To assess the predictive value of serum lipoprotein(a) [Lp(a)] for contrast-induced nephropathy in patients with type 2 diabetes mellitus (T2DM). Consecutive T2DM patients who underwent coronary angio Show more
To assess the predictive value of serum lipoprotein(a) [Lp(a)] for contrast-induced nephropathy in patients with type 2 diabetes mellitus (T2DM). Consecutive T2DM patients who underwent coronary angiography (CAG) or percutaneous coronary intervention (PCI) between January 2019 and December 2021 were enrolled. Baseline Lp(a) was measured before the operation. CIN was defined as an increase in serum creatinine of more than 25% or 44 μmol within 72 h of contrast administration. The relationship between Lp(a) and CIN risk was analyzed. A total of 928 T2DM patients were included. CIN developed in 11.1% (103/928) of patients. The Lp(a) level was significantly higher in patients with CIN than in non-CIN patients (311.12 ± 278.66 vs. 254.19 ± 274.56 mg/L, A higher serum Lp(a) level indicates an increased risk of CIN in T2DM patients undergoing CAG or PCI and can serve as an independent predictor of CIN in this population. This study's findings will aid in the clinical prevention and treatment of contrast agent-induced kidney disease. Show less
Enzyme immobilization is critical for enhancing enzyme stability and reusability. Catalytically active inclusion bodies (CatIBs) have emerged as a promising immobilization strategy due to their straig Show more
Enzyme immobilization is critical for enhancing enzyme stability and reusability. Catalytically active inclusion bodies (CatIBs) have emerged as a promising immobilization strategy due to their straightforward production, ease of separation, and high purity. Unlike traditional cross-linked enzyme aggregates (CLEAs) that require a precipitation step, CatIBs form through carrier-free self-aggregation during expression. To overcome the limitations of conventional methods, a novel technique has been developed in this study, focusing on L-phenylserine aldolase (LPA) as the model enzyme. A hybrid tag (HLHLHL) was fused to the N-terminus of LPA to generate 3HL-LPA, which promotes the formation of active inclusion bodies. Based on structural prediction and surface properties, the active aggregation process of 3HL tags through electrostatic interactions and hydrophobic interactions was analyzed. Innovatively, we combined CatIBs and CLEAs technologies to develop novel CatIBs-CLEAs. For comparison, a control was prepared by fusing a hexahistidine tag (HHHHHH) to LPA's N-terminus (6H-LPA) to enhance soluble expression, followed by conventional CLEAs preparation. Results showed that CatIBs-CLEAs achieved an activity recovery of 69.87% after glutaraldehyde crosslinking, significantly higher than the 48.1% for conventional CLEAs. CatIBs-CLEAs also exhibited superior thermal stability across temperatures, high stability between pH 5-9, and retained over 70% activity after seven batch cycles. The integrated CatIBs-CLEAs technology combines the production advantages of CatIBs with the stability benefits of CLEAs, offering a promising strategy for designing efficient, robust industrial biocatalysts with broad application potential. Show less
The international consensus classification or the World Health Organization classifications underrepresented driver alterations enriched in pediatric acute myeloid leukemia (AML). To address this, we Show more
The international consensus classification or the World Health Organization classifications underrepresented driver alterations enriched in pediatric acute myeloid leukemia (AML). To address this, we retrospectively characterized the genomic landscape of 105 pediatric patients with AML of East Asian ancestry using transcriptome and whole-exome sequencing (WES). In addition to the common recurrent fusions such as RUNX1::RUNX1T1 and CBFB::MYH11, we identified rearrangements involving KMT2A, NUP98, GLIS, as well as FLT3 and UBTF tandem duplications. The median somatic mutation rate in AML was 0.97 per megabase, as estimated by WES. Frequently mutated pathways included signaling: 68.6% (72/105), transcription: 37.1% (39/105), epigenetic regulation: 26.7% (28/105), cohesin: 7.6% (8/105), RNA binding: 3.8% (4/105), and protein modification: 5.7% (6/105). When analyzed together, high-risk genetic subtypes including GLISr, UBTF tandem duplications, PICALM::MLLT10, and HOXr were significantly associated with poorer 5 year overall survival (OS) in multivariable analysis (p-value = 0.037). Although FLT3 internal tandem duplications were significantly associated with inferior 5 year OS in univariable analysis, this effect was not significant in multivariable analysis (p-value = 0.382). Patients with RUNX1 mutations had inferior 5 year OS in multivariable analysis (p-value = 0.009). These findings suggest specific genomic alterations that may refine risk stratification and guide future therapeutic protocols in Taiwanese pediatric patients with AML. Show less
Gastric cancer remains a leading cause of cancer mortality worldwide, largely due to its high metastatic potential driven by epithelial-mesenchymal transition (EMT). Here, we identify Deltex E3 ubiqui Show more
Gastric cancer remains a leading cause of cancer mortality worldwide, largely due to its high metastatic potential driven by epithelial-mesenchymal transition (EMT). Here, we identify Deltex E3 ubiquitin ligase 3L (DTX3L) as a previously unrecognized tumor suppressor in gastric cancer. DTX3L expression is markedly reduced in metastatic and mesenchymal-type gastric cancers and positively correlates with favorable patient prognosis. Functional analyses in cell lines, organoids and animal models demonstrate that DTX3L depletion promotes gastric cancer cell migration, invasion, stem-like properties and metastasis, whereas its overexpression exhibits opposite effects. Mechanistically, DTX3L acts as an E3 ubiquitin ligase that directly interacts with and ubiquitinates SNAI1, a master EMT regulator, leading to its GSK-3β dependent proteasomal degradation. Loss of DTX3L stabilizes SNAI1 and enhances EMT and stem-like phenotypes. Moreover, we uncover that TGF-β1-induced miR-135b-5p downregulates DTX3L, forming a regulatory axis that promotes EMT. Collectively, our findings reveal a novel DTX3L-SNAI1 signaling pathway governing EMT and metastasis in gastric cancer, providing mechanistic insight and suggesting DTX3L as a potential prognostic biomarker and therapeutic target. Show less
Improving the patency rate of small-diameter vascular grafts in a pathological environment is the key to achieving their clinical translation and application. The current approach to in vivo implantat Show more
