ObjectiveTo investigate the potential mechanism of heat-sensitive moxibustion on chronic atrophic gastritis （CAG） through the phosphoinositide 3-kinase/protein kinase B （PI3K/Akt） signaling pathway. MethodsFifty-eight SD rats were randomly divided into blank group （n=14） and modeling group （n=44）. Rats in the blank group were fed routinely， while the rats in the modeling group received drinking water containing 1-methyl-3-nitro-1-nitrosoguanidine （MNNG） at a concentration of 140 μg/ml， combined with irregular fasting and feeding for 12 weeks to establish CAG model. After successful modeling， the rats were randomly divided into model group （n=10）， inhibitor group （n=10） and moxibustion group （n=20）. After 40 minutes of suspended moxibustion at "Zhongwan" （CV 12） daily， the rats in the moxibustion group were divided into heat-sensitive moxibustion group （n=10） and non-heat-sensitive moxibustion group （n=9） according to the change of tail temperature during moxibustion. The inhibitor group was bound for 40 minutes daily， and then administered with PI3K/Akt signaling pathway inhibitor， rapamycin solution， by gavage at a dose of 1 mg/kg. The model group received intragastric administration of 1 ml/kg normal saline after 40 minutes of restraint stress each day. All interventions were administered once daily for 28 consecutive days， while the blank group received no intervention. After the intervention finished， the body weight of rats in each group was compared. HE staining was used to observe the histopathological changes of gastric mucosa. The apoptosis-positive rate of gastric mucosal cells was detected by TUNEL assay. Immunohistochemistry was performed to determine the protein levels of matric metalloproteinase-7 （MMP7）， vascular endothelial growth factor A （VEGFA） and epidermal growth factor receptor （EGFR） in gastric mucosa. The mRNA expression levels of PI3K， Akt and mammalian target of rapamycin （mTOR） in gastric mucosal tissues were detected by qPCR. The protein levels of phosphorylated Akt （p-Akt） and phosphorylated mTOR （p-mTOR） in rat gastric mucosal tissues were measured by Western Blotting. ResultsCompared to the blank group， rats in all other groups exhibited decreased body weight， significantly increased gastric mucosal cell apoptosis-positive rates， elevated protein levels of MMP7， VEGFA and EGFR in gastric mucosa， increased mRNA expression levels of PI3K， Akt and mTOR， and enhanced protein expression levels of p-Akt and p-mTOR （P＜0.05 or P＜0.01）. Histopathological examination revealed thinning of the gastric mucosa， glandular disorganization and atrophy， accompanied by intestinal metaplasia.Compared to the model group， the heat-sensitive moxibustion group， the non-heat-sensitive moxibustion group and the inhibitor group all showed significant improvements in the above-mentioned indicators （P＜0.05 or P＜0.01）. Compared to the heat-sensitive moxibustion group， the non-heat-sensitive moxibustion group and the inhibitor group exhibited increased positive rates of gastric mucosal cell apoptosis； the non-heat-sensitive moxibustion group showed increased protein levels of MMP7， VEGFA and EGFR， as well as mRNA expression levels of PI3K， Akt and mTOR， and protein expressions of p-Akt and p-mTOR； the inhibitor group exhibited elevated protein expression level of EGFR （P＜0.05 or P＜0.01）. Histopathological examination showed that the gastric mucosal glands in the heat-sensitive moxibustion group were arranged more regularly， with an approximately normal structural appearance. ConclusionHeat-sensitive moxibustion can improve the body weight of CAG rats and repair gastric mucosal injury. Its therapeutic effects may be mediated by inhibiting excessive activation of gastric mucosal PI3K/Akt signaling pathway， thereby reducing gastric mucosal cell apoptosis.

