circS100A11 enhances M2a macrophage activation and lung inflammation in children with asthma.

BACKGROUND: Dysregulation of circRNAs is associated with a variety of human diseases; however, its role in childhood asthma is undefined. METHODS: The differential expression profiles of circRNAs were analyzed by microarray. The effects and mechanisms by which circRNAs influence macrophage activation were detected by quantitative real-time PCR, RNA immunoprecipitation assay, and chromatin immunoprecipitation assay, among others. The roles of circRNA and its host gene in asthma were tested in a cockroach allergen extract (CRE)-induced murine asthma model. RESULTS: We identified 372 circRNAs that were differentially expressed in PBMCs of children with asthma as compared with healthy controls. A circRNA with unknown function, circS100A11, was dominantly expressed in monocytes and significantly upregulated in children with asthma. circS100A11 facilitated M2a macrophage activation by enhancing translation of its host gene, S100A11, and exacerbated lung inflammation in a CRE-induced murine asthma model with macrophage-specific overexpression of circS100A11. Mechanistically, circS100A11 promoted S100A11 translation by competitively binding to CAPRIN1 to decrease the suppression of CAPRIN1 upon S100A11 translation. Then, S100A11 liberated SP3 from nucleolin and promoted SP3 binding to the STAT6 promoter to enhance STAT6 expression and M2a macrophage activation. Macrophage-specific knockdown of S100A11 could alleviate lung inflammation in a CRE-induced murine asthma model in vivo. CONCLUSIONS: circS100A11 and S100A11 promote M2a macrophage activation and lung inflammation in asthma model and may serve as potential therapeutic and diagnostic targets in children with asthma.

Hsa_circ_0004287 inhibits macrophage-mediated inflammation in an N6-methyladenosine-dependent manner in atopic dermatitis and psoriasis.

BACKGROUND: Circular RNA (circRNA) has been implicated in various diseases; however, its role in atopic dermatitis (AD) or psoriasis remains unclear. OBJECTIVE: We sought to determine the differential expression profiles of circRNAs in peripheral blood mononuclear cells between healthy controls and AD patients, and explore the mechanisms underlying the effects of circRNAs on the pathogenesis of AD. METHODS: The differential expression profiles of circRNAs were analyzed by circRNA microarray. In vitro function and mechanisms by which circRNAs regulate macrophage-mediated inflammation were detected by reverse transcription quantitative PCR, Western blot analysis, RNA stability assay, immunoprecipitation, ELISA, and methylated RNA immunoprecipitation assay. In vivo roles of circRNAs were determined in 2,4-dinitrochlorobenzene (DNCB)-induced dermatitis and imiquimod (IMQ)-induced psoriasis mouse model. RESULTS: We identified a functional unknown circRNA hsa_circ_0004287 from 88750 circRNAs, which was upregulated in peripheral blood mononuclear cells of both AD and psoriasis patients, and was mainly expressed by macrophages under inflammatory conditions. Hsa_circ_0004287 inhibited M1 macrophage activation in vitro, and macrophage-specific overexpression of hsa_circ_0004287 alleviated skin inflammation in both AD- and psoriasis-like mice. Mechanistically, hsa_circ_0004287 reduced the stability of its host gene metastasis associated lung adenocarcinoma transcript 1 (MALAT1) by competitively binding to IGF2BP3 with MALAT1 in an N6-methyladenosine (m6A)-dependent manner. Lower levels of MALAT1 promoted the ubiquitination degradation of S100A8/S100A9, thereby impeding p38/mitogen-activated protein kinase phosphorylation and macrophage-mediated inflammation. CONCLUSION: hsa_circ_0004287 inhibits M1 macrophage activation in an m6A-dependent manner in AD and psoriasis, and may serve as a general therapeutic candidate for AD and psoriasis.

Mechanism of enhanced production of triterpenoids in algal-fungal consortium.

