Diabetes drives a major burden of kidney failure, cardiovascular disease, and premature mortality, yet current clinical markers incompletely capture individual trajectories of organ decline. Soluble tumor necrosis factor receptors 1 and 2 (sTNFR1/2) have emerged as among the most reproducible circulating predictors of diabetic kidney disease progression, retaining prognostic value after adjustment for estimated glomerular filtration rate (eGFR) and albuminuria across multiple cohorts. Prospective studies in type 2 diabetes also associate higher sTNFR1/2 with incident cardiovascular events and all-cause mortality, supporting a systemic risk phenotype that is not fully explained by baseline kidney measures. Mechanistically, recent work has refined the classical view of tumor necrosis factor (TNF) as a generic inflammatory mediator by identifying proximal checkpoints that govern TNFR1 “injury-biased” outputs, including ubiquitination- and lipidation-dependent control of RIPK1, trafficking-dependent restraint of death-receptor signaling, and cross-pathway phosphorylation that retunes downstream complex assembly. In parallel, advances in therapeutic engineering are shifting the field from non-selective TNF neutralization toward receptor-selective modulation, including TNFR1-selective antagonists, allosteric inhibitors, and shedding strategies designed to reduce injury signaling while preserving TNFR2-linked immunoregulatory and reparative programs. This receptor-resolved framework provides a coherent basis for interpreting why soluble receptors outperform circulating TNF as prognostic biomarkers and for developing mechanism-informed interventions in diabetes.

Cryptococcal meningitis is a fatal complication. Macrophages have been proposed to function as candidate "Trojan horse" cells, transferring Cryptococcus neoformans (C. neoformans) into the brain. The mechanisms of Trojan horses in cryptococcal meningitis are largely elusive. In this study, we performed scRNA-Seq on immune cells infiltrating the brain in a murine model of cryptococcal meningitis. Bioinformatics analysis revealed that phosphodiesterase 4B (PDE4B) is a candidate regulator associated with C. neoformans infected-macrophage. C. neoformans increases the total level of PDE4B in macrophages. However, virulent strains with increased production of melanin paradoxically decreased PDE4B expression in macrophages, implying that PDE4B in macrophages may be negatively associated with C. neoformans invasion. PDE4B inhibition increased Arg1, CXCR4 and CCR7 expression in macrophages, a process regulated by the cAMP/PKA signaling pathway. As expected, PDE4B inhibitors promote the ability of C. neoformans infected-macrophages to cross the blood-brain barrier (BBB) in vitro. Similarly, PDE4B inhibitors or PDE4B knockout increase the fungal burden in the brain, which is, at least partially, rescued by macrophage depletion, and adoptive transfer experiments further support macrophage-mediated fungal delivery to the brain. In contrast, PDE4B activation reduces fungal burden in the brain, including when administered after infection onset. Overall, this study revealed that PDE4B functions as an important regulator of macrophage functional programming during infection and supports a macrophage-mediated dissemination mechanism contributing to brain invasion, and is a potential therapeutic target for cryptococcal meningitis.

BACKGROUND:Isolated small bowel Crohn's disease (ISBCD) is often associated with poorer clinical outcomes. This study aims to summarize the clinical characteristics of patients with ISBCD and to investigate the risk factors for surgical recurrence due to disease recurrence. METHODS:A retrospective study was conducted using a prospective database of Crohn's patients. Patients with ISBCD were screened and divided into stricturing and nonstricturing groups according to the Montreal classification behavior definition. The primary endpoint was reoperation due to postoperative recurrence of Crohn's disease. Other endpoints included intraoperative and postoperative outcomes, as well as clinical characteristics. Multivariable Cox regression analysis was used to assess the independent risk factors for surgical recurrence. RESULTS:From January 2017 to June 2024, totally 234 patients (135 in the stricturing group) were included. After propensity score matching, with 79 patients in each group. During the follow-up period (1-90 months), surgical recurrence rates were significantly higher in the stricturing group (11%) compared to the nonstricturing group (4%) (P = 0.04), this was confirmed in Kaplan-Meier curve with log-rank analysis (P = 0.04). No significant differences were observed in postoperative outcomes between the two groups. Variables with P < 0.1 in univariable analysis (stricturing behavior, smoking history, hypoalbuminemia, escalation, or conversion of biologic during follow-up) were incorporated into the multivariable Cox regression analysis, which demonstrated the stricturing behavior [hazard ratio (HR) 4.010; 95% confidence interval (CI) 1.024-15.704; P = 0.04] and the escalation or conversion of biologic agents (HR 6.453; 95% CI 1.906-21.844; P < 0.01) postoperatively were independent risk factors for surgical recurrence. CONCLUSION:The stricturing phenotype is associate with increased risk of operative surgical recurrence in patients with ISBCD. These patients should have a more active prophylactic strategy for the prevention of recurrence after surgery.

