Outcomes of Chengdu Pediatric Emergency Triage Criteria: A Retrospective Study of 198,628 Pediatric Patient Records.

BACKGROUND The Chengdu pediatric emergency triage criteria were developed at our hospital and consist of 4 triage levels: immediate treatment (level 1), treatment within 10 min (level 2), treatment within 30 min (level 3), and treatment within 240 min (level 4). This study aimed to evaluate outcomes from the levels 1 to 4 of this triage criteria. MATERIAL AND METHODS A self-designed survey form was used to collect pediatric Emergency Department (ED) patients' general data, including age, sex, and chief concern, and clinical data, including triage level, whether the patient had died, and whether the patient was admitted to our hospital. A total of 198,628 patient records that were triaged during January to May 2022 using Chengdu pediatric emergency triage criteria were included in this retrospective study. The numbers of patients triaged to levels 1, 2, 3, and 4 were 128, 1164, 14,560, and 182,776, respectively. RESULTS Statistically significant differences were found in waiting time for treatment, hospital admission rates, admission conversion rates, and case mix index at admission under different triage levels. The higher the triage priority level, the shorter the waiting time for ED treatment, higher the hospital admission and admission conversion rates, and higher case mix index value. CONCLUSIONS The Chengdu pediatric emergency triage criteria developed and applied within our hospital appears to be characterized by good clinical validity. Equipped with this triage criteria, triage nurses are more capable of determining the severity and emergency of the pediatric ED patients' health conditions and effectively triaging the patients.

Prevention and treatment of HPV-related cancer through a mRNA vaccine expressing APC-targeting antigen.

Persistent human papillomavirus (HPV) infection is associated with multiple malignancies. Developing therapeutic vaccines to eliminate HPV-infected and malignant cells holds significant value. In this study, we introduced a lipid nanoparticle encapsulated mRNA vaccine expressing tHA-mE7-mE6. Mutations were introduced into E6 and E7 of HPV to eliminate their tumourigenicity. A truncated influenza haemagglutinin protein (tHA), which binds to the CD209 receptor on the surface of dendritic cells (DCs), was fused with mE7-mE6 in order to allow efficient uptake of antigen by antigen presenting cells. The tHA-mE7-mE6 (mRNA) showed higher therapeutic efficacy than mE7-mE6 (mRNA) in an E6 and E7+ tumour model. The treatment resulted in complete tumour regression and prevented tumour formation. Strong CD8+ T-cell immune response was induced, contributing to preventing and curing of E6 and E7+ tumour. Antigen-specific CD8+ T were found in spleens, peripheral blood and in tumours. In addition, the tumour infiltration of DC and NK cells were increased post therapy. In conclusion, this study described a therapeutic mRNA vaccine inducing strong anti-tumour immunity in peripheral and in tumour microenvironment, holding promising potential to treat HPV-induced cancer and to prevent cancer recurrence.

Boosting sodium-ion battery performance by anion doping in NASICON Na4MnCr(PO4)3 cathode.

Na superionic conductor (NASICON)-structured Na4MnCr(PO4)3 (NMCP) possessing unique three-electron transfer process renders admirable energy density for sodium ion batteries (SIBs). However, the current issues like its sluggish Na+ diffusion kinetics, deficient intrinsic conductivity, and unsatisfactory structural stability, hinder its practical application. Herein, a selective replacement of O elements in PO4 group by Cl anions in the NMCP system was developed to significantly enhance its electrochemical performance. The results affirm that the enhanced performance of Cl doped samples can be attributed to the enlargement of cell size, the creation of Na vacancies and the weakness of Na2O bond after Cl doping. The as-prepared Na3.85□0.15MnCr(PO3.95Cl0.05)3/C (NMCPC - 15/C) cathode delivers a high capacity (128.0 mAh/g at 50 mA g-1) and excellent rate performance (73.0 mAh/g at 1000 mA g-1) in contrast to NMCP/C that merely provides 105.2 mAh/g at 50 mA g-1 and reduces to 47.4 mAh/g at 1000 mA g-1. Meanwhile, NMCPC - 15/C shows a capacity retention of 60.7 % at 1000 mA g-1 after 500 cycles, while only 37.1 % for NMCP/C in the same test conditions. Moreover, the satisfactory performance and energy density of NMCPC - 15/C||hard carbon (HC) full cell confirm the potential practicality of NMCPC - 15. Therefore, chloride ions doping into NMCP has practical application prospects in the preparation of high-performance cathode materials and our work also offers new inspiration to apply anion doping strategies in promoting the performance of the other NASICON-structured cathodes for SIBs.