Improving the patency rate of small-diameter vascular grafts in a pathological environment is the key to achieving their clinical translation and application. The current approach to in vivo implantation evaluations of small-diameter vascular grafts is predominantly based on healthy animal models. However, the majority of patients who undergo vascular transplantation are afflicted with vascular diseases, such as hyperlipidaemia or atherosclerosis. In this study, we constructed an ApoE gene knockout atherosclerotic mouse model and investigated the patency and regenerative performance of small-diameter vascular grafts in a diseased environment. We prepared heparinized Poly (ε-caprolactone) (PCL) vascular grafts (PCL-Hep) using electrospinning technology. By taking advantage of the physical adsorption of heparin, rapamycin (RM) was loaded onto the surface of grafts to obtain PCL-Hep-RM vascular grafts, which exhibited exceptional mechanical properties and drug sustained-release characteristics. Subsequently, the PCL-Hep-RM vascular grafts were implanted into the carotid arteries of atherosclerotic mice. The results demonstrated that PCL-Hep-RM significantly enhanced the patency rate and suppressed intimal hyperplasia in comparison with the PCL control group. This study offers novel concepts and methodologies for addressing challenges such as the low long-term patency rate and luminal stenosis of vascular grafts in a diseased environment, thereby promoting the translational medicine research of small-diameter vascular grafts. Show less
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable s Show more
Effective real-time monitoring and tracking of lipid droplets (LDs) are essential for the precise diagnosis of atherosclerotic plaques and the assessment of pathological progression. However, viable strategies for Show less
Glycolysis-derived lactate serves as a substrate for lysine lactylation, an epigenetic modification playing critical transcriptional regulatory roles in inflammatory diseases. Endothelial inflammation Show more
Glycolysis-derived lactate serves as a substrate for lysine lactylation, an epigenetic modification playing critical transcriptional regulatory roles in inflammatory diseases. Endothelial inflammation, characterized by upregulated glycolysis, initiates atherosclerosis, yet the contribution of histone lactylation remains undefined. Although narciclasine exhibits anti-inflammatory and antioxidant properties, its impact on endothelial inflammation in atherosclerosis is unknown. Connectivity Map (CMap) analysis predicted narciclasine as an inhibitor of oscillatory shear stress and TNF-α-induced endothelial inflammation. In vitro, treatment of human umbilical vein endothelial cells (HUVECs) with 20 nM narciclasine significantly suppressed ox-LDL-induced expression of VCAM1, ICAM1, SELE, and CCL2, reduced reactive oxygen species (ROS) production, and inhibited monocyte adhesion and migration. In vivo, administration of narciclasine (0.02 mg/kg) attenuated carotid artery endothelial inflammation and macrophage infiltration, consequently reducing early atherogenesis in partial carotid ligation model in ApoE Show less
To examine the causal association between obesity and osteoarthritis (OA) using an improved definition of obesity, and to identify mediating genes that may link obesity to OA pathogenesis. We analyzed Show more
To examine the causal association between obesity and osteoarthritis (OA) using an improved definition of obesity, and to identify mediating genes that may link obesity to OA pathogenesis. We analyzed data from the U.S. National Health and Nutrition Examination Survey (NHANES, 2011-2018; n = 8981). Obesity was defined using body mass index (BMI ≥ 30 kg/m²) combined with body fat percentage (BFP ≥ 25 % in men and ≥ 32 % in women). Logistic regression and subgroup analyses were conducted to evaluate associations with OA. Genetic correlation between obesity and OA was estimated using linkage disequilibrium score regression (LDSC). Two-sample Mendelian randomization (MR) was applied to assess causal effects using genome-wide association study (GWAS) summary statistics for BFP and OA. Transcriptome-wide association studies (TWAS) and colocalization analyses were performed to identify candidate genes. Mediation MR was conducted to verify their mediating roles. Obesity defined by BMI combined with BFP was significantly associated with OA (OR = 1.421, 95 %CI: 1.048-1.925, P = 0.025), and was independent of age, race, and various comorbidities. MR analysis confirmed a unidirectional causal effect of obesity on OA (IVW OR = 2.349, 95 %CI: 2.012-2.743, P < 0.001), with no reverse causality detected. TWAS and colocalization identified MAPK3, RBM6, and PRMT6 as potential mediators. Mediation MR confirmed significant effects of MAPK3 (β = 0.991, P = 0.015) and RBM6 (β = 2.740, P < 0.001) in the obesity-OA pathway. Obesity exerts a causal effect on OA, partially mediated by the downregulation of MAPK3 and RBM6. These genes represent potential targets for the prevention and treatment of obesity-related OA. Show less
Facial nerve injury (FNI) is a common peripheral neuropathy that severely impairs facial function and quality of life. Qianzheng Powder (QZP) is a traditional Chinese herbal formula used to treat faci Show more
Facial nerve injury (FNI) is a common peripheral neuropathy that severely impairs facial function and quality of life. Qianzheng Powder (QZP) is a traditional Chinese herbal formula used to treat facial paralysis clinically, yet its neuroprotective mechanisms remain unclear. This study aims to evaluate the therapeutic effects of QZP on FNI and potential underlying mechanisms. A FNI model was established in male C57BL/6 mice by performing facial nerve crush surgery. QZP (3.51 g/kg) was administered orally once daily for 14 days post-surgery. Facial function was assessed behaviorally. Tissue samples were collected on day 21 for histological evaluation, qPCR and Western blotting. Liver and kidney safety were also assessed via H&E staining and serum biochemical markers. QZP significantly improved facial motor function from day 7 post-injury. Additionally, QZP treatment mitigated neuronal loss in the facial motor nucleus, attenuated buccinator muscle atrophy, and enhanced myelin regeneration, as evidenced by increased MPZ and MBP expression. These were consistent with the increace of the BDNF, TrkB, and QZP promotes structural and functional recovery of facial nerve following injury, likely through activation of the BDNF/TrkB/CREB axis, and demonstrates a favorable safety profile. These findings support its potential as a therapeutic adjunct in peripheral nerve repair. Show less