Introduction and Objective: To investigate associations between a composite healthy lifestyle score (CHS) and type 1 diabetes (T1D) incidence, complications, and mortality, exploring gene-environment interactions and mediating pathways. Methods: Multi-cohort study integrating NHANES (cross-sectional), a Chinese case-control study (JSPH), and UK Biobank (prospective). CHS (0-100) included smoking, sleep, diet, and physical activity. Outcomes were T1D incidence, cardiovascular (CVD) and microvascular (MVD) disease, and mortality. Analyses used logistic/Cox regression, mediation, and LASSO for a metabolic signature. A polygenic risk score (PRS) assessed genetic susceptibility. Results: Among 297,400 UKB participants, each 1-SD increase in CHS was associated with lower T1D incidence (HR 0.80, 95% CI 0.73-0.89). Protective associations were consistent in NHANES (OR 0.82, 95% CI 0.70-0.97) and JSPH (OR 0.54, 95% CI 0.37-0.78), with strongest protection at intermediate genetic risk (HR 0.64, 95% CI 0.54-0.76). In T1D patients, healthier lifestyle reduced risks of CVD (HR 0.79, 95% CI 0.70-0.88), MVD (HR 0.83, 95% CI 0.75-0.91), and mortality (HR 0.74, 95% CI 0.68-0.80). Mediation analyses showed protection was mediated through immunometabolic pathways: 17.1% for T1D, 19.9% for CVD, and 21.4% for MVD, supported by a 68-metabolite signature. Conclusion: Adherence to a healthy lifestyle lowers T1D risk and complications, partly via immunometabolic pathways, with effect modification by genetic susceptibility. Disclosure S. Li: None. Y. Chen: None. Y. Gu: None. Funding Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0507400, 2023ZD0507402, 2023ZD0507403)

BACKGROUND AND AIMS:We aimed to explore whether saxagliptin, a dipeptidyl peptidase-IV inhibitor, could ameliorate glucose fluctuations and maintain β-cell function in T1DM. METHODS AND RESULTS:A multicentre, open-label, randomised trial was performed, including 184 T1DM patients from six medical centres. These patients received insulin with or without saxagliptin at 5 mg per day for 24 weeks. The primary endpoint was the change from the baseline value of the MAGE, as measured by a CGMS after 24 weeks. The secondary endpoints included the change from baseline value of islet function during the 3-hour BMTT, HbA1c, and insulin dosage. The exploratory analysis was the influence of SNPs in the incretin-related genes on saxagliptin treatment outcomes. No differences were observed between the two groups in MAGE after treatment for 24 weeks. The change of C-peptidemax levels from baseline to 24 weeks in SAXA group (insulin plus saxagliptin) was higher than in CONT group (insulin only) [p = 0.040]. No difference were observed between the groups in HbA1c, insulin dosage after 24 weeks. In SAXA group, rs10305439, rs10305441 of GLP1R and rs6233 of PCSK1/3 were associated with HbA1c response (p = 0.026, 0.019, and 0.048 respectively); the G allele of rs2143734 of GLP1R were associated with lower change of fasting C-peptide from baseline (p = 0.029) CONCLUSIONS: The saxagliptin did not ameliorate glucose fluctuations; however, it appeared to maintain β-cell function to some extent, and SNPs in the incretin-related gene may indicate responsiveness to DPP-IV inhibitors in T1DM. CLINICALTRIALS:Gov number, NCT02307695.

