The Immunobiology and Treatment of Food Allergy.

IgE-mediated food allergy (IgE-FA) occurs due to a breakdown in immune tolerance that leads to a detrimental type 2 helper T cell (TH2) adaptive immune response. While the processes governing this loss of tolerance are incompletely understood, several host-related and environmental factors impacting the risk of IgE-FA development have been identified. Mounting evidence supports the role of an impaired epithelial barrier in the development of IgE-FA, with exposure of allergens through damaged skin and gut epithelium leading to the aberrant production of alarmins and activation of TH2-type allergic inflammation. The treatment of IgE-FA has historically been avoidance with acute management of allergic reactions, but advances in allergen-specific immunotherapy and the development of biologics and other novel therapeutics are rapidly changing the landscape of food allergy treatment. Here, we discuss the pathogenesis and immunobiology of IgE-FA in addition to its diagnosis, prognosis, and treatment.

The Mevalonate Pathway Is a Druggable Target for Vaccine Adjuvant Discovery.

Motivated by the clinical observation that interruption of the mevalonate pathway stimulates immune responses, we hypothesized that this pathway may function as a druggable target for vaccine adjuvant discovery. We found that lipophilic statin drugs and rationally designed bisphosphonates that target three distinct enzymes in the mevalonate pathway have potent adjuvant activities in mice and cynomolgus monkeys. These inhibitors function independently of conventional "danger sensing." Instead, they inhibit the geranylgeranylation of small GTPases, including Rab5 in antigen-presenting cells, resulting in arrested endosomal maturation, prolonged antigen retention, enhanced antigen presentation, and T cell activation. Additionally, inhibiting the mevalonate pathway enhances antigen-specific anti-tumor immunity, inducing both Th1 and cytolytic T cell responses. As demonstrated in multiple mouse cancer models, the mevalonate pathway inhibitors are robust for cancer vaccinations and synergize with anti-PD-1 antibodies. Our research thus defines the mevalonate pathway as a druggable target for vaccine adjuvants and cancer immunotherapies.

A Structural Change in Butyrophilin upon Phosphoantigen Binding Underlies Phosphoantigen-Mediated Vγ9Vδ2 T Cell Activation.

Human Vγ9Vδ2 T cells respond to microbial infections and malignancy by sensing diphosphate-containing metabolites called phosphoantigens, which bind to the intracellular domain of butyrophilin 3A1, triggering extracellular interactions with the Vγ9Vδ2 T cell receptor (TCR). Here, we examined the molecular basis of this "inside-out" triggering mechanism. Crystal structures of intracellular butyrophilin 3A proteins alone or in complex with the potent microbial phosphoantigen HMBPP or a synthetic analog revealed key features of phosphoantigens and butyrophilins required for γδ T cell activation. Analyses with chemical probes and molecular dynamic simulations demonstrated that dimerized intracellular proteins cooperate in sensing HMBPP to enhance the efficiency of γδ T cell activation. HMBPP binding to butyrophilin doubled the binding force between a γδ T cell and a target cell during "outside" signaling, as measured by single-cell force microscopy. Our findings provide insight into the "inside-out" triggering of Vγ9Vδ2 T cell activation by phosphoantigen-bound butyrophilin, facilitating immunotherapeutic drug design.

The Phospho-Code Determining Circadian Feedback Loop Closure and Output in Neurospora.

In the negative feedback loop driving fungal and animal circadian oscillators, negative elements (FREQUENCY [FRQ], PERIODS [PERs], and CRYPTOCHROMES [CRYs]) are understood to inhibit their own expression, in part by promoting the phosphorylation of their heterodimeric transcriptional activators (e.g., White Collar-1 [WC-1]-WC-2 [White Collar complex; WCC] and BMAL1/Circadian Locomotor Output Cycles Kaput [CLOCK]). However, correlations between heterodimer activity and phosphorylation are weak, contradictions exist, and mechanistic details are almost wholly lacking. We report mapping of 80 phosphosites on WC-1 and 15 on WC-2 and elucidation of the time-of-day-specific code, requiring both a group of phosphoevents on WC-1 and two distinct clusters on WC-2, that governs circadian repression, leading to feedback loop closure. Combinatorial control via phosphorylation also governs rhythmic WCC binding to the promoters of clock-controlled genes mediating the essential first step in circadian output, a group encoding both transcription factors and signaling proteins. These data provide a basic mechanistic understanding for fundamental events underlying circadian negative feedback and output, key aspects of circadian biology.