This study investigated the relationships between vacant land and key adverse health behaviors, including smoking, insufficient sleep, and no leisure-time physical activity (No LPA), across census tra Show more
This study investigated the relationships between vacant land and key adverse health behaviors, including smoking, insufficient sleep, and no leisure-time physical activity (No LPA), across census tracts in Chicago, Illinois. Using both global regression and geographically weighted regression (GWR), we evaluated whether neighborhood vacant land ratios (VLRs) were associated with the prevalence of these adverse health behaviors and assessed how these associations varied spatially across the city. We found significant spatial clustering in both vacant land and health behavior indicators, and the spatial clustering patterns of neighborhood vacancy and adverse health behaviors were broadly consistent. In global models, higher VLRs were associated with higher prevalence of adverse health behaviors; after accounting for spatially autocorrelated errors, the associations remained robust for smoking and insufficient sleep but were attenuated for No LPA. GWR results further revealed clear spatial non-stationarity, with stronger positive local associations concentrated in low-income neighborhoods on the south and west sides. When overlaid with Healthy Chicago Zones (HCZs), the strong vacancy-behavior associations aligned primarily with the West, Southwest, Near South, and Far South zones, highlighting these HCZs as priority areas where vacancy was most strongly linked to adverse health behaviors. Our findings support theories of neighborhood disorder and spatial inequality, emphasizing that vacant land is a potentially modifiable environmental determinant of health behaviors and calling for tailored interventions that consider local social and economic contexts to improve community health and advance health equity. Show less
We aimed to identify key molecules that can moderately enhance the compensatory capacity of beta cells during obesity. Single-cell RNA-seq was used to profile the RNA expression of islet cells from di Show more
We aimed to identify key molecules that can moderately enhance the compensatory capacity of beta cells during obesity. Single-cell RNA-seq was used to profile the RNA expression of islet cells from diet-induced obese mice and pregnant mice. The gene and protein expression levels of ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) were verified by quantitative PCR and immunofluorescence, respectively. The roles of ENPP2 were investigated using gain-of-function and loss-of-function approaches in Min6 beta cells, global Enpp2-knockout mice and beta cell Enpp2-overexpressing transgenic (Enpp2-Tg) mice. Using single-cell RNA-seq, we demonstrated that proliferation is the primary and common mechanism for compensating for beta cell numbers during both mouse obesity and pregnancy, with proliferation being more pronounced in pregnancy than in obesity. Additionally, many differentially expressed genes were co-regulated in both conditions. Among these, the pro-proliferative phosphodiesterase ENPP2 showed the highest increase in beta cells of pregnant mice and a moderate increase in beta cells of obese mice. Overexpression or knockdown of ENPP2 in Min6 beta cells revealed that ENPP2 promoted beta cell proliferation, inhibited apoptosis and enhanced high-glucose-stimulated insulin secretion. These effects of ENPP2 were further validated in vivo using Enpp2-Tg mice. In Enpp2-knockout mice fed a high-fat diet, the deficiency of ENPP2 resulted in insufficient compensation of beta cells during obesity. The pro-proliferative role of ENPP2 in beta cells was mediated through the lysophosphatidic acid (LPA)-Akt/mammalian target of rapamycin (mTOR) signalling pathway via LPA receptor 2. However, the expression of ENPP2 was reduced in the mouse model of diabetes and in human participants with type 2 diabetes compared with non-diabetic control groups. Furthermore, ENPP2 was co-upregulated by a synergy of oestradiol and progesterone. ENPP2 may serve as a key regulator in beta cell compensation during obesity, and modulating its levels in beta cells could be a potential therapeutic target for mitigating beta cell deterioration in diabetes. Show less
Aniridia, driven by PAX6 mutations, causes aniridia-associated keratopathy (AAK), a progressive condition linked to limbal stem cell deficiency. A major hurdle to developing targeted therapies for AAK Show more
Aniridia, driven by PAX6 mutations, causes aniridia-associated keratopathy (AAK), a progressive condition linked to limbal stem cell deficiency. A major hurdle to developing targeted therapies for AAK is the incomplete understanding of the molecular abnormalities in affected corneas. To address this, we leveraged Pax6± (Pax6 het) mice, a model of AAK, and applied single-cell RNA sequencing (scRNA-seq) to profile the transcriptomic changes at a single-cell resolution. ScRNA-seq of corneal/limbal tissues of wild type (WT) and Pax6 het mice were conducted. Immunostaining was performed to examine the expression of specific markers for stem cells. ScRNA-seq identified a quiescent limbal epithelial stem cell (LESC)-like cell cluster and an early transient amplifying cell (eTAC)-like cluster. An increase in the cell numbers in these two clusters in the Pax6 het mouse corneas was observed. Immunostaining detected a marked increase in markers for these two clusters including Tmem176b, Apoe, and Krt15 in the corneal epithelium of Pax6 het mice, suggesting an increase of these LESC/eTA-like cells into the corneal epithelium. The Pax6 deficiency inhibited the expression of genes involved in cell proliferation in the eTAC-like cluster as well as the expression of genes related to corneal epithelial cell fate and differentiation compared with WT mice. Our single cell transcriptome of the limbus and cornea of Pax6 het mice indicates that AAK may be due to the increase of dysfunctional stem/eTACs with defects in committing to a corneal epithelial cell fate and differentiation. Show less
This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and Show more