Background/Objectives: MYC-driven tumors exhibit significant glutamine addiction, but the metabolic adaptation mechanisms enabling their survival under glutamine deprivation remain incompletely understood. Malic enzymes catalyze the oxidative decarboxylation of malate to pyruvate while generating NADPH, linking central carbon metabolism to redox homeostasis. This study investigates whether and how ME1 and ME2 mediate cell adaptation to glutamine starvation and explores their functional division in relation to p53 status. Methods: Using MYC-amplified, p53-mutant (G266E) SF188 glioblastoma cells, we performed siRNA-mediated knockdown, overexpression, and rescue experiments. Cell survival was assessed by trypan blue exclusion and Annexin V/PI staining. ROS levels and NADP+/NADPH ratios were measured by DCFH-DA fluorescence and enzymatic assays. Metabolite tracing was conducted using [U-13C5] glutamine followed by LC-MS. Key findings were validated in additional cell lines including HCT116, U2OS and MDA-MB-231. Results: ME1 and ME2 promote SF188 cell survival under glutamine deprivation, an effect that depends on their catalytic activity but is independent of TCA cycle anaplerosis. ME1 maintains redox balance by generating NADPH, and antioxidant treatment rescues the survival defect caused by ME1 knockdown. In contrast, ME2 does not contribute to redox regulation but stabilizes mutant p53 (G266E) via proteasome inhibition. Both of these pro-survival functions are attenuated upon MYC knockdown, suggesting a dependency on MYC expression. Across all cell lines tested, ME1 and ME2 also promote survival through redox maintenance, although the isoform responsible for antioxidant function differs. Conclusions: ME1 and ME2 support metabolic adaptation to glutamine starvation through distinct, isoform-specific mechanisms that depend on MYC expression and p53 mutation status. These findings suggest malic enzymes as potential therapeutic targets in MYC-driven, p53-mutant tumors.

BackgroundDiabetic foot ulcers (DFUs) represent a severe complication of diabetes, often leading to chronic non-healing wounds and high amputation risk. Lactylation, a recently recognized post-translational modification driven by lactate metabolism, has emerged as a key regulator of immune response and gene expression. However, its role in DFU pathogenesis remains largely unexplored. This study aims to systematically investigate lactylation-related genes and their association with immune dysregulation in DFUs.MethodsTranscriptomic data from three GEO datasets (GSE134431, GSE80178, GSE68183) were integrated and normalized to identify differentially expressed genes (DEGs). A lactylation-related gene set was compiled from published literature. Machine learning approaches, including LASSO regression and Random Forest, were applied to screen for core genes. Immune infiltration profiles were assessed using ssGSEA. Experimental validation was conducted in high-glucose-stimulated macrophages and human DFU tissues via qPCR, Western blot, immunohistochemistry, and immunofluorescence.ResultsWe integrated three transcriptomic datasets comprising 25 DFU and 14 normal tissues, identifying 1,234 differentially expressed genes (DEGs). Among these, 38 overlapped with lactylation-related genes, with 27 significantly downregulated in DFU. Machine learning algorithms identified three core lactylation-associated genes: CHD4, EEF1A1, and EEF1G, which exhibited significant downregulation in DFU and demonstrated high within cohort classification performance with AUC values of 0.860, 0.926, and 0.989, respectively. Immune infiltration analysis revealed these genes positively correlated with natural killer cells and negatively correlated with neutrophil infiltration. Experimental validation in high glucose-treated macrophages and human DFU tissues confirmed their reduced expression at both transcriptional and protein levels, particularly noting marked loss of EEF1A1 in epidermal layers and infiltrating CD68+ macrophages. Direct measurement of lysine lactylation (Kla) confirmed increased global lactylation under diabetic conditions.ConclusionThis study identifies CHD4, EEF1A1, and EEF1G as key lactylation-related genes involved in DFU progression, with significant classificational potential and close links to immune microenvironment dysregulation. These findings highlight lactylation as a promising regulatory mechanism in diabetic wound pathology and support further development of lactylation-targeted biomarkers and therapeutic strategies for DFU management, and require external validation and functional mechanistic studies.