Acetylation of WCC is dispensable for the core circadian clock but differentially regulates acute light responses in Neurospora.

In the Neurospora circadian system, the White Collar Complex (WCC) formed by WC-1 and WC-2 drives expression of the frequency (frq) gene whose product FRQ feedbacks to inhibit transcriptional activity of WCC. Phosphorylation of WCC has been extensively studied, but the extent and significance of other post-translational modifications (PTM) have been poorly studied. To this end, we used mass-spectrometry to study alkylation sites on WCC, resulting in discovery of nine acetylation sites. Mutagenesis analysis showed most of the acetylation events individually do not play important roles in period determination. Moreover, mutating all the lysines falling in either half of WC-1 or all the lysine residues in WC-2 to arginines did not abolish circadian rhythms. In addition, we also found nine mono-methylation sites on WC-1, but like acetylation, individual ablation of most of the mono-methylation events did not result in a significant period change. Taken together, the data here suggest that acetylation or mono-methylation on WCC is not a determinant of the pace of the circadian feedback loop. The finding is consistent with a model in which repression of WCC's circadian activity is mainly controlled by phosphorylation. Interestingly, light-induced expression of some light-responsive genes has been modulated in certain wc-1 acetylation mutants, suggesting that WC-1 acetylation events differentially regulate light responses.

Alteration of gut microbiota in post-stroke depression patients with Helicobacter pylori infection.

BACKGROUND: Several studies have identified an association between the gut microbiome and post-stroke depression(PSD), and Helicobacter pylori(H. pylori) infection cause significant alterations in the composition of the gastrointestinal microbiome. However, evidence regarding the role of the H. pylori infection in promoting PSD is still lacking. Here, we conducted a retrospective study to explore risk factors associated with PSD. METHODS: Patients with cerebral infarction were consecutively enrolled from December 2021 to October 2022. The diagnosis of PSD is based on the DSM-V criteria, and the Hamilton Depression Rating Scale(HAMD) was used to identify patients with PSD. White matter lesions were evaluated using magnetic resonance imaging(MRI) and H. pylori infection was detected by 13C-urea breath test. Further, 16S rRNA gene sequencing was used to evaluate the changes in gut microbiota composition of fecal samples from PSD patients. The concentration of short-chain fatty acids(SCFAs) was determined by gas chromatography-mass spectrometry(GC-MS). RESULTS: Multivariate regression analysis showed that deep white matter lesions(DWMLs) [odds ratio(OR) 3.382, 95% confidence interval(CI) 1.756-6.512; P = 0.001] and H. pylori infection(OR 2.186, 95% CI 1.149-4.159; P = 0.017) were the independent risk factors for PSD. Patients with H. pylori infection had more severe depressive symptoms than patients without infection. Intestinal microbiota was significantly different between H. pylori-positive PSD[H. pylori(+)] patients and H. pylori-negative PSD[H. pylori (-)] patients. Fecal SCFAs concentrations were significantly reduced in the H. pylori(+) group compared to the negative ones. CONCLUSION: DWMLs and H. pylori infection may play important roles in the development of PSD. H. pylori infection is likely to be involved in the pathogenesis of PSD by altering the intestinal flora.

Homoeologous exchanges contribute to branch angle variations in rapeseed: Insights from transcriptome, QTL-seq and gene functional analysis.

Branch angle (BA) is a critical morphological trait that significantly influences planting density, light interception and ultimately yield in plants. Despite its importance, the regulatory mechanism governing BA in rapeseed remains poorly understood. In this study, we generated 109 transcriptome data sets for 37 rapeseed accessions with divergent BA phenotypes. Relative to adaxial branch segments, abaxial segments accumulated higher levels of auxin and exhibited lower expression of six TCP1 homologues and one GA20ox3. A co-expression network analysis identified two modules highly correlated with BA. The modules contained homologues to known BA control genes, such as FUL, YUCCA6, TCP1 and SGR3. Notably, a homoeologous exchange (HE), occurring at the telomeres of A09, was prevalent in large BA accessions, while an A02-C02 HE was common in small BA accessions. In their corresponding regions, these HEs explained the formation of hub gene hotspots in the two modules. QTL-seq analysis confirmed that the presence of a large A07-C06 HE (~8.1 Mb) was also associated with a small BA phenotype, and BnaA07.WRKY40.b within it was predicted as candidate gene. Overexpressing BnaA07.WRKY40.b in rapeseed increased BA by up to 20°, while RNAi- and CRISPR-mediated mutants (BnaA07.WRKY40.b and BnaC06.WRKY40.b) exhibited decreased BA by up to 11.4°. BnaA07.WRKY40.b was exclusively localized to the nucleus and exhibited strong expression correlations with many genes related to gravitropism and plant architecture. Taken together, our study highlights the influence of HEs on rapeseed plant architecture and confirms the role of WRKY40 homologues as novel regulators of BA.