Hepatic Transcriptome and Its Regulation Following Soluble Epoxide Hydrolase Inhibition in Alcohol-Associated Liver Disease.

Alcohol-associated liver disease (ALD) is a serious public health problem with limited pharmacologic options. The goal of the current study was to investigate the efficacy of pharmacologic inhibition of soluble epoxide hydrolase (sEH), an enzyme involved in lipid metabolism, in experimental ALD, and to examine the underlying mechanisms. C57BL/6J male mice were subjected to acute-on-chronic ethanol (EtOH) feeding with or without the sEH inhibitor 4-[[trans-4-[[[[4-trifluoromethoxy phenyl]amino]carbonyl]-amino]cyclohexyl]oxy]-benzoic acid (TUCB). Liver injury was assessed by multiple end points. Liver epoxy fatty acids and dihydroxy fatty acids were measured by targeted metabolomics. Whole-liver RNA sequencing was performed, and free modified RNA bases were measured by mass spectrometry. EtOH-induced liver injury was ameliorated by TUCB treatment as evidenced by reduced plasma alanine aminotransferase levels and was associated with attenuated alcohol-induced endoplasmic reticulum stress, reduced neutrophil infiltration, and increased numbers of hepatic M2 macrophages. TUCB altered liver epoxy and dihydroxy fatty acids and led to a unique hepatic transcriptional profile characterized by decreased expression of genes involved in apoptosis, inflammation, fibrosis, and carcinogenesis. Several modified RNA bases were robustly changed by TUCB, including N6-methyladenosine and 2-methylthio-N6-threonylcarbamoyladenosine. These findings show the beneficial effects of sEH inhibition by TUCB in experimental EtOH-induced liver injury, warranting further mechanistic studies to explore the underlying mechanisms, and highlighting the translational potential of sEH as a drug target for this disease.

A Review of the Roles and Implementation of Pediatric Emergency Triage Systems in China and Other Countries.

A growing number of pediatric Emergency Department (ED) patients has become increasingly common in recent years, but only a small number of them are in true emergencies. It is particularly important to use pediatric triage systems to quickly assess the patients' conditions and determine the patients' priority in emergency treatment, ensuring timely treatment to critically ill patients and efficient utilization of medical resources. The Canadian Triage and Acuity Scale Paediatric Guidelines (PaedCTAS), Australasian Triage Scale (ATS), Emergency Severity Index (ESI), and Manchester Triage System (MTS) are internationally recognized pediatric triage systems. Some countries, such as China, Thailand, Singapore, Norway, South Africa, and South Korea, have created their own pediatric emergency triage systems in line with the situation of their respective countries. Pediatric Assessment Triangle (PAT) and Pediatric Early Warning Signs (PEWS) are usually used with triage systems for quick initial assessment of pediatric ED patients. The pediatric emergency triage systems developed in different countries have good reliability and are suitable for pediatric emergency triage. Because different triage systems had different performances, it is advisable to research the factors influencing the performance of pediatric triage systems. This was a narrative review. This article aims to review the roles and implementation of pediatric emergency triage systems in China and other countries.

Associations between resilience and symptoms of depression and anxiety among adolescents: Examining the moderating effects of family environment.