BackgroundType 1 diabetes (T1D) is an autoimmune disease characterized by progressive β-cell destruction, yet current risk stratification tools, which rely mainly on genetic susceptibility and autoantibody profiles, remain insufficient for accurately predicting disease progression. We aimed to characterize macrophage-related inflammatory transcriptional activity in T1D and to develop peripheral blood–based biomarkers for diagnosis and risk stratification.MethodsWe integrated bulk RNA-seq, single-cell RNA-seq, and spatial transcriptomic data from human islets with public and in-house peripheral blood transcriptomic datasets. Macrophage heterogeneity and remodeling trajectories were analyzed in the islet microenvironment, and machine learning was used to derive tissue- and blood-based proinflammatory macrophage-related genes (PMRG). Diagnostic and prognostic models were then constructed and validated in peripheral blood cohorts, including a longitudinal islet autoimmunity (IA) cohort. SHAP analysis was applied to improve model interpretability. Independent PBMC RT-qPCR and mouse pancreatic immunofluorescence were performed to validate selected PMRG-related genes.ResultsT1D islets showed marked immune remodeling with myeloid enrichment and five distinct macrophage subtypes. Pseudotime analysis identified a pro-inflammatory macrophage trajectory and 265 PMRGs, from which a 9-gene islet-derived PMRG (iPMRG) was obtained. Spatial transcriptomics supported the association of iPMRG-high macrophage signals with disrupted β-cell regions, and CellChat analysis inferred altered inflammatory communication programs. In peripheral blood mononuclear cells (PBMCs), the iPMRG-based diagnostic classifier distinguished T1D from healthy controls with an optimism-corrected AUC of 0.736. For prognosis, a 15-gene prognostic PMRGs was used to construct a risk score that, when integrated with clinical variables, predicted progression from IA to clinical T1D with time-dependent AUCs of 0.825, 0.814, and 0.860 at 12, 36, and 60 months, respectively. SHAP analysis identified the PMRG risk score as the dominant predictor and highlighted six core driver genes (PID1, TFPI2, SERPINB2, SOX4, DUSP2, and MT1X). The computational findings were further supported by independent validation in PBMCs and mouse pancreatic tissues.ConclusionsOur study highlights the heterogeneous and dynamic nature of macrophage remodeling in the T1D islet microenvironment, which is translated into accessible peripheral blood signatures. The resulting diagnostic and prognostic models provide an interpretable framework for T1D risk stratification and may support future strategies for earlier detection and precision prevention.

A proportion of patients with new-onset diabetes share similar symptoms with type 1 diabetes (T1D) patients but they are negative for islet antigen-specific autoantibodies. This study was to develop an islet antigen-specific CD8+ T-cell assay to provide autoimmune evidence regarding these “suspected” T1D patients. HLA-A*0201 individuals with autoAbs+ T1D, autoAbs− suspected T1D, and type 2 diabetes, along with HLA-A*0201 healthy controls were recruited. Using interferon-γ enzyme-linked immunospot assays, the percentages of participants in each group with various islet antigen-specific CD8+ T cells were determined. Sixteen out of the 28 islet antigen-specific epitopes tested were T1D specific, meaning that there was a significantly (P < 0.05) greater epitope positivity rate in the autoAbs+ T1D cohort than in the healthy controls. Using a cutoff value of two positive epitopes, the 16-epitope panel led to a sensitivity of 75.0