Chlorella pyrenoidosa-Ganoderma lucidum symbiotic systems were constructed. The mechanism of enhanced production of triterpenoids in algal-fungal consortium by comparing the contents of triterpenoids in individual fungal systems and algal-fungal consortium systems was investigated. The production of triterpenoids in C. pyrenoidosa-G. lucidum consortium increased significantly (P < 0.05). The categories and relative abundances of metabolites in the individual systems and algal-fungal systems were measured and analyzed by metabonomic tests. There were 57 significant different metabolites (VIP > 1 and P < 0.05) including 12 downregulated metabolites and 45 upregulated metabolites were obtained. The significant enriched metabolic pathways (VIP > 1 and P < 0.05) of citrate cycle (TCA cycle), tyrosine metabolism, glycolysis, and terpenoid backbone biosynthesis in algal-fungal consortium were obtained. The relative abundances of important precursors of triterpenoids including mevalonic acid, lanosterol, and hydroquinone were 1.4 times, 1.7 times, and 2 times, respectively, in algal-fungal consortium than that in the individual fungal systems. The presence of C. pyrenoidosa in algal-fungal consortium promoted the biosynthesis of triterpenoids in G. lucidum.

lnc-BAZ2B promotes M2 macrophage activation and inflammation in children with asthma through stabilizing BAZ2B pre-mRNA.

BACKGROUND: Dysregulation of long noncoding RNAs (lncRNAs) is associated with a variety of human diseases; however, whether they have a role in childhood asthma is unknown. OBJECTIVE: We sought to determine the differential expression profiles of lncRNAs in PBMCs of children with asthma and the mechanisms underlying the effects of lncRNAs on the pathogenesis of asthma. METHODS: The differential expression profiles of lncRNAs were analyzed by transcriptome microarray. The effects and mechanisms by which lncRNAs influence macrophage activation were detected by real-time quantitative PCR, Western blot, RNase protection assay, and chromatin immunoprecipitation assay. The roles played by lncRNAs in asthma were tested in a cockroach allergen extract (CRE)-induced mouse model. RESULTS: We identified 719 lncRNAs that were differentially expressed in PBMCs of children with asthma, 502 of which were upregulated and 217 were downregulated. An lncRNA of unknown function, lnc-BAZ2B, was dominantly expressed in monocytes and significantly upregulated in children with asthma. lnc-BAZ2B promotes M2 macrophage activation by enhancing BAZ2B expression and exacerbated lung inflammation in an M2 macrophage-associated CRE-induced asthma model. Mechanistically, lnc-BAZ2B promoted the expression of its cis target gene BAZ2B by stabilizing its pre-mRNA. BAZ2B, a reader of H3K14ac modification, enhanced the transcription of IRF4 and promoted M2 macrophage activation. lnc-BAZ2B expression was correlated with that of BAZ2B in PBMCs from children with asthma. Baz2b knockdown could alleviate asthma severity in a CRE-induced asthma model. CONCLUSION: lnc-BAZ2B promotes M2 macrophage activation and inflammation in children with asthma and may serve as a potential therapeutic and diagnostic target in children with asthma.

The source apportionment of N and P pollution in the surface waters of lowland urban area based on EEM-PARAFAC and PCA-APCS-MLR.

Multiple sources contribute to nitrogen(N) and phosphorus (P) pollution in lowland urban rivers, and apportioning the sources of N and P pollution is essential for improving the ecological health of urban environments. Three urban polders in Jiaxing were selected to investigate the temporal variations of N and P pollutants in lowland urban river waters under dry and wet conditions. Moreover, the main potential sources of N and P pollution were identified through the correlations of pollutants and components of dissolved organic matter (DOM) derived from excitation-emission matrix (EEM) and parallel factor analysis (PARAFAC). The results indicate that the main pollution sources identified with PCA method were consistent with the potential sources revealed by DOM's EEM-PARAFAC components. Furthermore, absolute principal components score combined with multivariate linear regression (APCS-MLR) was conducted. The results illustrated that domestic wastewater contributes more than 70% of N pollution and river-bottom sediments contribute more than 50% of P pollution under dry conditions. On the contrary, discharged water from the stormwater outlets contributes more than 41% of P and 75% of N under wet conditions. Specifically, about 48% of them come from domestic wastewater, and about 38% come from urban surface runoff. This study highlights the effectiveness of DOM components derived from EEM-PARAFAC in identifying the sources of N and P pollution and the PCA-APCS-MLR in apportioning the contributions of each potential pollution source in lowland urban rivers.