Depressive and anxiety symptoms in adolescents have experienced increase their risk of peripheral mental health and social problems. For adolescents, the role of family environmental factors should be taken into consideration. This study aimed to explore the association between resilience and depressive and anxiety symptoms in adolescents and to extend the findings by examining the moderating effects of family environment. A total of 35,573 adolescents in middle schools were recruited in China. Childhood abuse, resilience, and symptoms of depression and anxiety were evaluated in adolescents. We found a significant association between resilience and symptoms of depression and anxiety [OR = 0.976 (0.975-0.978), P < 0.001; OR = 0.980 (0.978-0.981), P < 0.001]. The adjusted ORs (95 % CIs) for mental health across the categories of resilience were as follows: 1 (reference) for low resilience, 0.660 (0.620-0.703) for medium resilience, 0.309 (0.286-0.333) for high resilience. The relationship between resilience and depressive symptoms was stronger for girls, non-only children, and those without child abuse experience compared to boys, only child, and those with child abuse experience (all p < 0.05). Our findings of a nationally representative sample in China suggest that gender, only child, parent-child relationship and child abuse moderated the relationship between resilience and symptoms of depression and anxiety.

Altered urinary tryptophan metabolites in alcohol-associated liver disease.

BACKGROUND: Alcohol-associated liver disease (ALD) leads to millions of deaths worldwide annually. A few potential biomarkers of ALD have been discovered through metabolomic or proteomic analysis. Tryptophan (Trp), one of nine essential amino acids, has been extensively studied and shown to play significant roles in many mammalian physiological processes. However, Trp metabolism changes in ALD are not yet fully understood. Whereas urine is an abundant and non-invasive source for disease biomarker discovery the current study investigated whether the abundance of Trp metabolites in the urine of ALD patients differs from that of healthy subjects. We also examined whether, if present in ALD, changes in urinary Trp metabolites can serve as markers for differentiating between mild/moderate and severe ALD. METHODS: We quantified the concentration of Trp and its metabolites in urine samples of healthy controls (n = 18), patients with mild or moderate alcohol-related liver injury (non-severe ALD; n = 21), and patients with severe alcohol-associated hepatitis (severe AH; n = 25) using both untargeted and targeted metabolomics. RESULTS: Eighteen Trp metabolites were identified and quantified from the untargeted metabolomics data. We developed a targeted metabolomics method to quantify the Trp and its metabolites and quantified 17 metabolites from the human urine samples. The data acquired in the untargeted and targeted platforms agreed and showed that the Trp concentration is not affected by the severity of ALD. However, the abundance of 10 Trp metabolites was correlated with the model for end-stage liver disease (MELD) score, with the abundance of nine metabolites significantly different between the healthy control and ALD patient groups. CONCLUSION: We found that Trp metabolism differs between ALD patients and healthy controls even though the concentration of Trp was not affected. Two Trp metabolites, quinolinic acid and indoxyl sulfate, correlate highly with the severity of ALD.

Reliability and validity of Chengdu pediatric emergency triage criteria: case study of a single center in China.

BACKGROUND: We aimed to examine the reliability and validity of Chengdu pediatric emergency triage criteria in order to provide a reference for the development of pediatric emergency triage within other hospitals. METHODS: We developed Chengdu pediatric emergency triage criteria based on the conditions/symptom, vital signs, and the Pediatric Early Warning Score system within our hospital using the Delphi method in 2020. The simulation scenario triage and real-life triage which were conducted in our hospital during January - March 2021, and the retrospective study of triage records extracted from our hospital's health information system in February 2022, were used to measure the agreement in triage decisions between the triage nurses, and between the triage nurses and the expert team. RESULTS: For the 20 simulation cases, the Kappa value of triage decisions between the triage nurses was 0.6 (95% CI 0.352-0.849), and the Kappa value of triage decisions between the triage nurses and the expert team was 0.73 (95% CI 0.540-0.911). For the 252 cases in the real-life triage, the Kappa value of triage decisions between the triage nurses and the expert team was 0.824 (95% CI 0.680-0.962). For the 20,540 cases selected for the retrospective study of triage records, the Kappa value of triage decisions between the triage nurses was 0.702 (95% CI 0.691-0.713); that between Triage Nurse 1 and the expert team was 0.634 (95% CI 0.623-0.647); and that between Triage Nurse 2 and the expert team was 0.725 (95% CI 0.713-0.736). The overall agreement rate in triage decisions between the triage nurses and the expert team in the simulation scenario triage was 80%; that between the triage nurses and the expert team in the real-life triage was 97.6%; and that between the triage nurses in the retrospective study was 91.9%. In the retrospective study, the agreement rates in triage decisions between Triage Nurse 1 and the expert team, and between Triage Nurse 2 and the expert team, were 88.0% and 92.3%, respectively. CONCLUSION: Chengdu pediatric emergency triage criteria that developed within our hospital is reliable and valid, and can promote rapid and effective triage by triage nurses.