This study investigated the impact of This retrospective case-control study involved 628 CAD patients and 628 matched controls without CAD. ApoE genotyping was conducted using PCR-chip technology, and genotype and allele frequencies were compared between groups. Multivariate logistic regression analyzed the link between ApoE polymorphisms and CAD risk in populations at middle and high altitudes. The data revealed significant differences in These findings validated that the Show less
To investigate the connection betweenischemic stroke (IS) patients' risk of dying after being discharged and their residual cholesterol (RC) levels uponadmission. 2021 IS patients between the ages of Show more
To investigate the connection betweenischemic stroke (IS) patients' risk of dying after being discharged and their residual cholesterol (RC) levels uponadmission. 2021 IS patients between the ages of 35 and 80were chosen as the study's subjects, and data on deathendpoints following discharge were gathered. The doseresponse association between the risk of death and the RCat admission was examined using restricted cubic spline(RCS) regression. The hazard ratio (HR) and 95% CI werecalculated via Cox regression to analyse the associationbetween the RC level at admission and the risk of deathafter discharge in patients with IS. According to the RCS model, RC levels were nonlinearly associated with deaths from IS and other causes(P<0.001). With the median RC level as the cutoff value,the subjects were divided into two groups: a low RC group(RC<0.72 mmol/L) and a high RC group (RC≥0.72mmol/L). Compared with those in the high RC group, theage and male ratio in the low RC group were significantlygreater. The fasting blood glucose (GLU), total cholesterol(TC), triglyceride (TG), low-density lipoprotein cholesterol(LDL-C), non-high-density lipoprotein cholesterol (nonHDL-C), apolipoprotein A-1 (ApoA-1), and apolipoproteinB (ApoB) levels, as well as diabetes rates, were lower (P=0.01). Cox regression analysis revealed that withoutadjusting for covariates, the high-level RC group presenteda lower risk of all-cause death than the low-level RC group(HR=0.765, 95% CI: 0.619~0.946, P=0.013) and alower risk of death from IS (HR = 0.638, 95% CI:0.435~0.936, P=0.022). After adjusting for sex, age,smoking status, drinking status, hypertension status, anddiabetes status, the high-level group still had a lower risk ofall-cause death (HR = 760, 95% CI: 0.614~0.941,P=0.012) and a lower risk of death from IS (HR=0.653,95% CI: 0.444-0.961, P=0.031). Male sex (HR=0.753,95% CI: 0.572~0.990, P=0.042). Age ≥65 years (HR=0.598, 95% CI: 0.391~0.916, P=0.018), nonsmokingstatus (HR=0.628, 95% CI: 0.408~0.967, P=0.035),nonalcoholic status (HR=0.656, 95% CI: 0.439~0.979,P=0.039), not complicated with hypertension (HR=0.321, 95% CI: 0.108~0.957, P=0.041), no diabetesmellitus (HR=0.607, 95% CI: 0.389~0.947, P=0.028).Compared with those in the high RC group, the IS patientsin the low RC group had a lower incidence of all-causedeath, IS death and other causes of death and a higher survival rate. An RC<0.72 mmol/L at admission is associated with an increased risk of all-cause death and longterm IS death after discharge. Show less
Carotid atherosclerosis is a significant risk factor for cardiovascular and cerebrovascular diseases. Maintaining plaque stability can prevent plaque rupture and thrombus formation, slow disease progr Show more
Carotid atherosclerosis is a significant risk factor for cardiovascular and cerebrovascular diseases. Maintaining plaque stability can prevent plaque rupture and thrombus formation, slow disease progression, and is critically important for preventing cerebrovascular events (such as stroke, transient ischemic attack (TIA), and similar events). Mechanisms influencing plaque stability are still unclear. In this study, stable plaques (n = 5) and unstable plaques (n = 5) were collected from patients and analyzed using RNA-sequencing. 594 differently expressed genes were found by RNA-seq. Pathways enriched by KEGG analysis of differentially expressed genes included inflammation related pathway, cell adhesion related pathway and TGFβ signaling pathway. Especially, we found AMIGO1 was significantly upregulated in stable plaques. Functional assays including cell adhesion, and inflammation-related factor detection revealed that AMIGO1 significantly promotes endothelial cell adhesion while downregulating inflammatory cytokines (e.g., IL-6, IL-1β, TNF-α) production, thereby mitigating inflammatory responses. Co-immunoprecipitation (Co-IP) experiments further found that AMIGO1 interacts with transforming growth factor beta receptor II (TGFRII), stabilizing TGFRII protein levels and subsequently activating the TGFβ signaling pathway. AMIGO1 overexpression with AAV9 virus tail vein injection markedly stabilized plaques in ApoE Show less
Dilated cardiomyopathy (DCM) is a leading cause of heart failure and the primary indication for heart transplantation. The intricate and poorly elucidated pathogenesis of genetic DCM, coupled with the Show more
Dilated cardiomyopathy (DCM) is a leading cause of heart failure and the primary indication for heart transplantation. The intricate and poorly elucidated pathogenesis of genetic DCM, coupled with the paucity of effective therapeutic options, imposes a substantial burden on both patients and their families. In this study, we identified a novel MYBPC3 mutation (c.194C > T) in a patient diagnosed with DCM and established a patient-specific human induced pluripotent stem cell (hiPSC) model. Cardiomyocytes derived from these patient-specific hiPSCs (hiPSC-CMs) exhibited hallmark features of DCM, including cell enlargement, aberrant distribution of sarcomeric α-actinin, and dysregulated calcium ion homeostasis, as compared to control hiPSC-CMs derived from a healthy individual. RNA sequencing analysis revealed a significant upregulation of CASQ2, which encodes calsequestrin, a protein that binds to Ryanodine receptor 2 (RyR2). Notably, treatment with the RyR2 inhibitor ryanodine effectively restored the abnormal calcium transients observed in DCM-hiPSC-CMs. In summary, our findings provide compelling evidence that the c.194 C > T mutation of MYBPC3 plays a definitive pathogenic role in DCM, and that modulation of the RyR2 receptor may alleviate calcium dysregulation in affected cardiomyocytes. These insights enhance our understanding of the molecular mechanisms underlying DCM and offer a promising therapeutic strategy for patients with calcium ion dysregulation associated with this condition. Show less
The mammalian class III phosphatidylinositol-3-kinase complex (PtdIns3K) forms two biochemically and functionally distinct subcomplexes including the ATG14-containing complex I (PtdIns3K-C1) and the U Show more