Glutathione regulates CIA-activated splenic-lymphocytes via NF-κB/MMP-9 and MAPK/PCNA pathways manipulating immune response.

Reduced glutathione (GSH) is an antioxidant involved in redox homeostasis, and recently regarded as an inducer of Reductive stress. Its immune-regulatory effects on lymphocytes have not been extensively studied. This study is based on the finding that much increased GSH level in collagen-induced arthritis (CIA) rat spleen, and aimed to investigate the effects of GSH (0, 1, 10, 100 mM) on normal and immune-stimulated spleen lymphocytes respectively. The elevated GSH level is associated with the increased levels of inflammatory factors; especially the increased DPP1 activity indicated immune-granulocytes activation in CIA rat spleen. Exogenous GSH had different influences on normal and CIA lymphocytes, affecting intracellular levels of GSH, Glutathione-S-transferases (GSTs) and Reactive oxygen species (ROS); as well as the expressions of NF-κB, MMP-9, Bcl-2, GST, P38, PCNA and TLR4. The increased extracellular GSH level disturbed redox homeostasis and induces reductive stress to spleen lymphocytes, which decreased intracellular GSH concentration and influenced the MAPK/PCNA and NF-κB/MMP-9 signaling pathways, as well as cell cycles respectively, leading to cell senescence/ferroptosis/apoptosis. This study also revealed the multiple faces of GSH in regulating spleen lymphocytes, which depended on its levels in tissue or in cells, and the activation status of lymphocytes. These findings indicate the immune-regulatory role of GSH on spleen-lymphocytes, and the high level GSH in CIA rat spleens may contribute to CIA development.

Characteristics of the oral and gastric microbiome in patients with early-stage intramucosal esophageal squamous cell carcinoma.

BACKGROUND: Oral microbiome dysbacteriosis has been reported to be associated with the pathogenesis of advanced esophageal cancer. However, few studies investigated the potential role of oral and gastric microbiota in early-stage intramucosal esophageal squamous carcinoma (EIESC). METHOD: A total of 104 samples were collected from 31 patients with EIESC and 21 healthy controls. The compositions of oral and gastric microbiota were analyzed using 16 S rRNA V3-V4 amplicon sequencing. Linear discriminant analysis effect size (LEfSe) analysis was performed to assess taxonomic differences between groups. The correlation between oral microbiota and clinicopathological factors was evaluated using Spearman correlation analysis. Additionally, co-occurrence networks were established and random forest models were utilized to identify significant microbial biomarkers for distinguishing between the EIESC and control groups. RESULTS: A total of 292 oral genera and 223 species were identified in both EIESC and healthy controls. Six oral genera were remarkably enriched in EIESC groups, including the genera Porphyromonas, Shigella, Subdoligranulum, Leptotrichia, Paludibacter, and Odoribacter. LEfSe analysis identified genera Porphyromonas and Leptotrichia with LDA scores > 3. In the random forest model, Porphyromonas endodontalis ranked the top microbial biomarker to differentiate EIESC from controls. The elimination rate of Porphyromonas endodontalis from the oral cavity to the stomach was also dramatically decreased in the EIESC group than controls. In the microbial co-occurrence network, Porphyromonas endodontalis was positively correlated with Prevotella tannerae and Prevotella intermedia and was negatively correlated with Veillonella dispar. CONCLUSION: Our study potentially indicates that the dysbacteriosis of both the oral and gastric microbiome was associated with EIESC. Larger scale studies and experimental animal models are urgently needed to confirm the possible role of microbial dysbacteriosis in the pathogenesis of EIESC. (Chinese Clinical Trial Registry Center, ChiCTR2200063464, Registered 07 September 2022, https://www.chictr.org.cn/showproj.html?proj=178563).