Particulate matter of 2.5 µm or less in diameter disturbs the balance of TH17/regulatory T cells by targeting glutamate oxaloacetate transaminase 1 and hypoxia-inducible factor 1α in an asthma model.

BACKGROUND: Epidemiologic evidence suggests that exposure to particulate matter of 2.5 µm or less in diameter (PM2.5) aggravates asthma. OBJECTIVE: We sought to investigate the underlying mechanisms between PM2.5 exposure and asthma severity. METHODS: The relationship between PM2.5 exposure and asthma severity was investigated in an asthma model with CD4+ T cell-specific aryl hydrocarbon receptor (AhR)-null mice. Effects of PM2.5 and polycyclic aromatic hydrocarbons (PAHs) on differentiation of TH17/regulatory T (Treg) cells were investigated by using flow cytometry and quantitative RT-PCR. Mechanisms were investigated by using mRNA sequencing, chromatin immunoprecipitation, bisulfite sequencing, and glycolysis rates. RESULTS: PM2.5 impaired differentiation of Treg cells, promoted differentiation of TH17 cells, and aggravated asthma in an AhR-dependent manner. PM2.5 and one of its prominent PAHs, indeno[1,2,3-cd]pyrene (IP), promoted differentiation of TH17 cells by upregulating hypoxia-inducible factor 1α expression and enhancing glycolysis through AhRs. Exposure to PM2.5 and IP enhanced glutamate oxaloacetate transaminase 1 (Got1) expression through AhRs and accumulation of 2-hydroxyglutarate, which inhibited ten-eleven translocation methylcytosine dioxygenase 2 activity, resulting in hypermethylation in the forkhead box P3 locus and impaired differentiation of Treg cells. A GOT1 inhibitor, (aminooxy)acetic acid, ameliorated asthma by shifting differentiation of TH17 cells to Treg cells. Similar regulatory effects of exposure to PM2.5 or IP on TH17/Treg cell imbalance were noted in human T cells, and in a case-control design PAH exposure appeared to be a potential risk factor for asthma. CONCLUSIONS: The AhR-hypoxia-inducible factor 1α and AhR-GOT1 molecular pathways mediate pulmonary responses on exposure to PM2.5 through their ability to disturb the balance of TH17/Treg cells.

Genetic analysis and mapping of genes for resistance to multiple strains of Soybean mosaic virus in a single resistant soybean accession PI 96983.

Soybean mosaic virus (SMV) is one of the most broadly distributed soybean (Glycine max (L.) Merr.) diseases and causes severe yield loss and seed quality deficiency. Multiple studies have proved that a single dominant gene can confer resistance to several SMV strains. Plant introduction (PI) 96983 has been reported to contain SMV resistance genes (e.g., Rsv1 and Rsc14) on chromosome 13. The objective of this study was to delineate the genetics of resistance to SMV in PI 96983 and determine whether one gene can control resistance to more than one Chinese SMV strain. In this study, PI 96983 was identified as resistant and Nannong 1138-2 was identified as susceptible to four SMV strains SC3, SC6, SC7, and SC17. Genetic maps based on 783 F2 individuals from the cross of PI 96983 × Nannong 1138-2 showed that the gene(s) conferring resistance to SC3, SC6, and SC17 were between SSR markers BARCSOYSSR_13_1114 and BARCSOYSSR_13_1136, whereas SC7 was between markers BARCSOYSSR_13_1140 and BARCSOYSSR_13_1185. The physical map based on 58 recombinant lines confirmed these results. The resistance gene for SC7 was positioned between BARCSOYSSR_13_1140 and BARCSOYSSR_13_1155, while the resistance gene(s) for SC3, SC6, and SC17 were between BARCSOYSSR_13_1128 and BARCSOYSSR_13_1136. We concluded that, there were two dominant resistance genes flanking Rsv1 or one of them at the reported genomic location of Rsv1. One of them (designated as "Rsc-pm") conditions resistance for SC3, SC6, and SC17 and another (designated as "Rsc-ps") confers resistance for SC7. The two tightly linked genes identified in this study would be helpful to cloning of resistance genes and breeding of multiple resistances soybean cultivars to SMV through marker-assisted selection (MAS).