The mammalian class III phosphatidylinositol-3-kinase complex (PtdIns3K) forms two biochemically and functionally distinct subcomplexes including the ATG14-containing complex I (PtdIns3K-C1) and the UVRAG-containing complex II (PtdIns3K-C2). Both subcomplexes adopt a V-shaped architecture with a BECN1-ATG14 or UVRAG adaptor arm and a PIK3R4/VPS15-PIK3C3/VPS34 catalytic arm. NRBF2 is a pro-autophagic modulator that specifically associates with PtdIns3K-C1 to enhance its kinase activity and promotes macroautophagy/autophagy. How NRBF2 exerts such a positive effect is not fully understood. Here we report that NRBF2 binds to PIK3R4/VPS15 with moderate affinity through a conserved site on its N-terminal MIT domain. The NRBF2-PIK3R4/VPS15 interaction is incompatible with the UVRAG-containing PtdIns3K-C2 because the C2 domain of UVRAG outcompetes NRBF2 for PIK3R4/VPS15 binding. Our crystal structure of the NRBF2 coiled-coil (CC) domain reveals a symmetric homodimer with multiple hydrophobic pairings at the CC interface, which is in distinct contrast to the asymmetric dimer observed in the yeast ortholog Atg38. Mutations in the CC domain that rendered NRBF2 monomeric led to weakened binding to PIK3R4/VPS15 and only partial rescue of autophagy deficiency in Show less
This study aims to investigate the role of DUSP6 in thyroid cancer metastasis and elucidate its underlying molecular mechanisms. Immunohistochemistry were performed to explore the expression of DUSP6, Show more
This study aims to investigate the role of DUSP6 in thyroid cancer metastasis and elucidate its underlying molecular mechanisms. Immunohistochemistry were performed to explore the expression of DUSP6, IL-8 and PAD4 in papillary thyroid carcinoma (PTC) tissues and adjacent non-cancerous thyroid tissues. Effects of DUSP6 on the proliferation, apoptosis, migration, and invasion of thyroid cancer cell lines TPC-1 and IHH4 were performed through in vitro experiments. A rescue experiment was performed to verified DUSP6 regulated the migration and invasion of thyroid cancer cells TPC-1 and IHH4 through IL-8 and neutrophil extracellular traps (NETs) formation. In addition, in vitro cell experiments were conducted to analyze the regulation of NETs formation by DUSP6 through IL-8. Finally, the effect of sh-DUSP6 on the growth of thyroid cancer tumors in mice were conducted through in vivo experiments. DUSP6 expression was significantly upregulated in PTC tissues. Moreover, the expression of DUSP6 in tumor tissues of TPC patients is positively correlated with the expression of IL-8 and PAD4. Overexpression of DUSP6 promotes the proliferation, migration, and invasion of thyroid cancer cells (TPC-1 and IHH4) while inhibiting apoptosis. Conversely, silencing DUSP6 exerts opposing effects. Knockdown of IL-8 reverses the enhanced migratory and invasive capabilities induced by DUSP6 overexpression in these cell lines. NETs treatment enhances the migration and invasion of TPC-1 and IHH4 cells, whereas the application of sh-DUSP6 or sh-IL-8 counteracts this NETs-mediated promotion. Furthermore, DUSP6 overexpression facilitates NETs formation by upregulating IL-8 expression. In vivo experiments demonstrate that sh-DUSP6 suppresses thyroid cancer tumor growth in mouse models. Conclusion: DUSP6 promotes the metastasis of thyroid cancer by facilitating the formation of neutrophil extracellular traps via IL-8. Show less
Coronary artery calcification (CAC) signifies advanced atherosclerosis and portends increased cardiovascular risk. Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerosis; however, its asso Show more
Coronary artery calcification (CAC) signifies advanced atherosclerosis and portends increased cardiovascular risk. Lipoprotein(a) [Lp(a)] is a causal risk factor for atherosclerosis; however, its association with in vivo lesion morphology and clinical outcomes in patients with symptomatic, advanced CAC remains incompletely characterized. This study aimed to investigate the association between elevated Lp(a) levels and both in vivo lesion morphology and clinical outcomes in this high-risk population. In this retrospective cohort, 292 patients with intravascular ultrasound(IVUS)-confirmed CAC were stratified into elevated (≥50 mg/dL,n = 77) or low (<50 mg/dL,n = 215) Lp(a) groups. The primary endpoint was major adverse cardiovascular events (MACEs). Associations were assessed via multivariable Cox models adjusted for clinical covariates. Patients in the elevated Lp(a) group presented a greater incidence of aortic valve calcification (p < 0.001). IVUS revealed constrictive remodeling with a smaller lumen and vessel dimensions. During a median follow-up of 17.2 months, the elevated Lp(a) cohort had a significantly higher MACE rate (37.7% vs. 15.8%; adjusted hazard ratio [aHR] 2.60, 95% CI 1.55-4.35, p < 0.001). Elevated Lp(a) independently predicted increased risks of ischemic stroke (aHR 7.14) and in-stent restenosis (aHR 2.78). In symptomatic patients with IVUS-confirmed CAC, elevated Lp(a) identifies a high-risk phenotype characterized by constrictive vascular remodeling and a markedly increased risk of MACEs, driven particularly by ischemic stroke and in-stent restenosis. These findings support the integration of routine Lp(a) testing into the risk stratification of patients with severe CAC, thereby identifying a precise high-risk phenotype that warrants intensified monitoring and represents an ideal target for emerging Lp(a)-lowering therapies. Show less
Patients on dialysis often suffer from carnitine deficiency due to reduced intake, reduced synthesis in the kidneys, and clearing through dialysis. Carnitine deficiency may lead to anemia, cardiomyopa Show more
