Shanghai First People's Hospital

Glycine, a non-essential amino acid, has been linked to improved metabolic health and enhanced insulin secretion, yet its mechanistic role in β-cell function remains poorly defined. Here, we identify a glycine-GLRA1-calmodulin signaling axis that regulates endoplasmic reticulum (ER) calcium homeostasis to support insulin biosynthesis and β-cell survival. Dietary glycine deficiency impairs insulin secretion, reduces islet mass, and worsens glucose intolerance, while overexpression of serine hydroxymethyltransferase 2 (Shmt2), a key glycine biosynthetic enzyme, increases circulating glycine, enhances insulin output, and improves glucose control. Conversely, β-cell-specific deletion of Glra1 phenocopies glycine deficiency, disrupting ER calcium dynamics, amplifying ER stress, and impairing insulin gene expression and secretion. Mechanistically, GLRA1 interacts with calmodulin to sustain ER calcium levels and alleviate ER stress, preserving β-cell viability under metabolic stress. Human genetic and transcriptomic analyses reveal that GLRA1 expression and variants are associated with insulin secretion and glycemic traits, underscoring clinical relevance. These findings establish glycine as a signaling metabolite that activates a receptor-calcium axis to maintain β-cell function, offering a mechanistic rationale for targeting GLRA1 or dietary glycine in diabetes therapy.

Early non-invasive detection is crucial for improving the prognosis of gastric cancer (GC). Dysbiosis in the oral and gastric microbiome is closely associated with GC development, yet its complex nature poses challenges for traditional analytical methods. This study aims to integrate oral and gastric microbial characteristics and employ machine learning algorithms to construct a high-precision GC diagnostic model. We collected saliva, gastric fluid, and gastric mucosa samples from 106 GC patients and 111 healthy controls. Microbiome data were obtained via 16S rRNA sequencing, with analyses conducted on species abundance, diversity and community composition. Algorithms including random forest and support vector machines were employed to identify the most discriminative bacterial genera. Multiple diagnostic models were trained based on these findings and evaluated through ten-fold cross-validation and independent external datasets. Results revealed significant differences in microbial composition between GC patients and healthy individuals. Diagnostic models constructed based on key bacterial genera demonstrated excellent performance: AUC values in the training set reached 0.96, 0.87, and 0.96 for oral, gastric fluid and gastric mucosa classifiers respectively, maintaining robust performance in external validation. Functional prediction revealed dysregulation in the microbiota of GC patients, while correlation analysis further indicated symbiotic relationships among cancer-associated bacterial genera. This study successfully established a GC diagnostic model based on oral and gastric microbial signatures. Its outstanding performance validates the substantial potential of the ‘oral-stomach’ microbial axis in GC auxiliary diagnosis, offering a novel cost-effective strategy for early screening.

BackgroundThe C-reactive protein-triglyceride-glucose index (CTI), a novel biomarker integrating inflammation and insulin resistance, has been linked to cardiovascular disease. However, its association with stroke risk across varying levels of renal function remains unclear.MethodsThis prospective cohort study included 8,808 participants aged ≥ 45 years from the China Health and Retirement Longitudinal Study (CHARLS), covering the period 2011 to 2018. CTI was calculated as 0.412×Ln (CRP [mg/L]) + Ln (TG [mg/dL]×FPG [mg/dL])/2. Multivariable Cox models and restricted cubic splines were employed to assess the association between CTI and incident stroke. We stratified the analysis by estimated glomerular filtration rate (eGFR) and introduced interaction terms between CTI and eGFR levels to evaluate potential effect modification.ResultsThe mean age of the participants was 59.48 (9.41) years, and 4098 (46.5%) were male. During a median follow-up of 7 years, 404 (4.6%) stroke events occurred. In the fully adjusted model, each 1-unit increase in CTI was associated with a 15% higher stroke risk [hazard ratios (HR) = 1.15, 95% confidence interval (CI) = 1.00-1.32]. A significant positive linear dose-response relationship was observed (Poverall <0.001, Pnon−linear= 0.289). Notably, we observed significant interaction between CTI and eGFR levels on stroke risk (P = 0.037). The association was markedly stronger in individuals with mildly reduced renal function (eGFR 60–89 mL/min/1.73 m²), where the highest CTI quartile (Q4) had an HR of 2.73 (95% CI: 1.16–6.40) compared to the Q1. Conversely, no significant associations were observed in participants with preserved (eGFR ≥ 90 mL/min/1.73 m²) or moderately-to-severely reduced renal function (eGFR < 60 mL/min/1.73 m²).ConclusionElevated CTI levels are associated with an increased risk of stroke in middle-aged and older Chinese adults, particularly among individuals with mild renal impairment. By combining inflammatory and metabolic markers, CTI might offer potential clinical value for risk assessment.Supplementary InformationThe online version contains supplementary material available at 10.1186/s12933-026-03135-x.