Removal mechanism of Microcystis aeruginosa in Fe2+/sodium percarbonate and Fe2+/sodium persulfate advanced oxidation-flocculation system.

Advanced oxidation process (AOPs) can be used for the treatment of harmful algal blooms (HABs). In this study, two systems of Fe2+/sodium percarbonate (Fe2+/SPC system) and Fe2+/sodium persulfate (Fe2+/PS system) were established to explore the removal mechanism of Microcystis aeruginosa (M. aeruginosa). The results indicated that the Fe2+/SPC system catalyzed H2O2 to generate a large amount of [Formula: see text] for oxidation by Fe2+ and formed Fe3+ to promote the flocculation of M. aeruginosa. The persulfate was activated by Fe2+ to generate [Formula: see text] with super-oxidizing properties, and Fe3+ was generated to realize the oxidation and flocculation of M. aeruginosa in the Fe2+/PS system. Compared with the traditional method in which the pre-oxidation and flocculation processes are carried out separately, the method in this study effectively improves the utilization rate of the flocculant and the removal effect of M. aeruginosa. The absolute value of zeta potential of Fe2+/PS system (|ζ|= 0.808 mV) was significantly lower than that of Fe2+/SPC system (|ζ|= 21.4 mV) (P < 0.05), which indicated that Fe2+/PS system was more favorable for the flocculation of M. aeruginosa cells than the Fe2+/SPC system.

Multidimensional Analysis of Lung Lymph Nodes in a Mouse Model of Allergic Lung Inflammation following PM2.5 and Indeno[1,2,3-cd]pyrene Exposure.

BACKGROUND: Ambient particulate matter with an aerodynamic diameter of ≤2.5 µm (PM2.5) is suggested to act as an adjuvant for allergen-mediated sensitization and recent evidence suggests the importance of T follicular helper (Tfh) cells in allergic diseases. However, the impact of PM2.5 exposure and its absorbed polycyclic aromatic hydrocarbon (PAHs) on Tfh cells and humoral immunity remains unknown. OBJECTIVES: We aimed to explore the impact of environmental PM2.5 and indeno[1,2,3-cd]pyrene (IP), a prominent PAH, as a model, on Tfh cells and the subsequent pulmonary allergic responses. METHODS: PM2.5- or IP-mediated remodeling of cellular composition in lung lymph nodes (LNs) was determined by mass cytometry in a house dust mite (HDM)-induced mouse allergic lung inflammation model. The differentiation and function of Tfh cells in vitro were analyzed by flow cytometry, quantitative reverse transcription polymerase chain reaction, enzyme-linked immunosorbent assay, chromatin immunoprecipitation, immunoprecipitation, and western blot analyses. RESULTS: Mice exposed to PM2.5 during the HDM sensitization period demonstrated immune cell population shifts in lung LNs as compared with those sensitized with HDM alone, with a greater number of differentiated Tfh2 cells, enhanced allergen-induced immunoglobulin E (IgE) response and pulmonary inflammation. Similarly enhanced phenotypes were also found in mice exposed to IP and sensitized with HDM. Further, IP administration was found to induce interleukin-21 (Il21) and Il4 expression and enhance Tfh2 cell differentiation in vitro, a finding which was abrogated in aryl hydrocarbon receptor (AhR)-deficient CD4+ T cells. Moreover, we showed that IP exposure increased the interaction of AhR and cellular musculoaponeurotic fibrosarcoma (c-Maf) and its occupancy on the Il21 and Il4 promoters in differentiated Tfh2 cells. DISCUSSION: These findings suggest that the PM2.5 (IP)-AhR-c-Maf axis in Tfh2 cells was important in allergen sensitization and lung inflammation, thus adding a new dimension in the understanding of Tfh2 cell differentiation and function and providing a basis for establishing the environment-disease causal relationship. https://doi.org/10.1289/EHP11580.