Western diet unmasks transient low-level vinyl chloride-induced tumorigenesis; potential role of the (epi-)transcriptome.

BACKGROUND & AIMS: Vinyl chloride (VC) monomer is a volatile organic compound commonly used in industry. At high exposure levels, VC causes liver cancer and toxicant-associated steatohepatitis. However, lower exposure levels (i.e., sub-regulatory exposure limits) that do not directly damage the liver, enhance injury caused by Western diet (WD). It is still unknown if the long-term impact of transient low-concentration VC enhances the risk of liver cancer development. This is especially a concern given that fatty liver disease is in and of itself a risk factor for the development of liver cancer. METHODS: C57Bl/6 J mice were fed WD or control diet (CD) for 1 year. During the first 12 weeks of feeding only, mice were also exposed to VC via inhalation at sub-regulatory limit concentrations (<1 ppm) or air for 6 h/day, 5 days/week. RESULTS: Feeding WD for 1 year caused significant hepatic injury, which was exacerbated by VC. Additionally, VC increased the number of tumors which ranged from moderately to poorly differentiated hepatocellular carcinoma (HCC). Transcriptomic analysis demonstrated VC-induced changes in metabolic but also ribosomal processes. Epitranscriptomic analysis showed a VC-induced shift of the modification pattern that has been associated with metabolic disease, mitochondrial dysfunction, and cancer. CONCLUSIONS: These data indicate that VC sensitizes the liver to other stressors (e.g., WD), resulting in enhanced tumorigenesis. These data raise concerns about potential interactions between VC exposure and WD. It also emphasizes that current safety restrictions may be insufficient to account for other factors that can influence hepatotoxicity.

Characterization of the microenvironment in different immune-metabolism subtypes of cervical cancer with prognostic significance.

Introduction: Immune cell infiltration and metabolic reprogramming may have great impact on the tumorigenesis and progression of malignancies. The interaction between these two factors in cervical cancer remains to be clarified. Here we constructed a gene set containing immune and metabolism related genes and we applied this gene set to molecular subtyping of cervical cancer. Methods: Bulk sequencing and single-cell sequencing data were downloaded from the Cancer Genome Atlas (TCGA) database and Gene Expression Omnibus (GEO) database respectively. Immune and metabolism related genes were collected from Immport and Kyoto encyclopedia of genes and genomes (KEGG) database respectively. Unsupervised consensus clustering was performed to identify the molecular subtypes. Cibersort was applied to evaluate the immune cells infiltration status. Differential expression analysis and Gene set enrichment analysis (GSEA) were performed to characterize the molecular pattern of different subtypes. Multivariate Cox regression analysis was used for prognosis prediction model construction and receiver operating characteristic (ROC) curve was used for performance evaluation. The hub genes in the model were verified in single-cell sequencing dataset and clinical specimens. In vitro experiments were performed to validate the findings in our research. Results: Three subtypes were identified with prognostic implications. C1 subgroup was in an immunosuppressive state with activation of mitochondrial cytochrome P450 metabolism, C2 had poor immune cells infiltration and was characterized by tRNA anabolism, and the C3 subgroup was in an inflammatory state with activation of aromatic amino acid synthesis. The area under the ROC curve of the constructed model was 0.8, which showed better performance than clinical features. IMPDH1 was found to be significantly upregulated in tumor tissue and it was demonstrated that IMPDH1 could be a novel therapeutic target in vitro. Discussion: In summary, our findings suggested novel molecular subtypes of cervical cancer with distinct immunometabolic profiles and uncovered a novel therapeutic target.