ObjectiveTo investigate the potential mechanism of heat-sensitive moxibustion on chronic atrophic gastritis （CAG） through the phosphoinositide 3-kinase/protein kinase B （PI3K/Akt） signaling pathway. MethodsFifty-eight SD rats were randomly divided into blank group （n=14） and modeling group （n=44）. Rats in the blank group were fed routinely， while the rats in the modeling group received drinking water containing 1-methyl-3-nitro-1-nitrosoguanidine （MNNG） at a concentration of 140 μg/ml， combined with irregular fasting and feeding for 12 weeks to establish CAG model. After successful modeling， the rats were randomly divided into model group （n=10）， inhibitor group （n=10） and moxibustion group （n=20）. After 40 minutes of suspended moxibustion at "Zhongwan" （CV 12） daily， the rats in the moxibustion group were divided into heat-sensitive moxibustion group （n=10） and non-heat-sensitive moxibustion group （n=9） according to the change of tail temperature during moxibustion. The inhibitor group was bound for 40 minutes daily， and then administered with PI3K/Akt signaling pathway inhibitor， rapamycin solution， by gavage at a dose of 1 mg/kg. The model group received intragastric administration of 1 ml/kg normal saline after 40 minutes of restraint stress each day. All interventions were administered once daily for 28 consecutive days， while the blank group received no intervention. After the intervention finished， the body weight of rats in each group was compared. HE staining was used to observe the histopathological changes of gastric mucosa. The apoptosis-positive rate of gastric mucosal cells was detected by TUNEL assay. Immunohistochemistry was performed to determine the protein levels of matric metalloproteinase-7 （MMP7）， vascular endothelial growth factor A （VEGFA） and epidermal growth factor receptor （EGFR） in gastric mucosa. The mRNA expression levels of PI3K， Akt and mammalian target of rapamycin （mTOR） in gastric mucosal tissues were detected by qPCR. The protein levels of phosphorylated Akt （p-Akt） and phosphorylated mTOR （p-mTOR） in rat gastric mucosal tissues were measured by Western Blotting. ResultsCompared to the blank group， rats in all other groups exhibited decreased body weight， significantly increased gastric mucosal cell apoptosis-positive rates， elevated protein levels of MMP7， VEGFA and EGFR in gastric mucosa， increased mRNA expression levels of PI3K， Akt and mTOR， and enhanced protein expression levels of p-Akt and p-mTOR （P＜0.05 or P＜0.01）. Histopathological examination revealed thinning of the gastric mucosa， glandular disorganization and atrophy， accompanied by intestinal metaplasia.Compared to the model group， the heat-sensitive moxibustion group， the non-heat-sensitive moxibustion group and the inhibitor group all showed significant improvements in the above-mentioned indicators （P＜0.05 or P＜0.01）. Compared to the heat-sensitive moxibustion group， the non-heat-sensitive moxibustion group and the inhibitor group exhibited increased positive rates of gastric mucosal cell apoptosis； the non-heat-sensitive moxibustion group showed increased protein levels of MMP7， VEGFA and EGFR， as well as mRNA expression levels of PI3K， Akt and mTOR， and protein expressions of p-Akt and p-mTOR； the inhibitor group exhibited elevated protein expression level of EGFR （P＜0.05 or P＜0.01）. Histopathological examination showed that the gastric mucosal glands in the heat-sensitive moxibustion group were arranged more regularly， with an approximately normal structural appearance. ConclusionHeat-sensitive moxibustion can improve the body weight of CAG rats and repair gastric mucosal injury. Its therapeutic effects may be mediated by inhibiting excessive activation of gastric mucosal PI3K/Akt signaling pathway， thereby reducing gastric mucosal cell apoptosis.