River ecological flow early warning forecasting using baseflow separation and machine learning in the Jiaojiang River Basin, Southeast China.

Ecological flow early warning is crucial for the rational management of watershed water resources. However, determining of accurate ecological flow threshold and choosing the appropriate forecasting model are challenging tasks. In this study, we initially developed a baseflow separation and Tennant method-based technique for calculating ecological river flow. Then an ecological flow early warning model was created using the machine learning technique based on distributed gradient enhancement framework (LightGBM). Finally, we utilized the framework of Shapley Additive Planning (SHAP) to explain how various hydrometeorological factors affect the variations in ecological flow conditions. The Jiaojiang River basin in southeast China is selected as the study area, and the hydrological stations in upstream of Baizhiao (BZA) and Shaduan (SD) are chosen for key analysis. The results of these applications show that the monthly baseflow frequency of the river ecological flow conditions of the two stations in the dry season is 20 % (7.49 m3/s) and 30 % (4.79 m3/s), respectively. The ecological flow level early warning forecasting accuracy is close to 90 % in the BZA and SD stations during dry and wet seasons. The variations of ecological flow are most affected by evaporation and base flow index. The results of this study can serve as a strong basis for the effective allocation and utilization of locally available water resources.

RNA m6A methylation modulates airway inflammation in allergic asthma via PTX3-dependent macrophage homeostasis.

N6-methyladenosine (m6A), the most prevalent mRNA modification, has an important function in diverse biological processes. However, the involvement of m6A in allergic asthma and macrophage homeostasis remains largely unknown. Here we show that m6A methyltransferases METTL3 is expressed at a low level in monocyte-derived macrophages from childhood allergic asthma patients. Conditional knockout of Mettl3 in myeloid cells enhances Th2 cell response and aggravates allergic airway inflammation by facilitating M2 macrophage activation. Loss and gain functional studies confirm that METTL3 suppresses M2 macrophage activation partly through PI3K/AKT and JAK/STAT6 signaling. Mechanistically, m6A-sequencing shows that loss of METTL3 impairs the m6A-YTHDF3-dependent degradation of PTX3 mRNA, while higher PTX3 expression positively correlates with asthma severity through promoting M2 macrophage activation. Furthermore, the METTL3/YTHDF3-m6A/PTX3 interactions contribute to autophagy maturation in macrophages by modulating STX17 expression. Collectively, this study highlights the function of m6A in regulating macrophage homeostasis and identifies potential targets in controlling allergic asthma.

Melatonin alleviates vascular endothelial cell damage by regulating an autophagy-apoptosis axis in Kawasaki disease.

OBJECTIVES: Melatonin has been reported to be an appropriate candidate for mitigating various cardiovascular injuries, owing to its versatility. This study aimed to explore the role of melatonin in Kawasaki disease (KD)-associated vasculitis and its underlying mechanisms. MATERIAL AND METHODS: The role of melatonin was evaluated in human coronary artery endothelial cells (HCAECs), peripheral blood mononuclear cells from KD patients, human THP1 cell line in vitro, and a Candida albicans water-soluble fraction (CAWS)-induced KD mouse model in vivo. Cell proliferation assay, cell apoptosis assay, cell co-culture, RNA extraction, RNA sequencing, reverse transcription quantitative PCR, enzyme-linked immunosorbent assay (ELISA), transwell assay, western blot, dual-luciferase reporter assay, and autophagic flux assay were performed to investigate the function and regulatory mechanisms of melatonin in vitro, while haematoxylin and eosin staining, Verhoeff's van Gieson staining, ELISA, and immunohistochemical analysis were performed to detect the effect of melatonin in vivo. RESULTS: Melatonin suppressed cell apoptosis directly reduced the expression of endothelial cell damage markers in HCAECs, and alleviated vasculitis in the CAWS-induced KD mouse model. Mechanistically, melatonin promoted autophagy by activating the melatonin/ melatonin receptor (MT)/cAMP-response element binding protein (CREB) pathway and upregulating the expression of autophagy-related gene-3, thereby suppressing cell apoptosis in an autophagy-dependent manner. Additionally, melatonin decreased the production of pro-inflammatory cytokines in macrophages and indirectly reduced the immunopathological damage of HCAECs. CONCLUSIONS: This study revealed that melatonin protects vascular endothelial cells in KD, by suppressing cell apoptosis in an autophagy-dependent manner and reducing the immunopathological damage mediated by macrophages.