Probiotic-derived nanoparticles inhibit ALD through intestinal miR194 suppression and subsequent FXR activation.

BACKGROUND AND AIMS: Intestinal farnesoid X receptor (FXR) plays a critical role in alcohol-associated liver disease (ALD). We aimed to investigate whether alcohol-induced dysbiosis increased intestinal microRNA194 (miR194) that suppressed Fxr transcription and whether Lactobacillus rhamnosus GG-derived exosome-like nanoparticles (LDNPs) protected against ALD through regulation of intestinal miR194-FXR signaling in mice. APPROACH AND RESULTS: Binge-on-chronic alcohol exposure mouse model was utilized. In addition to the decreased ligand-mediated FXR activation, alcohol feeding repressed intestinal Fxr transcription and increased miR194 expression. This transcriptional suppression of Fxr by miR194 was confirmed in intestinal epithelial Caco-2 cells and mouse enteriods. The alcohol feeding-reduced intestinal FXR activation was further demonstrated by the reduced FXR reporter activity in fecal samples and by the decreased fibroblast growth factor 15 (Fgf15) messenger RNA (mRNA) in intestine and protein levels in the serum, which caused an increased hepatic bile acid synthesis and lipogeneses. We further demonstrated that alcohol feeding increased-miR194 expression was mediated by taurine-upregulated gene 1 (Tug1) through gut microbiota regulation of taurine metabolism. Importantly, 3-day oral administration of LDNPs increased bile salt hydrolase (BSH)-harboring bacteria that decreased conjugated bile acids and increased gut taurine concentration, which upregulated Tug1, leading to a suppression of intestinal miR194 expression and recovery of FXR activation. Activated FXR upregulated FGF15 signaling and subsequently reduced hepatic bile acid synthesis and lipogenesis and attenuated ALD. These protective effects of LDNPs were eliminated in intestinal FxrΔIEC and Fgf15-/- mice. We further showed that miR194 was upregulated, whereas BSH activity and taurine levels were decreased in fecal samples of patients with ALD. CONCLUSIONS: Our results demonstrated that gut microbiota-mediated miR194 regulation contributes to ALD pathogenesis and to the protective effects of LDNPs through modulating intestinal FXR signaling.

Metabolomics analysis of urine from patients with alcohol-associated liver disease reveals dysregulated caffeine metabolism.

Excess alcohol intake causes millions of deaths annually worldwide. Asymptomatic early-stage, alcohol-associated liver disease (ALD) is easily overlooked, and ALD is usually only diagnosed in more advanced stages. We explored the possibility of using polar urine metabolites as biomarkers of ALD for early-stage diagnosis and functional assessment of disease severity by quantifying the abundance of polar metabolites in the urine samples of healthy controls (n = 18), patients with mild or moderate liver injury (n = 21), and patients with severe alcohol-associated hepatitis (n = 25). The polar metabolites in human urine were first analyzed by untargeted metabolomics, showing that 209 urine metabolites are significantly changed in patients, and 17 of these are highly correlated with patients' model for end-stage liver disease (MELD) score. Pathway enrichment analysis reveals that the caffeine metabolic pathway is the most affected in ALD. We then developed a targeted metabolomics method and measured the concentration of caffeine and its metabolites in urine using internal and external standard calibration, respectively. The described method can quantify caffeine and its 14 metabolites in 35 min. The results of targeted metabolomics analysis agree with the results of untargeted metabolomics, showing that 13 caffeine metabolites are significantly decreased in patients. In particular, the concentrations of 1-methylxanthine, paraxanthine, and 5-acetylamino-6-amino-3-methyluracil are markedly decreased with increased disease severity. We suggest that these three metabolites could serve as functional biomarkers for differentiating early-stage ALD from more advanced liver injury.NEW & NOTEWORTHY Our study using both untargeted and targeted metabolomics reveals the caffeine metabolic pathway is dysregulated in ALD. Three caffeine metabolites, 1-methylxanthine, paraxanthine, and 5-acetylamino-6-amino-3-methyluracil, can differentiate the severity of early-stage ALD.