Patients on dialysis often suffer from carnitine deficiency due to reduced intake, reduced synthesis in the kidneys, and clearing through dialysis. Carnitine deficiency may lead to anemia, cardiomyopathy, hypotension, and so on. Several studies have shown that supplementing with L-carnitine can diminish the above symptoms in adult dialysis patients, but whether children can benefit from L-carnitine remains unclear. This study was performed to investigate the effect of L-carnitine in children with kidney failure undergoing dialysis. PubMed, Embase, The Cochrane Library, China National Knowledge Infrastructure (CNKI), WanFang Data, and VIP database were electronically searched from database inception to December 2023. STUDY ELIGIBILITY CRITERIA: We included randomized controlled trials (RCTs), cohort studies, case-control studies, cross-section studies, and case series studies that evaluated the impact of L-carnitine on children. Patients aged less than 18 years with kidney failure undergoing dialysis. STUDY APPRAISAL AND SYNTHESIS METHODS: We assessed the quality of studies using the RoB2 tool recommended by the Cochrane Handbook, the Newcastle-Ottawa Quality Assessment Scale (NOS), the checklist recommended by Agency for Healthcare Research and Quality (AHRQ), and the quality evaluation tool recommended by the National Institutes of Health (NIH). We conducted only descriptive analyses and did not perform meta-analysis due to significant differences in study types and limited data. A total of 194 patients were included in 9 studies, of which 3 were RCT studies; 2 were cohort studies, and 4 were case series studies. Due to limited data, we only conducted descriptive analysis rather than meta-analysis. For children undergoing hemodialysis, cohort study of high-quality showed that L-carnitine significantly improved hemoglobin (Hb) and reduced the required erythropoiesis-stimulating agent (ESA) dose; RCT study of moderate-quality indicated that L-carnitine did not influence serum lipid profiles except for reducing apolipoprotein B (ApoB). Cohort study of moderate-quality showed that L-carnitine improved cardiac function; RCT study of moderate-quality indicated that L-carnitine did not influence albumin, C-reactive protein (CRP), interleukin-6 (IL-6), and quality of life. For children undergoing peritoneal dialysis, only serum lipid profiles were analyzed. RCT and case series studies of moderate-quality indicated that L-carnitine did not influence serum lipid profiles except for reducing ApoB. The number of studies enrolled was limited, and their quality was not high. Our study found that children with kidney failure requiring dialysis could partially benefit from L-carnitine, including increased Hb, decreased ESA requirement, reduced ApoB, and improved cardiac function. Further RCTs of high quality are still needed to clarify this issue. This study provided more comprehensive and credible evidence for clinical use of L-carnitine in children. PROSPERO registration number CRD420250649553. Show less
Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. T Show more
Hepatocellular carcinoma (HCC) exhibits diverse aetiologies and molecular heterogeneity, with a median 5-year overall survival of <70% due to high recurrence rates following curative-intent surgery. This study investigated the complex tumour microenvironment (TME) in HCC and explored interactions between various cell types and their roles in disease recurrence. Using a multi-omics approach on multi-region samples of surgically resected HCC from the PLANet 1.0 cohort (NCT03267641), we performed spatial transcriptomics on 17 tissue samples from four patients and bulk RNA sequencing on 329 sectors from 90 patients. Findings were validated using immunofluorescence and multiplex immunohistochemistry. Our analysis revealed extensive intra- and intertumour gene expression heterogeneity and identified a specific subset of endothelial cells (ECs), INTS6 INTS6 The spatial co-localisation of cell types plays a significant role in the recurrence of hepatocellular carcinoma. In this study, we have pinpointed a particular group of endothelial cells, known as INTS6+ endothelial cells, which are spatially colocalised with tumour cells and enriched in microvascular invasion regions in patients experiencing recurrence. These discoveries highlight novel therapeutic targets that focus on endothelial cell interactions within the tumour microenvironment to prevent recurrence and enhance overall patient survival. Show less
C1q/TNF-related proteins (CTRPs) belong to the adipokine family. Here, we aimed to assess the relation of CTRP4 levels in serum and perivascular adipose tissue (PVAT) with coronary artery disease (CAD Show more
C1q/TNF-related proteins (CTRPs) belong to the adipokine family. Here, we aimed to assess the relation of CTRP4 levels in serum and perivascular adipose tissue (PVAT) with coronary artery disease (CAD), and investigate the effect of CTRP4 on atherosclerosis and the underlying mechanisms. CTRP4 levels were examined in serum and epicardial adipose tissue (a major PVAT) from patients with CAD. Atherosclerotic lesions were analysed in CTRP4 CTRP4 levels were lower in serum and epicardial adipose tissue of patients with CAD compared to non-CAD controls. CTRP4 knockout promoted atherosclerosis in ApoE Decreased CTRP4 levels in serum and epicardial adipose tissue are associated with CAD in patients. CTRP4 deficiency promotes the development of atherosclerosis in ApoE Show less
Longevity and muscle strength are heritable traits, and age-related muscle weakness is a major contributor to disability in older adults. However, the susceptibility genes and shared genetic mechanism Show more
Longevity and muscle strength are heritable traits, and age-related muscle weakness is a major contributor to disability in older adults. However, the susceptibility genes and shared genetic mechanisms underlying lifespan and sarcopenia remain unclear. This study aimed to identify genes associated with longevity and muscle weakness and to characterize their shared genetic architecture. We integrated the largest genome-wide association studies (GWAS) on longevity (age > 90th: n = 11 262 cases; age > 99th: n = 3484 cases) and muscle weakness (European Working Group on Sarcopenia in Older People (EWGSOP): n = 48 596 cases; Foundation for the National Institutes of Health (FNIH): n = 20 335 cases) with Genotype-Tissue Expression (GTEx) v8 multi-tissue expression quantitative trait locus (eQTL) data. Gene-trait associations were evaluated using multi-tissue and single-tissue TWAS, and validated using Multi-marker Analysis of GenoMic Annotation (MAGMA). Mendelian randomization (MR) and colocalization were applied to test causality and shared variants. Cross-trait genetic correlation was estimated with LDSC, and pleiotropic loci were identified by pleiotropy analysis under the composite null hypothesis (PLACO) followed by Functional Mapping and Annotation (FUMA)/MAGMA annotation. Across TWAS approaches, APOC1 and TOMM40 were identified as longevity-associated genes, while DYM and TGFA were susceptibility genes for muscle weakness. In MR analysis, higher expression of APOC1 and TOMM40 increased the odds of longevity (OR > 1, p < 0.05), whereas higher expression of DYM and TGFA reduced the risk of muscle weakness (OR < 1, p < 0.05). Colocalization supported shared causal variants for APOC1 (rs429358, PP.H4 = 0.81) and TOMM40 (rs429358, PP.H4 = 0.85) with longevity (age > 90th survival percentile), and for DYM and TGFA with muscle weakness defined by both EWGSOP and FNIH (PP.H4 > 0.80). A significant negative genetic correlation was observed between longevity and muscle weakness (Rg < 0, p < 0.05). Cross-trait pleiotropy analysis identified several pleiotropic genes (PVRL2, PPP1R9A, SLC39A8 and the TOMM40/APOE/APOC1 gene cluster) that influence both longevity and muscle weakness. We identified susceptibility genes for longevity (APOC1, TOMM40) and muscle weakness (DYM, TGFA) and uncovered shared pleiotropic loci linking aging and muscle decline. These findings improve the understanding of the genetic architecture underlying aging-related phenotypes and provide potential molecular targets for promoting healthy aging and reducing late-life disability. Show less