ABSTRACT Parent–adult children's conflict is a big challenge faced by grandparents during grandparenting, but its impacts on the mental health of the grandparents remain unclear. This study aimed to explore the roles of parent–adult children's conflict on the associations between caregiving burden, social capital and uncertainty stress among older adults involved in grandparenting. We conducted a cross‐sectional survey on 975 older adults engaged in grandparenting in Hangzhou, China. The findings indicated that 24.8% ( n = 242) of the grandparents reported high uncertainty stress, and 6.4% ( n = 63) reported general or profound parent–adult children conflict. Parent–adult children's conflict was significantly correlated with caregiving burden ( r = 0.13, p &lt; 0.05) and social capital (social participation: r = −0.17, p &lt; 0.05; social network: r = −0.12, p &lt; 0.05), strong and independent predictors of uncertainty stress in grandparents ( p &lt; 0.05). Interactive effects analysis indicated that buffering effects of social capital on uncertainty stress may vary with the degrees of caregiving burden and parent–adult children's conflict. Overall, the buffering effects of social capital on uncertainty stress were likely to be more pronounced when parent–adult children's conflict was general, and the caregiving burden was high. Our findings may assist in comprehensively understanding the social determinants of the mental health of grandparents involved in grandparenting.

Ocular surface microbiota (OSM) dysbiosis is associated with dry eye disease (DED), but the underlying mechanisms remain poorly understood. This study investigated the role of lipoteichoic acid (LTA), a Gram-positive bacterial product, in DED pathogenesis. A cross-sectional study was conducted involving 277 participants to analyze OSM composition via 16S rRNA sequencing and quantify tear LTA levels. In vitro experiments using human corneal epithelial cells (HCE-T) and in vivo mouse models were used to explore LTA-induced inflammation. The involvement of Toll-like receptor 2 (TLR2) and platelet-activating factor receptor (PAFR) was assessed using siRNAs and the PAFR antagonist Apafant. Patients with DED showed functional enrichment in LTA synthesis-related pathways in their OSM. Tear LTA levels were significantly elevated in patients with DED and correlated positively with disease risk and clinical severity. Mechanistically, LTA activated p38 MAPK and NF-κB signaling pathways via TLR2 and PAFR, upregulating pro-inflammatory cytokine expression. In mice, topical LTA administration induced corneal epithelial damage, reduced tear secretion, and caused histopathological changes. Treatment with Apafant significantly alleviated LTA-induced corneal inflammation, improved tear secretion, and preserved epithelial integrity. Our findings establish a mechanistic link between OSM-derived LTA and DED. LTA promotes ocular surface inflammation and dysfunction through TLR2 and PAFR signaling, suggesting that targeting microbial products or their receptors, such as PAFR, may offer a novel therapeutic strategy for DED.