Glycosylation constitutes a critical, highly intricate, and diverse co- and post-translational modification characterized by the covalent attachment of sugar moieties to proteins, lipids, or small RNAs. Complex glycans are ubiquitously present across nearly all living organisms. Despite their prevalence, our comprehension of glycan diversity remains limited, likely due to the inherent challenges associated with elucidating their structural complexity. Among post-translational modifications, protein glycosylation is notably prevalent, involving the enzymatic transfer of oligosaccharides to specific amino acid residues by glycosyltransferases. This modification plays a pivotal role in modulating protein function, including participation in various biological and biochemical recognition processes. G protein-coupled receptors (GPCRs), encoded by approximately one thousand genes, share a conserved architecture comprising seven transmembrane helices interconnected by three intracellular and three extracellular loops. Representing the largest family of human membrane proteins, GPCRs regulate a vast array of physiological and pathological processes, thereby constituting the most extensive class of therapeutic targets. In mammalian systems, the majority of GPCRs undergo glycosylation predominantly at their extracellular N-terminus or extracellular loops, primarily through N-linked and O-linked glycosylation. These covalent carbohydrate modifications exert profound effects on multiple facets of GPCR biology, including endoplasmic reticulum folding and quality control, membrane trafficking and surface expression, receptor internalization and recycling or degradation, ligand binding and signal transduction, biased signaling, and receptor dimerization. Notably, glycosylation can exert both positive and negative regulatory influences on these processes. Dysregulation of GPCR glycosylation has been implicated in a range of pathological conditions, such as cancer, diabetes, and neurological disorders, underscoring its physiological and pathological significance. Aberrant glycosylation patterns may lead to dysfunctional receptor signaling, thereby contributing to disease progression. Consequently, elucidating the precise roles of glycosylation in GPCR function not only enhances fundamental understanding of receptor biology but also facilitates the development of novel therapeutic strategies targeting glycosylation pathways or specific GPCR glycoforms. Although the functional consequences of glycosylation have been investigated for several decades, delineating their exact structural underpinnings has remained challenging due to the intrinsic flexibility and heterogeneity of carbohydrate structures. Recent advances in structural biology, particularly single-particle cryo-electron microscopy (cryo-EM) and X-ray crystallography, have catalyzed a paradigm shift in our understanding of GPCR glycosylation. The integration of these sophisticated structural techniques with biochemical approaches has redefined glycosylation as a complex structural element integral to receptor function. These developments provide a molecular framework for comprehending how glycans influence receptor pharmacology and open new avenues for the rational design of glyco-engineered biologics and allosteric modulators targeting specific extracellular motifs. This mini-review concentrates on glycosylation within the GPCR superfamily, summarizing the impact of glycosylation modifications on receptor function and regulatory mechanisms, recent progress in the structural biology of GPCR glycosylation, and prospective directions for future research in this field.

ObjectiveMethylthioadenosine phosphorylase (MTAP) is found to be frequently deleted in malignant cancers, but the role of MTAP underlying metastasis and stemness of liver cancer remains far from clear. 5-fluorouracil (5-Fu) is clinically used in treating advanced liver cancer, however, chemoresistance is one of the major barriers impeding its efficacy. Liver cancer stem cells are considered to be the reservoir for tumor progression and chemoresistance. This study aims to explore the role of MTAP in regulating stemness and chemoresistance of 5-Fu in liver cancer. It is designed to elucidate the molecular mechanisms underlying MTAP-manipulated stemness. How MTAP influences metastasis and chemoresistance against 5-Fu in liver cancer is also elaborated. MethodsThe correlation of MTAP expression with stemness marker CD133 was evaluated by flow cytometry. Colony formation assays were conducted to analyze the tumorigenic ability. Western blot assays were applied to delineate the molecular mechanisms underlying MTAP-regulated stemness. Trans-well assays were conducted to analyze the metastatic potential of liver cancer cells.In vivo experiments were performed using subcutaneous xenograft and lung metastasis model on nude mice. Tumor size and weight were analyzed upon 5-Fu treatment. Metastatic nodules on lungs were evaluated. Immunohistochemical and TUNNEL assays were performed on slides obtained from tumor tissues. ResultsMTAP overexpression inhibited expression of CD133 and colony formation, which is further ablated by MTAP inhibitor. MTAP deprivation augmented stemness and colony formation, which is reversed by protein arginine methyltransferase 5 (PRMT5) overexpression but not its catalytically inactive counterparts. Critically, SRY-box transcription factor 2 (SOX2) was found to be a downstream regulator of MTAP/PRMT5, leading to stemness of liver cancer cells. MTAP overexpression suppressed SOX2 expression, while MTAP inhibition augmented expression of SOX2. Critically, MTAP overexpression inhibited migration and invasion of liver cancer cells. In vivo experiments in animal model found that MTAP deprivation promotes tumor growth and metastatic nodules of liver cancer. Additionally, MTAP overexpression inhibits tumor growth. Moreover, MTAP deprivation contributes to chemoresistance shown by increased tumor size and weight treated by 5-Fu. In contrast, MTAP overexpression led to further decline in tumor size and weight elicited by 5-Fu treatment. Accordingly, SOX2 was inhibited in tumor tissues after MTAP overexpression. Marker of proliferation Ki67 (Ki67) expression was dampened while apoptosis was found in MTAP-overexpressed tumor tissues. ConclusionIn this study, plethora of experimental studies collectively demonstrated that MTAP deprivation enhances stemness of liver cancer by regulating SOX2, exerting anti-cancer and chemoresistant role against 5-Fu in liver cancer. It is also worth noting that MTAP inhibition promoted metastasis of liver cancer. MTAP overexpression augmented tumor shrinking elicited by 5-Fu and SOX2 was involved in this process. These results concluded that MTAP/PRMT5/SOX2 signaling axis was involved in regulating stemness and chemoresistance of liver cancer. These findings help to exploit novel therapies by targeting stemness in MTAP-depleted liver cancer. It shed novel light on unveiling MTAP-regulated stemness in antagonizing 5-Fu treatment in liver cancer. It also adds mounting evidence to the theoretical basis for accomplishing personalized chemotherapy of liver cancer patients by targeting MTAP or its downstream PRMT5/SOX2.