Gate tunable linear dichroism in monolayer 1T'-MoS2.

The linear dichroism demonstrates promising applications in the fields of polarization-resolved photodetectors and polarization optical imaging. Herein, we study the optical properties of monolayer 1T'-MoS2 based on a four-band effective k · p Hamiltonian within the framework of linear response theory. Owing to the anisotropic band structure, the k-resolved optical transition matrix elements associated with armchair(x) and zigzag(y) direction polarized light exhibit a staggered pattern. The anisotropy of the optical absorption spectrum is shown to sensitively depend on the photon energy, the light polarization and the gate voltage. A gate voltage can continuously modulate the anisotropy of the optical absorption spectra, rendering it isotropic or even reversing the initial anisotropy. This modulation leads to linear dichroism conversions across multiple wavelengths. Our findings are useful to design polarized photodetectors and sensors based on monolayer 1T'-MoS2. Our results are also applicable to other monolayer transition metal dichalcogenides with 1T' structure.

HLA-DR+ regulatory T cells and IL-10 are associated with success or failure of desensitization outcomes.

BACKGROUND: Omalizumab (XOLAIR®)-assisted multi-food oral immunotherapy (mOIT) has been shown to safely, effectively, and rapidly desensitize patients with multiple food allergies. In our clinical trial (NCT02626611) on omalizumab-assisted mOIT, different desensitization outcomes (success or failure of desensitization) were observed following a period of either continued or discontinued mOIT. However, the association between the immunological changes induced by omalizumab-assisted mOIT and desensitization outcomes has not yet been fully elucidated. In this study, due to the key roles of regulatory T (Treg) cells and the type 2 helper T cell (Th2) pathway in immune tolerance to food allergens, we aimed to characterize their association with the desensitization outcomes of omalizumab-assisted mOIT. METHODS: Mass cytometry and multiplex cytokine assays were performed on blood samples obtained from participants with allergies to peanut, cashew, or milk in our phase 2 clinical study (NCT02626611). Comprehensive statistical and bioinformatic analyses were conducted on high-dimensional cytometry-based single-cell data and high-throughput multiplex cytokine data. RESULTS: Our results demonstrated that the frequency of HLA-DR+ Treg cells, and the production of Th2 cytokines (IL-4, IL-5, IL-13, and IL-9) as well as the immunoregulatory cytokine IL-10 by peripheral blood mononuclear cells (PBMCs) was significantly increased in cultures with allergen compared to cultures with media alone at baseline (Week 0). We also observed increased frequency of allergen responsive HLA-DR+ Treg cells and enhanced production of IL-10 by PBMCs in participants who achieved successful desensitization compared to those with failure of desensitization. However, the production of Th2 cytokines by PBMCs did not show significant differences between participants with different desensitization outcomes (success vs. failure of desensitization), despite omalizumab-assisted mOIT inducing a significant reduction in the production of Th2 cytokines. CONCLUSIONS: We demonstrated that the frequency of HLA-DR+ Treg cells and IL-10 cytokine production by PBMCs are associated with desensitization outcomes of omalizumab-assisted mOIT. These findings suggest potential immunological parameters that could be targeted to enhance desensitization success rates.

Investigating Xiaochaihu Decoction's fever-relieving mechanism via network pharmacology, molecular docking, dynamics simulation, and experiments.

Xiaochaihu Decoction（XCHD）is a classic prescription for the treatment of fever, but the mechanism is not clear. In this study, We elucidated the mechanism of action through network pharmacology and molecular docking. A rat fever model was established to verify the prediction results of network pharmacology. The analysis revealed that 120 intersection targets existed between XCHD and fever. The TP53, STAT3, RELA, MAPK1, AKT1, TNF and MAPK14 as potential core targets of XCHD in fever treatment. GO and KEGG pathway enrichment analyses indicated that XCHD may act through pathways such as the AGE-RAGE signaling pathway in diabetic complications, TNF signaling pathway, IL-17 signaling pathway. Molecular docking results demonstrated that quercetin, kaempferol, ß-sitosterol, stigmasterol and baicalein exhibited strong binding activity to key targets. Animal experiments showed that XCHD significantly reduced body temperature and levels of IL-1ß, IL-6, TNF-α, NO, PGE2, and cAMP in rats with fever. Importantly, no significant difference was observed between the XCHD self-emulsifying nano phase plus suspension phase and XCHD group. XCHD exerts its therapeutic effects on fever through a multi-ingredient, multi-target, and multi-pathway approach.