Diabetes mellitus predisposes patients to severe vascular and organ complications, in part driven by persistent inflammation and oxidative stress. Emerging evidence highlights the ELABELA (ELA)–APJ axis as a multifaceted regulator of diabetes-induced tissue injury and a potential target for preventing diabetic complications. This minireview synthesizes peer-reviewed experimental and clinical studies on ELABELA/APJ signaling in diabetes and related complications, with emphasis on inflammatory/oxidative injury and mechanistic pathways relevant to organ protection. Across diabetic settings, ELABELA shows protective effects against inflammation, oxidative stress, apoptosis, ferroptosis, and pyroptosis, and circulating ELABELA levels have been reported to correlate with complication severity. Mechanistically, reported pathways include NF-κB and NLRP3 inflammasome regulation, antioxidant programs (e.g., Nrf2), mitochondrial redox control (SIRT3–FOXO3a), and APJ-linked AMPK signaling, with evidence spanning kidney and heart complications. Therapeutic development is progressing along three main tracks: ELABELA peptides/analogs, gene-delivery strategies, and small-molecule APJ agonists. Targeting the ELABELA–APJ axis represents a promising, multi-pathway strategy to mitigate diabetes-related organ injury; however, translation will require improved delivery strategies, optimized pharmacodynamics, and rigorous safety/clinical validation.

OBJECTIVES:This study investigated the relationship between serum 25-Hydroxyvitamin D [25(OH)D] levels, vitamin D receptor (VDR) gene polymorphisms, and the prognosis of acute pancreatitis (AP). METHODS:This prospective observation study included patients with AP admitted to the Jinling Hospital between January 2018 and December 2019. Clinical information, laboratory tests, and single-nucleotide polymorphisms (SNPs) of the VDR gene were collected. RESULTS:A total of 508 AP patients were included, with a mean age of 44.81 ± 13.80 years. Among them, 158 (31.10%) cases developed sepsis, 211 (41.54%) cases had serious AP, and 47 (9.25%) patients died before discharge. The multivariate regression analysis showed that VD deficiency was an independent risk factor for the occurrence of sepsis (OR=3.768, 95% CI: 2.368-5.997, P <0.001), progression of AP patients to serious AP (OR=4.297, 95% CI: 2.806-6.582, P <0.001), and in-hospital mortality in AP patients (OR=2.406, 95% CI: 1.162-4.984, P =0.018). SNPs of VDR associated with sepsis, serious AP, or in-hospital death were identified, including rs12721375, rs2853559, rs11168287, rs2853559, and rs11168283 (all P <0.05). The Generalized Multifactor Dimensionality Reduction model analysis revealed that a 4-order model (rs11168283, rs11168287, rs2853559, and 25(OH)D) was the best model for predicting death ( P <0.01). CONCLUSIONS:VD deficiency and VDR genetic polymorphisms are associated with AP prognosis in Chinese Han patients with AP. VDR genetic polymorphism may influence the outcomes of AP patients by affecting the levels of inflammatory cytokines.

CONTEXT:Metabolic dysfunction-associated steatotic liver disease is prevalent in type 2 diabetes (T2D) and exacerbates hyperglycemia, but its impact on postprandial glucagon suppression remains unclear. OBJECTIVE:To investigate the association between hepatic steatosis and impaired glucagon suppression during oral glucose tolerance tests (OGTTs), and to evaluate the mediating role of glucagon dysregulation in linking liver fat to glycemic control. METHODS:In this cross-sectional study, 604 patients with T2D underwent liver fat quantification via the FibroScan Pro controlled attenuation parameter (CAP) and liver ultrasound. Postprandial glucagon suppression was assessed during 180-minute OGTTs (0, 30, 60, 120, 180 minutes), with continuous glucose monitoring (CGM) in 287 participants. Glucagon suppression was calculated for early (0-30 minutes), late (30-180 minutes), and overall (0-180 minutes) phases. Multivariable regression and mediation analyses tested associations between CAP, glucagon dynamics, and CGM-derived glycemic profiles. RESULTS:Patients with T2D with MASLD (CAP ≥238 dB/m, n = 414) exhibited significantly impaired glucagon suppression compared to non-MASLD controls (n = 190) across all phases (all P < .05). Each 1-SD CAP increase independently predicted attenuated dose-dependent suppression in all phases (standardized β = 0.183-0.303, P < .001). Males showed greater suppression impairment than females and stronger CAP-associated dysregulation. Mediation analysis revealed that glucagon suppression mediated 14.9% to 33.9% of the adverse effects of liver fat on hyperglycemia. CONCLUSION:Liver fat accumulation in T2D is strongly associated with defective postprandial glucagon suppression, particularly in males, which mediates nearly one-third of its detrimental impact on glycemic control. Targeting hepatic steatosis and glucagon signaling may offer novel therapeutic strategies for T2D management.