Hepatotoxicity induced by environmental pollutants can be regulated at the transcriptional, translational, and post-translational levels. However, few studies have investigated the changes in liver ac Show more
Hepatotoxicity induced by environmental pollutants can be regulated at the transcriptional, translational, and post-translational levels. However, few studies have investigated the changes in liver acetylomics caused by pollutant exposure. In the present study, we demonstrated that perfluorooctanoate (PFOA) and its potential alternative, perfluoro-(3,5,7,9-tetraoxadecanoic) acid (PFO4DA), modified the liver acetylation profile in male mice exposed to 10 mg/kg/d PFOA or PFO4DA for 28 days. Relative to the control group, liver proteins in the exposed mice exhibited altered acetylation patterns, with 1508 and 498 differentially acetylated sites identified in the PFOA- and PFO4DA-exposed groups, respectively. These modifications were not confined to lipid metabolism, but also extended to the urea cycle and hyperammonemia. Furthermore, in vitro and in silico experiments revealed that mutation of CPS1-1168K to CPS1-1168R restored enzymatic activity under PFOA/PFO4DA exposure, while mutation to CPS1-1168Kac reduced the adenosine triphosphate (ATP) binding capacity, suggesting that CPS1-1168K may be a key acetylation site for PFOA and PFO4DA disruption of the urea cycle. Additionally, both chemicals exhibited the potential to compete with ATP for the ATP-binding site, which is essential for CPS1 activity. These findings contribute to understanding the mechanisms underlying PFAS toxicity and support the establishment of an adverse outcome pathway framework. Show less
The bioactive peptide setmelanotide is a validated MC4R agonist, yet its clinical utility is constrained by poor aqueous solubility and dose-limiting, off-target hyperpigmentation. To overcome these d Show more
The bioactive peptide setmelanotide is a validated MC4R agonist, yet its clinical utility is constrained by poor aqueous solubility and dose-limiting, off-target hyperpigmentation. To overcome these dual liabilities, we executed a synergistic optimization strategy guided by detailed SAR investigation. This approach unveiled two critical design principles: a C-terminal "cationic imperative", where lysine uniquely conferred a > 20-fold solubility enhancement while retaining potency, and rational manipulation of the core pharmacophore, which imparted >100-fold selectivity over MC1R/MC3R. This synergy yielded the lead compound SC19, which integrates these features into a balanced profile of sub-nanomolar potency (EC₅₀ = 0.12 nM; pEC₅₀ = 9.93), exceptional selectivity, and high aqueous solubility. In a diet-induced obesity model, SC19 demonstrated robust efficacy comparable to setmelanotide in reducing weight gain and improving lipid profiles, affirming its therapeutic potential. This work not only presents a promising lead compound but also validates a synergistic optimization blueprint for concurrently enhancing the pharmacological and drug-like properties of therapeutic peptides. Show less
To evaluate the current status and latent profiles of caregiver self-care contributions for patients with chronic obstructive pulmonary disease (COPD) and examine the associations between demographic Show more
To evaluate the current status and latent profiles of caregiver self-care contributions for patients with chronic obstructive pulmonary disease (COPD) and examine the associations between demographic characteristics, health literacy, confidence in self-care contributions, family intimacy, and profile membership. We recruited 275 dyads of patients with COPD and their family caregivers from five tertiary hospitals between May and November 2022 using convenience sampling. Latent profile analysis (LPA) was used to identify distinct profiles of caregiver self-care contributions. Univariate analysis and multinomial logistic regression were subsequently conducted to examine associations between participant characteristics and profile membership. LPA identified four distinct profiles of caregiver self-care contributions: low-contributing, under-monitored, maintenance-prioritized, and high-contributing. Significant differences were observed across these profiles in terms of patients' symptom severity, exacerbation frequency, number of hospitalizations, caregivers' education levels, caregiving duration, health literacy, confidence in self-management contributions, and family intimacy using univariate analysis. Multinomial logistic regression analysis revealed that caregivers' education levels, caregiving duration, confidence in self-management contributions, and health literacy were significant predictors of profile membership. Caregiver self-care contributions for patients with COPD can be characterized by four distinct profiles, with caregivers' educational level, health literacy, and confidence in self-management identified as key factors associated with profile membership. Show less
This study explores the influence of congruence and incongruence in father-mother co-parenting on adolescent depression, as well as the mediating effect of self-esteem. A total of 1389 adolescents com Show more