Effect of air pollution on asthma.

Asthma is a chronic inflammatory airway disease characterized by respiratory symptoms, variable airflow obstruction, bronchial hyperresponsiveness, and airway inflammation. Exposure to air pollution has been linked to an increased risk of asthma development and exacerbation. This review aims to comprehensively summarize recent data on the impact of air pollution on asthma development and exacerbation. Specifically, we reviewed the effects of air pollution on the pathogenic pathways of asthma, including type 2 and non-type 2 inflammatory responses, and airway epithelial barrier dysfunction. Air pollution promotes the release of epithelial cytokines, driving TH2 responses, and induces oxidative stress and the production of proinflammatory cytokines. The enhanced type 2 inflammation, furthered by air pollution-induced dysfunction of the airway epithelial barrier, may be associated with the exacerbation of asthma. Disruption of the TH17/regulatory T cell balance by air pollutants is also related to asthma exacerbation. As the effects of air pollution exposure may accumulate over time, with potentially stronger impacts in the development of asthma during certain sensitive life periods, we also reviewed the effects of air pollution on asthma across the lifespan. Future research is needed to better characterize the sensitive period contributing to the development of air pollution-induced asthma and to map air pollution-associated epigenetic biomarkers contributing to the epigenetic ages onto asthma-related genes.

Association of vitamin D with risk of warts: A retrospective and Mendelian randomization study.

BACKGROUND: The clinical strategy of oral supplementation of Vitamin D (VD) as a preventive and therapeutic measure for warts needs further exploration. METHODS: The clinical data of patients with skin diseases who visited the Children's Hospital affiliated with Chongqing Medical University from February 2018 to June 2024 were collected. The serum VD levels in patients with warts (common warts, flat warts, and plantar warts) and patients with other common skin diseases (atopic dermatitis, psoriasis, alopecia areata, vitiligo, and chronic urticaria) were compared. Two-sample bidirectional Mendelian randomization (MR) analysis was performed to investigate potential causal associations between VD and warts. RESULTS: The average serum VD level of children with warts was 23.27 ± 7.07 ng/mL, which showed no statistically significant difference compared to children with other common skin diseases. The inverse variance weighted (IVW) method analysis indicated a positive causal relationship between VD and warts (Odds Ratio [OR] = 1.86, [95% CI: 1.19-2.92], p = 0.007). Sensitivity analysis did not show any indication of horizontal pleiotropy or heterogeneity. The MR-PRESSO method did not identify any outliers. CONCLUSION: The levels of serum VD in children with warts do not significantly decrease compared to children with other common skin conditions. The evidence from the MR analysis indicates a positive causal relationship between VD and warts, suggesting caution in supplementing VD for children with warts who have normal or elevated serum VD levels. Further clinical studies are needed for validation in the future.

Unexplained colonic necrosis in a patient with end-stage kidney disease on chronic hemodialysis: case report and review of uremic colitis.

BACKGROUND: Intestinal necrosis in uremic patients has been reported but is rare. CASE PRESENTATION: A 56-year-old male patient who underwent long-term regular haemodialysis was admitted to the hospital due to involuntary shaking of the limbs and nonsense speech. The patient's symptoms improved after continuous blood purification under heparin anticoagulation, rehydration, sedation, and correction of electrolyte disturbances. However, the patient experienced a sudden onset of abdominal pain and a rapid decrease in blood pressure; high-dose norepinephrine were required to maintain his blood pressure. A plain abdominal radiograph performed at bedside showed intestinal dilation. Colonoscopy revealed inflammation and oedema of the entire colon, with purulent secretions and multiple areas of patchy necrosis. The cause of intestinal ischaemia was not clear. CONCLUSIONS: Although rare, previous causes of uremic colitis have been reported. As the patient developed abdominal pain before the onset of shock and the necrosis was seen on colonoscopy, we suspect that this is a case of fulminant uremic colitis.

Alternation of the gut microbiota in irritable bowel syndrome: an integrated analysis based on multicenter amplicon sequencing data.