Objective To investigate the value of peripheral blood T-lymphocyte subsets and mitochondrial damage index(MDI)in evaluating the pregnancy outcome of patients with diminished ovarian reserve(DOR).Methods A total of 230 DOR patients admitted to the hospital from August 2020 to August 2023 were selected as DOR group,230 healthy women with normal ovarian reserve function were selected as control group,and all subjects were tested for peripheral blood T-lymphocyte subsets and MDI.DOR patients were di-vided into clinical pregnancy group(n=86)and non-clinical pregnancy group(m=144)according to clinical pregnancy.The influencing factors of pregnancy outcomes of DOR patients were analyzed by multivariate Lo-gistic regression model,and the predictive value of peripheral blood T-lymphocyte subsets and MDI for poor pregnancy outcomes of DOR patients was analyzed by receiver operating characteristic(ROC)curve.Results Com-pared with control group,CD3+,CD4+and CD4+/CD8+in DOR group were decreased(P＜0.05),and CD8+,positive rate of helper T cell(Th)-MDI and positive rate of suppressor T cell(Ts)-MDI were increased(P＜0.05).The clinical pregnancy rate of 230 DOR patients was 37.39％(86/230).Compared with clinical pregnancy group,CD4+in non-clinical pregnancy group was decreased(P＜0.05),and CD8+,CD4+/CD8+and the positive rates of Th-MDI and Ts-MDI were increased(P＜0.05).There was no significant difference in CD3+between two groups(P＞0.05).The levels of anti-Müllerian hormone(AMH)and estradiol(E2)in non-clinical pregnancy group were lower than those in clinical pregnancy group(P＜0.05).Th-MDI positive and Ts-MDI positive were independent risk factors for poor pregnancy outcomes in DOR patients(P＜0.05),and high levels of CD4+/CD8+,AMH and E2 were protective factors for poor pregnancy outcomes in DOR patients(P＜0.05).The area under the curve of AMH,E2,CD4+/CD8+,Th-MDI,Ts-MDI alone and com-bined in predicting poor pregnancy outcome in DOR patients were 0.735,0.784,0.767,0.691,0.703,0.882,respectively,and the predictive efficacy of combined application was significantly higher than that of each sin-gle application(P＜0.05).Conclusion DOR patients have immune dysfunction and oxidative activation,low CD4+/CD8+,Th-MDI positive and Ts-MDI positive are risk factors for poor pregnancy outcomes in DOR pa-tients,and the detection of the three has a high predictive effect on poor pregnancy outcomes in DOR patients.

