusion chromatography.

Accurate measurement of molecular weight averages (M¯n,M¯w,M¯z) and molecular weight distributions (MWD) of polyether polyols by conventional SEC (size exclusion chromatography) is not as straightforward as it would appear. Conventional calibration with polystyrene (PS) standards can only provide PS apparent molecular weights which do not provide accurate estimates of polyol molecular weights. Using polyethylene oxide/polyethylene glycol (PEO/PEG) for molecular weight calibration could improve the accuracy, but the retention behavior of PEO/PEG is not stable in THF-based (tetrahydrofuran) SEC systems. In this work, two approaches for calibration curve conversion with narrow PS and polyol molecular weight standards were developed. Equations to convert PS-apparent molecular weight to polyol-apparent molecular weight were developed using both a rigorous mathematical analysis and graphical plot regression method. The conversion equations obtained by the two approaches were in good agreement. Factors influencing the conversion equation were investigated. It was concluded that the separation conditions such as column batch and operating temperature did not have significant impact on the conversion coefficients and a universal conversion equation could be obtained. With this conversion equation, more accurate estimates of molecular weight averages and MWDs for polyether polyols can be achieved from conventional PS-THF SEC calibration. Moreover, no additional experimentation is required to convert historical PS equivalent data to reasonably accurate molecular weight results.

Validation of the Mandarin version of the LittlEARS® Auditory Questionnaire.

OBJECTIVES: To evaluate the psychometric properties of the Mandarin version of the LittlEARS(®)Auditory Questionnaire and to compare the parameters with those of the original German version of the questionnaire. The results would indicate whether the Mandarin version of the questionnaire can be applied in Mandarin speaking children or not. METHODS: A "back-translation" method was used to translate and adapt the LittlEARS(®) Auditory Questionnaire into Mandarin. A group of 157 Mandarin speaking parents of children below 24 months of age with normal hearing completed the LittlEARS(®) Auditory Questionnaire. Various psychometric analyses (scale analysis and item analysis) were conducted and compared with the original German version. RESULTS: The following scale characteristics were found with the above sample: internal consistency: Cronbach's alpha = 0.945; reliability: split-half r = 0.914; predictive accuracy: Guttman's lambda = 0.882; correlation between overall score and age of the children: r = 0.841. Several parameters (correlation between age and item score, index of difficulty, discrimination coefficient) of each item were also calculated. The regression curve, which reflects the age-dependence of auditory behavior, was produced. All parameters above had no significant differences with the corresponding ones of the original German version. Standardized values (expected and minimum values) of the Mandarin LittlEARS(®) Auditory Questionnaire were provided. CONCLUSION: The Mandarin version of the LittlEARS(®) Auditory Questionnaire is reliable and valid as a sensitive tool to assess the development of auditory behavior in Mandarin speaking children up to 24 months of age. The Mandarin standardized values are helpful for clinicians to reach a preliminary judgment in children's hearing screening or for parents to monitor the auditory development of their hearing-impaired children.

[Feeding habits of Trichiurus lepturus in Beibu Gulf of South China Sea].

From August 2008 to September 2009, the feeding habits of Trichurus lepturus L. in Beibu Gulf of South China Sea were studied by monthly sampling and stomach content analysis. In study area, T. lepturus was euryphagous, which fed on fish, cephalopoda, benthic crustacean, and zooplankton, etc., among which, Bregmaceros rarisquamosu, Decapterus maruadsi, and Acetes chinensis were the main prey components, accounting for 37.99%, 16.42%, and 10.03%, respectively. D. maruadsi and Anchoviella heteroloba appeared throughout the Beibu Gulf all year round, and could be served as the index species for the migration and fishing ground distribution of T. lepturus. The indices feeding intensity and stomach fullness differed significantly among seasons (P < 0.001); while the index prey diversity had no significant seasonal difference (P > 0.05), which peaked in autumn and had an annual average value of 1.97. Cluster analysis revealed that when the preanal length of T. lepturus was 190 mm, i. e., at 50% of maturity length, a clear diet shift happened, from small zooplankton, pelagic fishes, and crustacean for the juveniles to predominantly larger fish and cephalopoda for the adults.