The effect of carbon-based copper nanocomposites on Microcystis aeruginosa and the movability of antibiotic resistance genes in urban water.

The presence of Microcystis aeruginosa (M. aeruginosa) can affect the transference of antibiotic resistance genes (ARGs), and the presence of carbon-based copper nanocomposites (CCN) can affect the growth of M. aeruginosa. However, the effect of CCN on M. aeruginosa and ARGs is not fully understood. In this study, metagenomic sequencing was employed to analyze the movability of ARGs, their potential transfer, and possible hosts in photobioreactor treating urban water. The results uggested that 20 mg/L of CCN changed the composition and abundance of microorganisms in urban water, significantly promoted the flocculation of M aeruginosa, and decreased the composing proportion of Cyanophyta sp. and M aeruginosa. The results indicated that 20 mg/L of CCN significantly decreased the absolute abundance and ARGs proportions which mediated by plasmids (32.7 %). Furthermore, the lower co-occurrence probability of ARGs and mobile genetic elements (MGEs) suggested that 20 mg/L of CCN weakened the movability potential of ARGs mediated by MGEs such as plasmids. Among the 452 metagenome-assembled genomes (MAGs), 95 MAGs belonging to 41 bacterial categories were identified as possible ARG hosts. These results will provide insights into the control of harmful cyanobacteria and the management of ARGs in urban water.

Algal-bacterial consortium mediated system offers effective removal of nitrogen nutrients and antibiotic resistance genes.

The sulfonamide antibiotic resistance genes (ARGs) especially sul1 was identified as the dominant in eutrophic water. The performance of Chlorella vulgaris-B. licheniformis consortium toward sul1 removal, total nitrogen (TN) removal, and the mechanism of sul1 removal was investigated. The removal efficiency of exogenous ARGs plasmids carrying sul1 reached (97.2 ± 2.3)%. The TN removal rate reached (98.5 ± 1.2)%. The enhancements of carbon metabolism, nitrogen metabolism, aminoacyl-tRNA biosynthesis, and glycoproteins had significant influences on sul1 and TN removals, under the premise of normal growth of algae and bacteria. The quantitative polymerase chain reaction (qPCR) results suggested that the absolute abundances of sul1 were low in algal-bacterial systems (0 gene copies/mL) compared with individual systems ((1 × 106 ± 15) gene copies/mL). The duplication of sul1 was inhibited in algal cells and bacterial cells. The algal-bacterial consortium seems to be a promising technology for wastewater treatment with a potential to overcome the eutrophication and ARGs challenges.

Exosomal miR-101-3p and miR-423-5p inhibit medulloblastoma tumorigenesis through targeting FOXP4 and EZH2.

Exosomal microRNAs (miRNAs) have been implicated in the development and progression of a variety of tumors; however, whether they contribute to medulloblastoma (MB) tumorigenesis remains to be elucidated. To address this, we first characterized the miRNA profiles of circulating exosomes by miRNA sequencing to identify miRNAs differentially expressed between children with MB and healthy controls. Then, we conducted in vitro and in vivo functional assays with the identified miRNAs and their predicted targets. We found that, compared with healthy controls, 35 miRNAs were upregulated and 5 downregulated in exosomes isolated from the plasma of MB patients. We further found that the expression of miR-101-3p and miR-423-5p was significantly higher in plasma exosomes from MB patients than in healthy controls in an expanded cohort and these exosomal miRNAs could be delivered to tumor cells via exosomes. An in vitro functional analysis of miR-101-3p and miR-423-5p showed that treating MB cells with the corresponding mimics significantly inhibited the proliferation, colony-forming ability, migratory ability, and invasive capacity of tumor cells, and promoted cell apoptosis. Additionally, miR-101-3p and miR-423-5p were found to act as tumor suppressors by directly targeting a common gene, FOXP4, which encodes a transcription factor with a vital role in embryonic development and tumorigenesis. Moreover, miR-101-3p also targeted EZH2, a histone methyltransferase, to reinforce its tumor inhibitory effects. Using a xenograft nude mouse model of MB, we further identified that the overexpression of miR-101-3p and miR-423-5p inhibited tumorigenesis in vivo. Our findings provide novel insights into the functions of exosomal miRNAs in mediating MB progression and suggest a potential therapeutic approach for the treatment of children with MB.