BACKGROUND: Gut dysbacteriosis has been reported as one of the etiologies for irritable bowel syndrome (IBS). However, the association between gut microbiota and IBS is still inconclusive. METHOD: A paired-sample study was designed by retrieving original multicenter 16 s-rRNA data of IBS patients and healthy controls from the GMrepo database. The propensity score matching (PSM) algorithm was applied to reduce confounding bias. The differential analysis of microbiota composition was performed at different taxonomic levels. The co-occurrence network was established. Subgroup analysis was performed to identify specific microbial compositions in different IBS subtypes. RESULTS: A total of 1522 amplicon samples were initially enrolled. After PSM, 708 individuals (354 IBS and 354 healthy controls) were eligible for further analysis. A total of 1,160 genera were identified. We identified significantly changed taxa in IBS groups (IBS-enriched: the families Enterobacteriaceae, Moraxellaceae and Sphingobacteriaceae; the genera Streptococcus, Bacillus, Enterocloster, Sphingobacterium, Holdemania and Acinetobacter. IBS-depleted: the phyla Firmicutes, Euryarchaeota, Cyanobacteria, Acidobacteria and Lentisphaerae; the families Bifidobacteriaceae, Ruminococcaceae, Methanobacteriaceae and the other 25 families; the genera Faecalibacterium, Bifidobacterium and other 68 genera). The co-occurrence network identified three hub genera and six hub species (including Faecalibacterium prausnitzii) that may be involved in IBS pathophysiology. Strong positive interactions were identified among the Bifidobacterium longum, Bifidobacterium breve and Bifidobacterium adolescentis in the Bifidobacterium community. CONCLUSION: This study provides quantitative analysis and visualization of the interaction between the gut microbiota and IBS. The identification of key species should be further validated to evaluate their causal relationships with the pathogenesis of IBS.

The causal role of gut microbiota in susceptibility and severity of COVID-19: A bidirectional Mendelian randomization study.

Growing evidence has shown that altered gut microbiota is associated with the pathogenesis of COVID-19, but their causal effects are still unclear. We conducted a bidirectional Mendelian randomization (MR) study to assess the causal effects of gut microbiota on COVID-19 susceptibility or severity, and vice versa. The microbiome genome-wide association studies (GWAS) data of 18 340 individuals and GWAS statistics from the COVID-19 host genetics initiative (38 984 European patients and 1 644 784 controls) were used as exposure and outcomes. The inverse variance weighted (IVW) was used as the primary MR analysis. Sensitivity analyses were performed to validate the robustness, pleiotropy, and heterogeneity of results. In the forward MR, we identified several microbial genera with causal effects on COVID-19 susceptibility (p < 0.05 and FDR < 0.1): Alloprevotella (odds ratio [OR]: 1.088, 95% confidence interval [CI]: 1.021-1.160), Coprococcus (OR: 1.159, 95% CI: 1.030-1.304), Parasutterella (OR: 0.902, 95% CI: 0.836-0.973), and Ruminococcaceae UCG014 (OR: 0.878, 95% CI: 0.777-0.992). The Reverse MR identified that exposure to COVID-19 had causal effects on the depletion of the families Lactobacillaceae (Beta [SE]: -0.220 [0.101]) and Lachnospiraceae (-0.129 [0.062]), the genera Flavonifractor (-0.180 [0.081]) and Lachnoclostridium [-0.181 [0.063]). Our findings supported the causal effect of gut microbiota on the pathogenesis of COVID-19, and infection of COVID-19 might further causally induce gut microbiota dysbiosis.

Proinflammatory polarization of monocytes by particulate air pollutants is mediated by induction of trained immunity in pediatric asthma.

BACKGROUND: The impact of exposure to air pollutants, such as fine particulate matter (PM), on the immune system and its consequences on pediatric asthma, are not well understood. We investigated whether ambient levels of fine PM with aerodynamic diameter ≤2.5 microns (PM2.5 ) are associated with alterations in circulating monocytes in children with or without asthma. METHODS: Monocyte phenotyping was performed by cytometry time-of-flight (CyTOF). Cytokines were measured using cytometric bead array and Luminex assay. ChIP-Seq was utilized to address histone modifications in monocytes. RESULTS: Increased exposure to ambient PM2.5 was linked to specific monocyte subtypes, particularly in children with asthma. Mechanistically, we hypothesized that innate trained immunity is evoked by a primary exposure to fine PM and accounts for an enhanced inflammatory response after secondary stimulation in vitro. We determined that the trained immunity was induced in circulating monocytes by fine particulate pollutants, and it was characterized by the upregulation of proinflammatory mediators, such as TNF, IL-6, and IL-8, upon stimulation with house dust mite or lipopolysaccharide. This phenotype was epigenetically controlled by enhanced H3K27ac marks in circulating monocytes. CONCLUSION: The specific alterations of monocytes after ambient pollution exposure suggest a possible prognostic immune signature for pediatric asthma, and pollution-induced trained immunity may provide a potential therapeutic target for asthmatic children living in areas with increased air pollution.