Metabolic Analysis of Nucleosides/Bases in the Urine and Serum of Patients with Alcohol-Associated Liver Disease.

Accumulating evidence supports the important role of RNA modifications in liver disease pathogenesis. However, RNA modifications in alcohol-associated liver disease (ALD) have not yet been reported. Modified ribonucleosides/bases are products of RNA degradation; therefore, we investigated whether modified ribonucleosides/bases in human urine and serum are changed and whether these changes are associated with the severity of ALD. Human urine and serum samples from patients with ALD and appropriate controls were collected. Free nucleosides/bases were extracted from these samples and quantified using untargeted and targeted metabolomic approaches. Thirty-nine and forty free nucleosides/bases were respectively detected in human urine and serum samples. Twelve and eleven modified nucleosides are significantly changed in patients' urine and serum (q < 0.05 and fold-change > 20%). The abundance of modified nucleobase and ribonucleoside, 7,9-dimethylguanine in urine and 2-methylthio-N6-threonylcarbamoyladenosine (ms2t6A) in serum are strongly associated with the severity of ALD. Spearman's rank correlation coefficient of these two metabolites with the Model for End-stage Liver Disease (MELD) score are 0.66 and 0.74, respectively. Notably, the abundance changes in these two metabolites are sufficiently large to distinguish severe alcohol-associate hepatitis (AH) from non-severe ALD and non-severe ALD from healthy controls.

Using the Delphi method to establish pediatric emergency triage criteria in a grade A tertiary women's and children's hospital in China.

BACKGROUND: We aimed to establish simplified and quantifiable triage criteria in pediatric emergency care, improving the efficiency of pediatric emergency triage and ensuring patient safety. METHODS: We preliminarily determined the pediatric emergency triage criteria with references to pediatric emergency department characteristics and internationally recognized triage tools after literature review and discussion. The final determination of the triage criteria was reached after two rounds of Delphi surveys completed by18 experts from 3 hospitals in China. RESULTS: Both round 1 and round 2 surveys had a 100% response rate. The overall expert authority coefficient in the two rounds of surveys was 0.872. The experts had 100% enthusiasm for participating in the surveys. Kendall's coefficients of concordance for conditions/symptoms in patients triaged to level 1, 2, 3, and 4 were 0.149, 0.193, 0.102, and 0.266, respectively. All p-values were less than 0.05. The coefficients of variation in conditions/symptoms, vital signs, and the Pediatric Early Warning Score (PEWS) ranged between 0.00 and 0.205, meeting the inclusion criteria. The pediatric emergency triage criteria containing conditions/symptoms, vital signs, PEWS scores, and other 4 level 1 indicators, 51 level 2 indicators and 23 level 3 indicators were built. The maximum waiting time to treatment for the patients triaged to level 1, 2, 3, and 4 was immediate, within 10 min, within 30 min, and within 240 min, respectively. CONCLUSION: The pediatric emergency triage criteria established in this study was scientific and reliable. It can be used to quickly identify the patients requiring urgent and immediate care, thereby ensuring the priorities for the care of critically ill patients.

Integrated Multilayer Omics Reveals the Genomic, Proteomic, and Metabolic Influences of Histidyl Dipeptides on the Heart.

Background Histidyl dipeptides such as carnosine are present in a micromolar to millimolar range in mammalian hearts. These dipeptides facilitate glycolysis by proton buffering. They form conjugates with reactive aldehydes, such as acrolein, and attenuate myocardial ischemia-reperfusion injury. Although these dipeptides exhibit multifunctional properties, a composite understanding of their role in the myocardium is lacking. Methods and Results To identify histidyl dipeptide-mediated responses in the heart, we used an integrated triomics approach, which involved genome-wide RNA sequencing, global proteomics, and unbiased metabolomics to identify the effects of cardiospecific transgenic overexpression of the carnosine synthesizing enzyme, carnosine synthase (Carns), in mice. Our result showed that higher myocardial levels of histidyl dipeptides were associated with extensive changes in the levels of several microRNAs, which target the expression of contractile proteins, ß-fatty acid oxidation, and citric acid cycle (TCA) enzymes. Global proteomic analysis showed enrichment in the expression of contractile proteins, enzymes of ß-fatty acid oxidation, and the TCA in the Carns transgenic heart. Under aerobic conditions, the Carns transgenic hearts had lower levels of short- and long-chain fatty acids as well as the TCA intermediate-succinic acid; whereas, under ischemic conditions, the accumulation of fatty acids and TCA intermediates was significantly attenuated. Integration of multiple data sets suggested that ß-fatty acid oxidation and TCA pathways exhibit correlative changes in the Carns transgenic hearts at all 3 levels. Conclusions Taken together, these findings reveal a central role of histidyl dipeptides in coordinated regulation of myocardial structure, function, and energetics.