To identify distinct Th-like regulatory T cell (Treg) subsets in the peripheral blood of individuals with type 1 diabetes (T1D) and investigate potential factors that affect Treg polarization within the context of autoimmunity. A total of 49 T1D patients and 20 healthy controls (HCs) were enrolled in this study. Th-like Treg subsets, including Th1-like, Th2-like and Th17-like Tregs, as well as Th cell subsets in peripheral blood were assessed by flow cytometry. Single nucleotide polymorphisms in Treg-related genes were analyzed. The levels of inflammatory cytokines were measured by ELISA. We observed a decreased frequency of Th1-like Tregs in peripheral blood of T1D patients, while the proportion of total Foxp3+ Tregs remained unchanged. Moreover, an imbalance of Th17-like Treg/Th17 cells was noted, characterized by a decreased frequency of Th17-like Tregs and an increased proportion of Th17 cells. Further analysis revealed a correlation between the frequency of Th2-like Tregs and the risk variants of IL-2RA rs3118470. Notably, T1D patients with a normal weight exhibited a higher frequency of Th1-like Tregs compared to their lean and overweight counterparts. However, Treg plasticity was not associated with disease characteristics. Additionally, the serum levels of IL-1β, TNF-α and IL-6 in T1D patients were significantly higher than those in HCs, and the proportions of Th1-like and Th2-like Tregs were negatively associated with IL-6 and TNF-α concentrations in T1D patients, respectively. Nevertheless, the proportions of Th-like Treg subsets in the peripheral blood of HCs exhibited no significant correlation with age, BMI, or the levels of inflammatory cytokines. Our study has provided novel evidence on the altered plasticity and the possible mechanisms underlying the transformation of conventional Tregs towards Th1-like and Th17-like Tregs in the peripheral blood of T1D patients. The findings serve to further augment our understanding of the Treg-mediated immune imbalance that plays a crucial role in the immunopathogenesis of T1D.

To investigate the correlation between serum uric acid (SUA) levels and the risk for diabetic nephropathy (DN) in Chinese patients with type 1 diabetes mellitus (T1DM) and determine the potential optimal SUA threshold. In this case-control study, 913 T1DM patients were matched 1:1 with healthy controls by age and sex. Multivariable adjusted logistic regression analysis was used to investigate the association between SUA levels and the risk of developing DN. Restricted cubic spline (RCS) was applied to investigate the optimal threshold for SUA. Additionally, longitudinal analysis of 94 patients with at least three visits accessed SUA variability correlations with estimated glomerular filtration rate (eGFR) and urinary albumin creatinine ratio (UACR) changes using Spearman’s correlation analysis. A linear mixed-effects model was performed to access the correlations in SUA, eGFR, and UACR over time. T1DM patients exhibited significantly lower median SUA levels (4.24 vs. 4.93 mg/dL, P < 0.001) than controls. The incidence of DN was 12