To compare the oncologic outcomes of intermediate-risk prostate cancer (FIR-PCa) patients receiving different initial treatment regimens as more FIR-PCa patients are now recommended for non-radical treatment due to the side effects of radical therapy. 8616 FIR prostate cancer patients were retrospectively evaluated using the Surveillance, Epidemiology, and End Results (SEER) database (2010-2015) and reported prostate cancer-specific survival (PCSS) for groups defined by the initial treatment category. Statistical analysis was performed using Pearson's chi-square test, Multivariate Cox proportional hazard regression, and Kaplan-Meier method. Kaplan-Meier curves of PCSS revealed that non-curative treatment provided worse disease control than curative management for FIR-PCa patients (Hazard ratio 5.9061; 95% confidence interval 3.3398-10.4446; p < 0.0001). After adjusting for age at diagnosis, race, T stage, PSA level, and Gleason score, non-curative management was significantly associated with a decrease in PCSS (Adjusted hazard ratio 3.34; 95% CI 1.97-5.67; p = 0.0027). Pending prospective validation, our findings do not support a 'uniform' increment in current utilization practices for non-curative treatment strategies for FIR-PCa.

ABSTRACT Endoscopic sphincterotomy (EST) remains essential for managing biliary obstruction but lacks tools that both restore tissue integrity and continuously monitor sphincter mechanics post‐procedure. This work introduces a catheter‐deployable, magnetically guided Janus hydrogel actuator patch that couples precise biliary sealing with real‐time mechano‐sensing. The bilayer design integrates a hydrophobic PDMS/Fe 3 O 4 top layer for magnetic steering and anti‐adhesion with a hydrophilic PNIPAM bottom layer that swells to conform and adhere to mucosa, enabling secure deployment and anti‐reflux sealing. Mechanical deformations are transduced into resistance changes with fast electrical response (≈79 ms) and recovery (≈85 ms), supporting continuous readout of contraction, dilation and subtle vibrations. In benchtop ducts and ex vivo intestinal models, the patch exhibits directed motion under uniform fields, stable adhesion under sustained flushing and agitation, and repeatable thermo‐/swelling‐driven actuation. Waveform features of relative resistance enable machine‐learning classifiers to discriminate multiple deformation states with high accuracy, providing objective indicators of healing progression. This soft, steerable hydrogel platform addresses an unmet need in post‐EST care by unifying minimally invasive deployment, robust sealing and quantitative biomechanical monitoring, and it offers a generalizable route to personalized management of biliary and other soft‐tissue repairs.

Background and aimsAntibiotic use in early life is increasingly being scrutinized for its potential effects on health, particularly its association with inflammatory bowel disease (IBD). The weaning period is a critical developmental window for maturation of the intestinal barrier, immune system and gut microbiota. However, it remains unknown how administering antibiotics to male mice starting at weaning affects the susceptibility of their future offspring to IBD.MethodsThree-week-old weaned male mice were used to investigate the effects of short-term (1 week) and long-term (6 weeks) administration with ampicillin and cefixime on colitis susceptibility in adulthood and in the subsequent F1 generation. Paternal and F1 offspring were administered dextran sodium sulfate (DSS) to induce colitis. Quantitative real-time polymerase chain reaction, immunoblotting, immunofluorescence staining, and histological examination were used to assess mRNA and protein expression and morphological changes. Full 16S rRNA and miRNA sequencing was used to assess changes in the gut microbiota compositions and the mechanisms of intergenerational transmission of intestinal phenotypes. A dual-luciferase reporter assay was used to decipher the direct regulation of miR-10b-5p and miR-200b-3p on Occludin 3′ UTR.ResultsBoth short- and long-term antibiotic administration during the weaning period significantly alleviated DSS-induced colitis in male paternal mice, with long-term administration conferring a more pronounced protective effect. Interestingly, the protective effect against DSS-induced colitis was observed in LONG_F1 offspring, which was more pronounced in F1 males than in F1 females. Mechanistically, the protective effect was associated with increased expression of Occludin in epithelial cells, which was negatively modulated by miR-10b-5p and miR-200b-3p. This effect was inherited via the sperm. Furthermore, long-term antibiotic administration significantly altered the gut microbiota of paternal males, increasing the abundance of certain beneficial bacteria, such as Lactobacillus gasseri and Parabacteroides merdae, while promoting the enrichment of antibiotic-resistant strains.ConclusionsLong-term antibiotic administration initiated at the weaning stage in male mice improves colitis in adulthood and in their offspring that associates with decreasing miR-10b-5p and miR-200b-3p expression, thus providing a theoretical basis for optimizing the use of antibiotics and prevention of IBD.