Exosomal miR-130b-3p targets SIK1 to inhibit medulloblastoma tumorigenesis.

Exosomes are an important carrier for cell communication. miRNAs in exosomes are potential biomarkers and therapeutic targets in different types of cancer. However, the role of exosomal miRNAs in medulloblastoma (MB) patients is largely unknown. In this study, we reported that there was a higher level of miR-130b-3p in exosomes derived from MB patient plasma compared with exosomes from healthy control plasma. Exosomes from MB patient plasma could transfer miR-130b-3p to an MB cell line and played suppressor roles for cell proliferation. miR-130b-3p suppressed MB tumorigenesis by targeting a previously unknown target, serine/threonine-protein kinase 1 (SIK1), through the p53 signaling pathways. In addition, we found an unreported role of SIK1 in promoting MB tumor growth and an SIK1 inhibitor could inhibit MB cell proliferation. This research provides new insight into the molecular mechanism of MB and may provide a new therapeutic strategy for MB treatment.

Hsa_circ_0060450 Negatively Regulates Type I Interferon-Induced Inflammation by Serving as miR-199a-5p Sponge in Type 1 Diabetes Mellitus.

Circular RNAs (circRNAs) constitute a class of covalently circular non-coding RNA molecules formed by 5' and 3' end back-splicing. The rapid development of bioinformatics and large-scale sequencing has led to the identification of functional circRNAs. Despite an overall upward trend, studies focusing on the roles of circRNAs in immune diseases remain relatively scarce. In the present study, we obtained a differential circRNA expression profile based on microarray analysis of peripheral blood mononuclear cells (PBMCs) in children with type 1 diabetes mellitus (T1DM). We characterized one differentially expressed circRNA back-spliced from the MYB Proto-Oncogene Like 2 (MYBL2) gene in patients with T1DM, termed as hsa_circ_0060450. Subsequent assays revealed that hsa_circ_0060450 can serve as the sponge of miR-199a-5p, release its target gene, Src homology 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2), encoded by the tyrosine-protein phosphatase non-receptor type 11 gene (PTPN11), and further suppress the JAK-STAT signaling pathway triggered by type I interferon (IFN-I) to inhibit macrophage-mediated inflammation, which indicates the important roles of circRNAs in T1DM and represents a promising therapeutic molecule in the treatment of T1DM.

Circular RNA circPPM1F modulates M1 macrophage activation and pancreatic islet inflammation in type 1 diabetes mellitus.