Airway remodeling is a key characteristic of allergic asthma. Epithelial-mesenchymal transition (EMT) induced by various factors, particularly transforming growth factor (TGF)-(31, orchestrates airway remodeling. Protein phosphatase 2A (PP2A), an important serine-threonine phosphatase, is involved in TGF-(31 production and EMT. Long noncoding RNAs (lncRNAs) have emerged as novel players in regulating EMT. Here, we aimed to explore the effects and mechanisms of action of lincR-PPP2R5C, a lncRNA that affects PP2A activity, on airway remodeling in a mouse model of chronic allergic asthma. LincR-PPP2R5C knockout (KO) alleviated inflammatory responses in house dust mite (HDM)-induced chronic allergic asthma. Moreover, airway remodeling and EMT were reduced in lung tissues of lincRPPP2R5C KO mice. HDM extract induced EMT in airway epithelial cells, which was decreased following lincR-PPP2R5C KO. Mechanistically, lincR-PPP2R5C deficiency enhanced PP2A activity, which inhibited TGF-(31 production in epithelial cells. In conclusion, lincR-PPP2R5C deficiency prevented HDM-induced airway remodeling in mice by reversing EMT, which was mediated by the PP2A/TGF-(31 signaling pathway. Thus, lncRNAs, i.e., lincR-PPP2R5C, may be potential targets to prevent airway remodeling in allergic asthma.

Objective: Genome-wide association studies (GWAS) have identified that 6p22.2 region is associated with type 1 diabetes (T1D) risk in the Chinese Han population. This study aims to reveal associations between this risk region and T1D subgroups and related clinical features, and further identify causal variant(s) and target gene(s) in this region. Methods: 2608 T1D and 4814 healthy controls were recruited from East, Central, and South China. Baseline data and genotyping for rs4320356 were collected. The most likely causal variant and gene were identified by bioinformatics analysis, dual-luciferase reporter assays, expression quantitative trait loci (eQTL), and functional annotation of the non-coding region within the 6p22.2 region. Results: The leading variant rs4320356 in the 6p22.2 region was associated with T1D risk in the Chinese and Europeans. However, this variant was not significantly associated with islet function or autoimmunity. In silico analysis suggested rs9379874 was the most potential causal variant for T1D risk among thymus, spleen, and T cells, overlapping with the enhancer-related histone mark in multiple T cell subsets. Dual luciferase reporter assay and eQTL showed that the T allele of rs9379874 increased BTN3A1 expression by binding to FOXA1. Public single-cell RNA sequencing analysis indicated that BTN3A1 was related to T-cell activation, ATP metabolism, and cytokine metabolism pathways, which might contribute to T1D development. Conclusion: This study indicates that a functional variant rs9379874 regulates BTN3A1 expression, expanding the genomic landscape of T1D risk and offering a potential target for developing novel therapies.

Pre-existing of pulmonary tuberculosis (PTB) poses increased lung cancer risk, yet the molecular mechanisms remain inadequately understood. This study sought to elucidate the potential mechanisms by performing comprehensive analyses of differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) from patients with PTB, lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). Microarray assays were employed to analyze the DEGs in PBMCs of these patients. The analyses revealed that, compared to healthy controls, the number of differentially expressed LncRNA in PBMCs from patients with PTB, LUAD, and LUSC were 801, 8,541, and 7,796, respectively. Similarly, the differentially expressed mRNA in PBMCs from patients with PTB, LUAD, and LUSC were 629, 4,865, and 4,438, respectively. These differentially expressed transcripts represent significant resources for the identifying diagnostic and differential diagnostic biomarkers for lung cancer and PTB. Pathways enriched by dysregulated mRNAs in patients with PTB, LUAD, and LUSC were identified through GO and KEGG pathway analyses. The results indicated that 9 pathways including the NOD-like receptor signaling pathway, pathways in cancer, and the MAPK signaling pathway were co-enriched across the PTB, LUAD, and LUSC groups, providing insights into the mechanisms by which PTB may increase the risk of cancer development and progression.

Immune checkpoint blockade (ICB) has emerged as a promising immunotherapeutic approach for the treatment of various tumors. However, the efficacy of this therapy is limited in a subset of patients, and it is important to develop strategies to enhance immune responses. Studies have demonstrated a critical role of gut microbiota in regulating the therapeutic response to ICB. Gut microbiota composition, diversity, and function are mediated by metabolites, such as short-chain fatty acids and secondary bile acids, that interact with host immune cells through specific receptors. In addition, gut bacteria may translocate to the tumor site and stimulate antitumor immune responses. Therefore, maintaining a healthy gut microbiota composition, for instance through avoiding the use of antibiotics or probiotic interventions, can be an effective approach to optimize ICB therapy. This review summarizes the current understanding of the microbiota-immunity interactions in the context of ICB therapy, and discusses potential clinical implications of these findings.