Differential metabolic requirement governed by transcription factor c-Maf dictates innate γδT17 effector functionality in mice and humans.

Cellular metabolism has been proposed to govern distinct γδ T cell effector functions, but the underlying molecular mechanisms remain unclear. We show that interleukin-17 (IL-17)-producing γδ T (γδT17) and interferon-γ (IFN-γ)-producing γδ T (γδT1) cells have differential metabolic requirements and that the rate-limiting enzyme isocitrate dehydrogenase 2 (IDH2) acts as a metabolic checkpoint for their effector functions. Intriguingly, the transcription factor c-Maf regulates γδT17 effector function through direct regulation of IDH2 promoter activity. Moreover, mTORC2 affects the expression of c-Maf and IDH2 and subsequent IL-17 production in γδ T cells. Deletion of c-Maf in γδ T cells reduces metastatic lung cancer development, suggesting c-Maf as a potential target for cancer immune therapy. We show that c-Maf also controls IL-17 production in human γδ T cells from peripheral blood and in oral cancers. These results demonstrate a critical role of the transcription factor c-Maf in regulating γδT17 effector function through IDH2-mediated metabolic reprogramming.

Alcohol-driven metabolic reprogramming promotes development of RORγt-deficient thymic lymphoma.

RORγt is a master regulator of Th17 cells. Despite evidence linking RORγt deficiency/inhibition with metastatic thymic T cell lymphomas, the role of RORγt in lymphoma metabolism is unknown. Chronic alcohol consumption plays a causal role in many human cancers. The risk of T cell lymphoma remains unclear in humans with alcohol use disorders (AUD) after chronic RORγt inhibition. Here we demonstrated that alcohol consumption accelerates RORγt deficiency-induced lymphomagenesis. Loss of RORγt signaling in the thymus promotes aerobic glycolysis and glutaminolysis and increases allocation of glutamine carbon into lipids. Importantly, alcohol consumption results in a shift from aerobic glycolysis to glutaminolysis. Both RORγt deficiency- and alcohol-induced metabolic alterations are mediated by c-Myc, as silencing of c-Myc decreases the effects of alcohol consumption and RORγt deficiency on glutaminolysis, biosynthesis, and tumor growth in vivo. The ethanol-mediated c-Myc activation coupled with increased glutaminolysis underscore the critical role of RORγt-Myc signaling and translation in lymphoma.

Combined exposure to polychlorinated biphenyls and high-fat diet modifies the global epitranscriptomic landscape in mouse liver.