Objective To analyze the relationships of familial affective expression with anxiety and depression in adolescents,and to explore the related factors influencing familial affective expres-sion among adolescents.Methods This cross-sectional study employed a multi-stage stratified clus-ter random sampling method to select 2,216 middle school students in Hefei from January 2 to 15,2024,for an online questionnaire survey.The Adolescent Affective Expression Scale,the Screen for Child Anxiety Related Emotional Disorders(SCARED),and the Depression Self-Rating Scale for Children(DSRSC)were used to assess the level of familial affective expression and the status of anxi-ety and depression among adolescents.The familial affective expression of adolescents with different demographic characteristics was compared;the Pearson correlation analysis was used to explore the correlations of familial affective expression with anxiety and depression;the multiple linear regression analysis was conducted to identify the influencing factors of familial affective expression among adoles-cents.Results A total of 2,216 questionnaires were distributed,and 2,017 valid questionnaires were returned,yielding a response rate of 91.02％.The total score on the Adolescent Affective Expression Scale was(24.91±7.98),with a detection rate of 17.06％for high familial affective expression.The correlation analysis revealed positive correlations of the total score on the Adolescent Affective Expression Scale with the scores on the SCARED and DSRSC(P＜0.05).The results of multiple linear regression analysis indicated that male(B=-2.321,95％CI,-2.587 to-2.106),living in an urban environment(B=-1.196,95％CI,-1.636 to 0.154),having a harmonious parent-child relationship without frequent arguments(B=-2.348,95％CI,-2.631 to-1.759),expe-riencing marital conflict(B=3.615,95％CI,3.015 to 4.123),adopting negative coping strate-gies(B=0.107,95％CI,0.033 to 0.196),and having lower psychological flexibility(B=0.212,95％CI,0.115 to 0.289)were influencing factors of familial affective expression among ad-olescents(P＜0.05).Conclusion Familial affective expression is associated with anxiety and de-pression in adolescents.Gender,living environment,parent-child relationship,marital relationship,coping styles,and psychological flexibility may have certain impacts on familial affective expression among adolescents.

Objective:s To investigate the risk factors for delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) in patients with acute carbon monoxide poisoning (ACOP) and to develop predictive models based on machine learning algorithms.Methods:Patients with ACOP hospitalized at the First Affiliated Hospital of Zhengzhou University from August 2019 to October 2024 were included, with the occurrence of DEACMP as the outcome measure. The dataset was randomly divided into training and validation sets at a ratio of 7:3. Lasso regression was used to select features influencing the outcome in training sets. Nine machine learning models—including Random Forest (RF), Extreme Gradient Boosting (XGBoost), and Support Vector Machine (SVM)—were constructed. Receiver operating characteristic (ROC) curves were plotted and the area under the curve (AUC) calculated for each model. Calibration curves were used to assess accuracy, and decision curve analysis (DCA) was applied to evaluate clinical utility. The SHapley Additive exPlanations (SHAP) method was employed to visualize and interpret the best-performing model.Results:A total of 264 ACOP patients were included, of whom 54 (20.5%) developed DEACMP. Lasso regression identified eight key feature variables. Based on these factors, predictive models were constructed, showing good AUC stability across the nine machine learning models in both training (0.92–0.99) and validation sets (0.85–0.91). The RF model performed best, with an AUC of 0.99 in the training set and 0.90 in the validation set; its calibration curve and DCA curve also demonstrated excellent performance. SHAP analysis of the RF model revealed the importance ranking of factors from highest to lowest as follows: Glasgow Coma Scale (GCS) score, duration of coma, age, history of coronary heart disease, CK-MB level, monocyte count, diastolic blood pressure (DBP), and drinking history.Conclusions:The RF model exhibited the highest predictive performance for DEACMP occurrence in ACOP patients. The influencing factors, ranked in order of importance from highest to lowest, are as follows: GCS score, duration of coma, age, history of coronary heart disease, CK-MB level, monocyte count, DBP, and drinking history.

The immune microenvironment plays a pivotal role in maintaining ovarian homeostasis. Polycystic ovary syndrome (PCOS), a common endocrine and metabolic disorder, is closely associated with immune microenvironment imbalance. This review systematically describes the dysregulation of innate immune cells (e.g., macrophages, natural killer cells and dendritic cells) and adaptive immune cells (e.g., Th1, Th2, Treg and Th17) in PCOS, highlighting their impacts on ovarian function, insulin resistance, and hyperandrogenemia. These findings underscore the central role of immune microenvironment disturbances in PCOS pathogenesis. Additionally, the association between gut microbiota dysbiosis and PCOS is explored, emphasizing how gut microbiota influences metabolic byproducts and hormonal levels to contribute to PCOS development. Furthermore, therapeutic strategies targeting immune microenvironment imbalance such as modulating macrophage polarization, restoring Th1/Th2 and Th17/Treg balance, and ameliorating gut microbiota dysbiosis are discussed, offering novel insights for PCOS immunotherapy. In conclusion, this review comprehensively analyzes the pathogenesis of PCOS from the perspective of the immune microenvironment, aiming to provide a theoretical foundation and reference for future research and clinical practice.