Rationale: Macrophages play critical roles in the pathogenesis of type 1 diabetes mellitus (T1DM). Circular RNAs (circRNAs) are a novel class of endogenous RNAs with covalently closed loop structures, implicated in various disease processes. However, their impact on macrophage activation and T1DM pathogenesis remains elusive. Methods: circRNA expression profiles of peripheral blood mononuclear cells (PBMCs) from T1DM children were determined by whole transcriptome microarray. Bioinformatics, quantitative real-time PCR, Western blot, RNA immunoprecipitation (RIP), cell co-culture, cell proliferation, and cell apoptosis assays were performed to investigate the expression, function, and regulatory mechanisms of circPPM1F in vitro. The regulatory role of circPPM1F in vivo was evaluated in the streptozocin-induced diabetic mouse model. Results: We identified 27 upregulated and 31 downregulated differentially expressed circRNAs in T1DM patients. circPPM1F, a circRNA with unknown function, was dominantly expressed in monocytes and significantly upregulated in T1DM patients. Functionally, circPPM1F promoted lipopolysaccharide (LPS)-induced M1 macrophage activation via enhancement of the NF-κB signaling pathway. Mechanistically, circPPM1F competitively interacted with HuR to impair the translation of protein phosphatase, Mg2+/Mn2+ dependent 1F (PPM1F), thus alleviating the inhibitory effect of PPM1F on the NF-κB pathway. Moreover, eukaryotic initiation factor 4A-III (EIF4A3) and fused in sarcoma (FUS) coordinately regulated circPPM1F expression during M1 macrophage activation. In addition, circPPM1F could exacerbate pancreas injury in the streptozocin-induced diabetic mice by activation of M1 macrophages in vivo. Conclusions:circPPM1F is a novel positive regulator of M1 macrophage activation through the circPPM1F-HuR-PPM1F-NF-κB axis. Overexpression of circPPM1F could promote pancreatic islet injury by enhancing M1 macrophage activation and circPPM1F may serve as a novel potential therapeutic target for T1DM in children.

LncRNA PTPRE-AS1 modulates M2 macrophage activation and inflammatory diseases by epigenetic promotion of PTPRE.

Long noncoding RNAs (lncRNAs) are important regulators of diverse biological processes; however, their function in macrophage activation is undefined. We describe a new regulatory mechanism, where an unreported lncRNA, PTPRE-AS1, targets receptor-type tyrosine protein phosphatase ε (PTPRE) to regulate macrophage activation. PTPRE-AS1 was selectively expressed in IL-4-stimulated macrophages, and its knockdown promoted M2 macrophage activation via MAPK/ERK 1/2 pathway. In vivo, PTPRE-AS1 deficiency enhanced IL-4-mediated M2 macrophage activation and accelerated pulmonary allergic inflammation while reducing chemical-induced colitis. Mechanistically, PTPRE-AS1 bound WDR5 directly, modulating H3K4me3 of the PTPRE promoter to regulate PTPRE-dependent signaling during M2 macrophage activation. Further, the expression of PTPRE-AS1 and PTPRE was significantly lower in peripheral blood mononuclear cells from patients with allergic asthma. These results provide evidence supporting the importance of PTPRE-AS1 in controlling macrophage function and the potential utility of PTPRE-AS1 as a target for controlling inflammatory diseases.

Rapid Generation of Barley Mutant Lines With High Nitrogen Uptake Efficiency by Microspore Mutagenesis and Field Screening.

In vitro mutagenesis via isolated microspore culture provides an efficient way to produce numerous double haploid (DH) lines with mutation introduction and homozygosity stabilization, which can be used for screening directly. In this study, 356 DH lines were produced from the malt barley (Hordeum vulgare L.) cultivar Hua-30 via microspore mutagenic treatment with ethyl methane sulfonate or pingyangmycin during in vitro culture. The lines were subjected to field screening under high nitrogen (HN) and low nitrogen (LN) conditions, and the number of productive tillers was used as the main screening index. Five mutant lines (A1-28, A1-84, A1-226, A16-11, and A9-29) with high numbers of productive tillers were obtained over three consecutive years of screening. In the fifth year, components related to N-use efficiency (NUE), including N accumulation, utilization, and translocation, were characterized for these lines based on N uptake efficiency (NUpE), N utilization efficiency (NUtE), and N translocation efficiency (NTE). The results show that the NUpE of four mutant lines (A1-84, A1-226, A9-29, and A16-11) improved significantly under HN, whereas that of two lines (A1-84 and A9-29) improved under LN. As a result, their NUE improved greatly. No improvement in NUtE was observed in any of the five mutant lines. A1-84 and A9-29 were selected as an enhanced genotype in N uptake, and A1-28 showed improved NTE at the grain-filling stage. Our results imply that high-NUpE mutants can be produced through microspore mutagenesis and field screening, and that improvement of NUE in barley depends on enhancement of N uptake.