Adenoma Detection Rate in Average-Risk Population: An Observational Consecutive Retrospective Study.

BACKGROUND: Although colonoscopy is considered the most effective tool for reducing colorectal cancer-related morbidity, the age at which average-risk individuals begin colonoscopic screening is undetermined. This study aimed to compare the adenoma and advanced adenoma detection rates according to age and sex in a large average-risk population in the rural areas of Eastern China. METHODS: This observational, single-center, retrospective study included patients with average colorectal cancer risk and examined the adenoma and advanced adenoma detection rates using age intervals of 5 years. We also compared the size and age of patients with and without advanced adenoma. RESULTS: We included 18 928 patients with a median age of 54 years (range 15-90 years), including 10 143 men and 8785 women. The adenoma and advanced adenoma detection rates were 17.08% and 5.24%, respectively, and increased with age in the whole population. The adenoma detection rates increased from 8.97% (aged 40-44) to 14.98% (aged 45-49) and 6.24% (aged 45-49) to 11.00% (aged 50-54) in men and women (both P < .001), respectively. The advanced adenoma detection rates increased from 2.19% (aged 40-44) to 4.76% (aged 45-49) and 1.89% (aged 45-49) to 3.13% (aged 50-54) in men (P = .002) and women (P = .056), respectively. Patients with advanced adenomas were significantly older than those with non-advanced adenomas (P < .001). The tumors in the advanced adenoma group were significantly larger than those in the non-advanced adenoma group (P < .001). CONCLUSION: The adenoma and advanced adenoma detection rates increased significantly in average-risk population aged 45 years and older, especially in men.

Exosomal PPARγ derived from macrophages suppresses LPS-induced peritonitis by negative regulation of CD14/TLR4 axis.

BACKGROUND: Intercellular communication between macrophages and peritoneal mesothelial cells (PMCs) has been suggested as a key factor regulating peritonitis development. Here, we explored whether PPARγ (peroxisome proliferator-activated receptor gamma) can be packaged into macrophage exosomes to mediate intercellular communication and regulate peritonitis. METHODS: Macrophage exosomes were isolated by ultracentrifugation and identified by nanoparticle tracking analysis and transmission electron microscopy. Proteomic analysis of macrophage-derived exosomes was performed using mass spectrometry. Co-culture models of supernatants or exosomes with PMCs, as well as a mouse peritonitis model induced by lipopolysaccharide (LPS), were employed. RESULTS:  In this study, using stable Raw264.7 cells overexpressing GFP-FLAG-PPARγ (OE-PPARγ), we found that PPARγ inhibited LPS-induced inflammatory responses in Raw264.7 cells and that PPARγ was incorporated into macrophage exosomes during this process. Overexpression of PPARγ mainly regulated the secretion of differentially expressed exosomal proteins involved in the biological processes of protein transport, lipid metabolic process, cell cycle, apoptotic process, DNA damage stimulus, as well as the KEGG pathway of salmonella infection. Using co-culture models and mouse peritonitis model, we showed that exosomes from Raw264.7 cells overexpressing PPARγ inhibited LPS-induced inflammation in co-cultured human PMCs and in mice through downregulating CD14 and TLR4, two key regulators of the salmonella infection pathway. Pretreatment of the PPARγ inhibitor GW9662 abolished the anti-inflammatory effect of exosomes from Raw264.7 OE-PPARγ cells on human PMCs. CONCLUSIONS: These results suggested that overexpression of PPARγ largely altered the proteomic profile of macrophage exosomes and that exosomal PPARγ from macrophages acted as a regulator of intercellular communication to suppress LPS-induced inflammatory responses in vitro and in vivo via negatively regulating the CD14/TLR4 axis.