Context Single positive islet autoantibodies (IAbs), sometimes detected in healthy individuals and patients with low-risk of developing type 1 diabetes (T1D), are considered to be irrelevant to the development of diabetes, making it difficult to diagnose and classify adult-onset diabetes. Objective To determine the significance and clinical value of IAbs in T1D diagnosis in the low-prevalence population, and to explore whether an electrochemiluminescence IAb detection assay can improve the clinical utility of IAbs in the immunodiagnosis of T1D in the low-prevalence population. Methods A total of 633 newly diagnosed patients with adult-onset diabetes (>= 18 years old) were divided into 2 groups according to their clinical phenotypes: 575 patients with age at diagnosis >= 35 years and body mass index (BMI) >= 24 kg/m(2) were considered a low-prevalence population (population with a low prevalence of T1D) and the other 58 patients were considered a high-prevalence population. All the samples from 633 participants were tested with IAbs using standard radiobinding assays (RBAs) and electrochemiluminescence (ECL) assays in parallel. Results Compared with the high-prevalence population, fewer positive IAbs (94/575, 16.3% vs 28/58, 48.3%) were detected in the low-prevalence population, and more of whom (69/94, 73.4% vs 9/28, 32.2%) were positive for a single IAb, with glutamate decarboxylase antibodies being the most prevalent single IAb. Single-IAb detection in the low-prevalence population did not always suggest the T1D phenotype. Combined detection of IAbs by RBA and ECL assay had a significant clinical utility to distinguish autoimmune diabetes in the low-prevalence population with low BMI, poor beta-cell function at the diagnosis, and an accelerated decline in beta-cell function during the follow-up. Conclusion Combined autoantibody detection by RBA and ECL assays improved differentiating autoimmune from nonautoimmune diabetes in the low-prevalence population.

During the pathogenesis of type 1 diabetes (T1D) and type 2 diabetes (T2D), pancreatic islets, especially the β cells, face significant challenges. These insulin-producing cells adopt a regeneration strategy to compensate for the shortage of insulin, but the exact mechanism needs to be defined. High-fat diet (HFD) and streptozotocin (STZ) treatment are well-established models to study islet damage in T2D and T1D respectively. Therefore, we applied these two diabetic mouse models, triggered at different ages, to pursue the cell fate transition of islet β cells. Cre-LoxP systems were used to generate islet cell type-specific (α, β, or δ) green fluorescent protein (GFP)-labeled mice for genetic lineage tracing, thereinto β-cell GFP-labeled mice were tamoxifen induced. Single-cell RNA sequencing (scRNA-seq) was used to investigate the evolutionary trajectories and molecular mechanisms of the GFP-labeled β cells in STZ-treated mice. STZ-induced diabetes caused extensive dedifferentiation of β cells and some of which transdifferentiated into a or δ cells in both youth- and adulthood-initiated mice while this phenomenon was barely observed in HFD models. β cells in HFD mice were expanded via self-replication rather than via transdifferentiation from α or δ cells, in contrast, α or δ cells were induced to transdifferentiate into β cells in STZ-treated mice (both youth- and adulthood-initiated). In addition to the re-dedifferentiation of β cells, it is also highly likely that these "α or δ" cells transdifferentiated from pre-existing β cells could also re-trans-differentiate into insulin-producing β cells and be beneficial to islet recovery. The analysis of ScRNA-seq revealed that several pathways including mitochondrial function, chromatin modification, and remodeling are crucial in the dynamic transition of β cells. Our findings shed light on how islet β cells overcome the deficit of insulin and the molecular mechanism of islet recovery in T1D and T2D pathogenesis.