Exposure to a single dose of polychlorinated biphenyls (PCBs) and a 12-week high-fat diet (HFD) results in nonalcoholic steatohepatitis (NASH) in mice by altering intracellular signaling and inhibiting epidermal growth factor receptor signaling. Post-transcriptional chemical modification (PTM) of RNA regulates biological processes, but the contribution of epitranscriptomics to PCB-induced steatosis remains unknown. This study tested the hypothesis that PCB and HFD exposure alters the global RNA epitranscriptome in male mouse liver. C57BL/6J male mice were fed a HFD for 12 weeks and exposed to a single dose of Aroclor 1260 (20 mg/kg), PCB 126 (20 µg/kg), both Aroclor 1260 and PCB 126 or vehicle control after 2 weeks on HFD. Chemical RNA modifications were identified at the nucleoside level by liquid chromatography-mass spectrometry. From 22 PTM global RNA modifications, we identified 10 significant changes in RNA modifications in liver with HFD and PCB 126 exposure. Only two modifications were significantly different from HFD control liver in all three PCB exposure groups: 2'-O-methyladenosine (Am) and N(6)-methyladenosine (m6A). Exposure to HFD + PCB 126 + Aroclor 1260 increased the abundance of N(6), O(2)-dimethyladenosine (m6Am), which is associated with the largest number of transcript changes. Increased m6Am and pseudouridine were associated with increased protein expression of the writers of these modifications: Phosphorylated CTD Interacting Factor 1 (PCIF1) and Pseudouridine Synthase 10 (PUS10), respectively, in HFD + PCB 126- + Aroclor 1260-exposed mouse liver. Increased N1-methyladenosine (m1A) and m6A were associated with increased transcript levels of the readers of these modifications: YTH N6-Methyladenosine RNA Binding Protein 2 (YTHDF2), YTH Domain Containing 2 (YTHDC2), and reader FMRP Translational Regulator 1 (FMR1) transcript and protein abundance. The results demonstrate that PCB exposure alters the global epitranscriptome in a mouse model of NASH; however, the mechanism for these changes requires further investigation.

Lemon exosome-like nanoparticles enhance stress survival of gut bacteria by RNase P-mediated specific tRNA decay.

Diet and bile play critical roles in shaping gut microbiota, but the molecular mechanism underlying interplay with intestinal microbiota is unclear. Here, we showed that lemon-derived exosome-like nanoparticles (LELNs) enhance lactobacilli toleration to bile. To decipher the mechanism, we used Lactobacillus rhamnosus GG (LGG) as proof of concept to show that LELNs enhance LGG bile resistance via limiting production of Msp1 and Msp3, resulting in decrease of bile accessibility to cell membrane. Furthermore, we found that decline of Msps protein levels was regulated through specific tRNAser UCC and tRNAser UCG decay. We identified RNase P, an essential housekeeping endonuclease, being responsible for LELNs-induced tRNAser UCC and tRNAser UCG decay. We further identified galacturonic acid-enriched pectin-type polysaccharide as the active factor in LELNs to increase bile resistance and downregulate tRNAser UCC and tRNAser UCG level in the LGG. Our study demonstrates a tRNA-based gene expression regulation mechanism among lactobacilli to increase bile resistance.

Metabolic Profiling of Bile Acids in the Urine of Patients with Alcohol-Associated Liver Disease.

Bile acids (BAs) play important functions in the development of alcohol-associated liver disease (ALD). In the current study, urine BA concentrations in 38 patients with well-described alcohol-associated hepatitis (AH) as characterized by Model for End-Stage Liver Disease (MELD), 8 patients with alcohol-use disorder (AUD), and 19 healthy controls (HCs) were analyzed using liquid chromatography-mass spectrometry. Forty-three BAs were identified, and 22 BAs had significant changes in their abundance levels in patients with AH. The potential associations of clinical data were compared to candidate BAs in this pilot proof-of-concept study. MELD score showed positive correlations with several conjugated BAs and negative correlations with certain unconjugated BAs; taurine-conjugated chenodeoxycholic acid (CDCA) and MELD score showed the highest association. Cholic acid, CDCA, and apocholic acid had nonsignificant abundance changes in patients with nonsevere ALD compared to HCs but were significantly increased in those with severe AH. Receiver operating characteristic analysis showed that the differences in these three compounds were sufficiently large to distinguish severe AH from nonsevere ALD. Notably, the abundance levels of primary BAs were significantly increased while most of the secondary BAs were markedly decreased in AH compared to AUD. Most importantly, the amount of total BAs and the ratio of primary to secondary BAs increased while the ratio of unconjugated to conjugated BAs decreased as disease severity increased. Conclusion: Abundance changes of specific BAs are closely correlated with the severity of AH in this pilot study. Urine BAs (individually or as a group) could be potential noninvasive laboratory biomarkers for detecting early stage ALD and may have prognostic value in AH morbidity.