This study explores the influence of congruence and incongruence in father-mother co-parenting on adolescent depression, as well as the mediating effect of self-esteem. A total of 1389 adolescents completed questionnaires assessing their levels of depression and self-esteem, while their fathers and mothers correspondingly reported on their own co-parenting behaviors using the Parental Co-parenting Scale in this cross-sectional study. Dates were analyzed using LPA, RSA, and mediation consecutively. The results show that: (1) We identified three distinct co-parenting profiles: positive parental co-parenting, negative parental co-parenting, and mixed parental co-parenting. (2) In cases of congruent parental co-parenting, high positive parental co-parenting was associated with lower adolescent depression, whereas high negative parental co-parenting was linked to higher depression, and the difference manifests in different forms among boys and girls. Girls showed nonlinear changes in depression while boys exhibited linear trends. (3) In cases of incongruence in parental co-parenting, mothers' co-parenting exerted a stronger influence on boys' depression, while girls were not affected by mothers' and fathers' discrepancies. (4) Self-esteem mediated the relationship between parental co-parenting (in)congruence and depression across both genders. This study provides evidence for the mechanism through which parental coparenting influences adolescent depression and offers a basis for future interventions targeting adolescent depression. Show less
Astrocyte-derived extracellular vesicles (ADEVs) have emerged as a novel research tool in the field of central nervous system disorders. However, significant differences in yield and purity exist amon Show more
Astrocyte-derived extracellular vesicles (ADEVs) have emerged as a novel research tool in the field of central nervous system disorders. However, significant differences in yield and purity exist among extracellular vesicles (EVs) isolated by different methods, leading to considerable heterogeneity in clinical study outcomes. Therefore, establishing appropriate normalization strategies to enhance comparability across results is a key prerequisite for their clinical translation. This study included 15 patients with major depressive disorder (MDD) and 15 healthy controls (HCs). ADEVs were isolated from plasma using ultracentrifugation combined with immunoaffinity capture. Subsequently, the levels of brain-derived neurotrophic factor (BDNF), five EV biomarkers (CD9, CD63, CD81, Alix, and TSG101), and particle counts in ADEVs were quantified. In addition, plasma lipoprotein levels were measured. Our results demonstrated a lack of significant correlation between particle counts and the levels of five EV biomarkers in plasma ADEVs, whereas strong correlations were observed among the five biomarkers themselves. Normalization of BDNF levels to CD81 or CD9 revealed a significant decrease in the MDD group, whereas normalization to EV particle counts or other EV biomarkers did not show such differences. Notably, plasma levels of apolipoprotein B (APOB), low-density lipoprotein (LDL), and total cholesterol (TC) significantly interfered with the measurement of particle counts. In summary, under conventional EV isolation and detection conditions, our findings support the use of EV biomarker levels rather than particle counts as a normalization method for quantifying target proteins of ADEVs in plasma. [Image: see text] The online version contains supplementary material available at 10.1186/s12888-026-07796-6. Show less
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive amyloid-β (Aβ) accumulation, neuroinflammation, and oxidative stress. Exosomes derived from human umbili Show more
Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by excessive amyloid-β (Aβ) accumulation, neuroinflammation, and oxidative stress. Exosomes derived from human umbilical cord mesenchymal stem cells (hUC-MSC@Exo) represent promising nanoscale carriers for targeted drug delivery. In this study, Baicalein (Bac), a potent antioxidant and anti-inflammatory flavonoid, was encapsulated into hUC-MSC-derived exosomes (Exo@Bac) to enhance its therapeutic efficacy. The neuroprotective potential of Exo@Bac was evaluated in a rat model of Aβ1-42-induced AD. Rats received intraperitoneal injections of Bac, hUC-MSC@Exo, or Exo@Bac, and cognitive performance was assessed using the passive avoidance test and Morris water maze. Exo@Bac treatment significantly improved memory deficits and elevated brain-derived neurotrophic factor (BDNF) expression compared to controls. Histopathological analyses revealed reduced neuronal damage and apoptosis, alongside decreased Aβ1-42 deposition in Exo@Bac-treated rats. Furthermore, Exo@Bac enhanced antioxidant defense (increased SOD), attenuated pro-inflammatory cytokines (TNF-α, IL-6, IL-1β), and lowered lipid peroxidation (MDA). Mechanistically, Exo@Bac promoted AMPK phosphorylation while suppressing NF-κB p65 signaling, indicating modulation of both oxidative stress and neuroinflammatory pathways. These findings demonstrate that Exo@Bac acts as a nanotherapeutic agent capable of mitigating AD pathology, highlighting its potential as a novel strategy for Alzheimer's disease therapy. Show less
Influenza vaccination coverage among older adults in China is low. We sought to identify latent vaccine-hesitancy profiles and their correlates. This community-based cross-sectional survey from May to Show more
Influenza vaccination coverage among older adults in China is low. We sought to identify latent vaccine-hesitancy profiles and their correlates. This community-based cross-sectional survey from May to July 2025 involved 1773 older adults from various areas in Jiangsu province. Data were collected via Wenjuanxing and included demographics, the Influenza Vaccine Hesitancy Scale, and the vaccine literacy scale. Group differences were examined using chi-square tests and one-way ANOVA; latent profile analysis (LPA) identified vaccine hesitancy subgroups, and multinomial logistic regression estimated correlates of profile membership. Three profiles emerged: Low Hesitancy (23.0%), Moderate Hesitancy (35.0%), and High Hesitancy (42.0%). Rural residence predicted Moderate (OR = 2.030) and High (OR = 2.993) hesitancy. Lower household income and chronic disease were associated with the Moderate Hesitancy profile, whereas male sex was associated with the High Hesitancy profile. Higher interactive (OR = 0.686) and critical (OR = 0.599) vaccine literacy were inversely associated with High hesitancy.Concerns about vaccine quality predicted both Moderate (OR = 1.433) and High (OR = 1.376) groups; knowledge gaps and fear of adverse reactions concentrated in the High group. Older adults show heterogeneous vaccine hesitancy phenotypes. Uptake efforts should move beyond one-size-fits-all messaging toward segmented strategies. These strategies should integrate cost-related measures with literacy-sensitive, trust-oriented communication, prioritizing rural residents, older men, and those with chronic conditions. The reported proportions of hesitancy profiles reflect our sample only and should not be viewed as nationally representative. Show less