Cross-border teaching provides new opportunities for college students to gain diverse insights amid the globalization and internationalized education, In July 2024, guided by the Chinese Association for Science and Technology, the Chinese Nutrition Society and the Hong Kong Nutrition Association collaborated to host a three-week clinical nutrition internship at Peking Union Medical College Hospital for five college students from Hong Kong SAR, China. This program included participating in outpatient rounds, attending in inpatient nutrition management, and attending lectures, aiming to enhance students' professional skills and clinical experience. Cultural exchange and value-based education also enriched students' social responsibility and cultural understanding. The Hong Kong students also brought diverse cultural backgrounds and inputs, enabling multidimensional communication during the training. Post-internship feedback survey showed that the students found the inernship valuable for their career development and hoped for more learning opportunities. This cross-border high-quality internship program fostered skill enhancement, cultural exchange between young students in Beijing and Hong Kong and contributed to advancement of clinical nutrition.

OBJECTIVE To explore the molecular mechanism of Xijiao Dihuang Decoction(XJDHT)in inhibiting inflammatory response in sepsis based on network pharmacology,molecular docking and in vitro and in vivo experiments.METHODS Active com-ponents of XJDHT were screened using the TCMSP and HERB databases.Sepsis-related targets and histone H3K36 trimethylation(H3K36me3)-associated targets were retrieved from GeneCard,OMIM,and DisGeNet databases.A protein-protein interaction(PPI)network was constructed using the STRING database,and core targets were identified via Cytoscape 3.9.1.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)pathway enrichment analyses were performed to predict potential mechanisms.Mo-lecular docking validated ligand-receptor binding affinity.A cecal ligation and puncture(CLP)model was established in mice to evalu-ate 24-hour sepsis scores(MSS)and survival rates.Blood routine parameters were analyzed using an automated hematology analyzer.Serum IL-1β and TNF-α levels were measured by ELISA.Liver histopathology was assessed via HE staining,and H3K36me3 expression in Kupffer cells was detected by immunofluorescence.In vitro,LPS-induced THP-1 cells were used as an in-flammatory model.ChIP-qPCR evaluated H3K36me3 enrichment at IL-1β and TNF-α gene loci.Western blot analyzed HIF-1α,EGFR,and AKT1 pathway proteins.RESULTS A total of 28 active components of XJDHT were identified,corresponding to 987 gene targets,with 189 overlapping sepsis-related targets.Core targets included TNF,IL1B,and GAPDH.Enriched pathways includ-ed EGFR tyrosine kinase inhibitor resistance.Molecular docking confirmed strong binding between core components and key targets.In vivo,compared to the sham group,the CLP group exhibited significantly reduced 24-hour survival(P<0.01),elevated MSS(P<0.01),immune imbalance,and increased serum IL-1β and TNF-α levels(P<0.01).High-and low-dose XJDHT intervention im-proved survival(P<0.01),reduced MSS(P<0.01),restored immune homeostasis,and dose-dependently suppressed IL-1β and TNF-α(P<0.01).CLP mice showed elevated H3K36me3 in Kupffer cells and severe hepatic inflammation,while XJDHT dose-de-pendently reduced H3K36me3(P<0.05)and attenuated liver injury.In peritoneal macrophages,CLP upregulated H3K36me3,IL-1β,TNF-α,HIF-1α,p-AKT1/AKT1,and EGFR(P<0.01),which were reversed by XJDHT(P<0.05,P<0.01).In vitro,LPS increased H3K36me3 and IL-1β and TNF-α expression(P<0.01),with ChIP-qPCR confirming H3K36me3 enrichment at IL-1β lo-ci(P<0.01).Treatment with 15%XJDHT-containing serum for 24 h reduced H3K36me3(P<0.01),diminished its recruitment to IL-1β loci(P<0.01),and inhibited LPS-induced activation of EGFR,HIF-1α,and p-AKT1/AKT1(P<0.05,P<0.01).HIF-1α agonist Dimethyloxallyl Glycine(DMOG)further validated that XJDHT suppressed H3K36me3-mediated epigenetic remodeling via HIF-1α-related pathways.CONCLUSION XJDHT inhibits inflammatory responses,regulates immune homeostasis,and improves sepsis prognosis,potentially by modulating H3K36me3 epigenetic modifications at IL-1β loci.