To compare lower limb joint angle variability between functional ankle instability (FAI) and healthy controls (CONs) at different running speeds using linear and nonlinear methods. Fifteen males with right-side FAI and fifteen matched CONs ran on a treadmill at self-selected, 20% faster, and 20% slower speeds. From 25 gait cycles, the mean coefficient of variation (CV), Sample Entropy (SampEn), and largest Lyapunov Exponent (LyE) of hip, knee, and ankle angles were computed. A two-way (two groups × three speeds) mixed-design ANOVA was applied (α = 0.05). No significant interaction effects were observed. No significant differences were observed in the CV. SampEn showed group effects: FAI had lower values in hip horizontal, knee sagittal/coronal, and ankle coronal planes, but higher in the hip sagittal plane. Speed effects showed greater SampEn in the ankle sagittal and lower in the hip coronal plane at slow speed. LyE was reduced in FAI for hip, knee, and ankle sagittal planes. Speed effects indicated higher LyE in the knee sagittal and lower in the hip coronal plane at slow speed. FAI showed reduced variability, particularly in the sagittal plane, reflecting rigid control. Slower speeds increased ankle and knee sagittal variability but decreased hip coronal variability.

Adenosine-to-inosine RNA editing can affect miRNA activity, but its role in skeletal muscle development remains unclear. Here, we investigated miR-376b-3p in goat skeletal muscle satellite cells (MuSCs), which undergo adenosine deaminase acting on RNA 1-mediated editing at the sixth nucleotide of its seed sequence. Although both isoforms were detected, the unedited miR-376b-3p (miR-WT) predominated over the edited form (miR-E) during skeletal muscle development and MuSC differentiation. Functional assays revealed that miR-WT, but not the miR-E type, enhanced MuSC proliferation and differentiation by upregulating Pax7, PCNA, MyoD, MyoG, and MyHC, and promoting myotube formation. Furthermore, we identified Ring1 and YY1 binding protein (RYBP), a repressor of myogenesis, as a direct target of miR-WT. Overexpression of RYBP inhibited MuSC differentiation, whereas miR-WT relieved this repression through direct binding to the RYBP 3'UTR. In contrast, miR-E failed to target RYBP and lacked promyogenic activity. These findings demonstrate that adenosine-to-inosine editing attenuates the function of miR-376b-3p, highlighting its role as a post-transcriptional regulator of skeletal muscle development.

Pediatric metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly prevalent among children with overweight or obesity, yet its early diagnosis remains a major clinical challenge. This study aimed to identify circulating inflammatory proteins associated with MASLD and to develop a proteomic risk score (ProScore) to improve diagnostic accuracy.

Neuroblastoma tightly linked with genetic abnormality. The core genes responsible for RNA N1-methyladenosine (m1A) modification are critical in tumor development. Nevertheless, few reports revealed the function of m1A modification core gene polymorphisms and the neuroblastoma risk. We carried out this study to verify the association of 12 single-nucleotide polymorphisms (SNPs) with neuroblastoma susceptibility. This study recruited 898 cases with newly diagnosed neuroblastoma and 1734 Healthy controls from eight medical centers. We selected 12 SNPs from m1A modification genes ALKBH1, TRMT6, TRMT61B, and TRMT10C, and genotypes were determined by the TaqMan method. We used univariable and multivariable logistic regression models to analyze the association of SNPs with neuroblastoma risk, followed by stratified analysis. Statistical analysis showed that TRMT6 rs236170 GG (AOR = 1.23, 95% CI = 1.02-1.50, P = 0.034), rs451571 CC (AOR = 1.46, 95% CI = 1.01-2.11, P = 0.043), rs236188 AA (AOR = 2.65, 95% CI = 1.16-6.07, P = 0.021), rs236110 AA (AOR = 1.91, 95% CI = 1.29-2.82, P = 0.001), and ALKBH1 rs6494 AA (AOR = 4.27, 95% CI = 1.31-13.93, P = 0.016), rs176942 GG (AOR = 1.98, 95% CI = 1.35-2.89, P = 0.0005) were neuroblastoma risk variants; the ALKBH1 rs1048147 CC (AOR = 0.80, 95% CI = 0.68-0.94, P = 0.007) was inverse associated with neuroblastoma risk. The eQTL analysis showed that functional annotation of rs6494 T > A may be potential function variants through decreasing ALKBH1 gene expression mRNA, rs451571 T > C, rs236188 G > A, rs236110 C > A are associated with neuroblastoma risk through increasing the expression of its nearby genes RP5-967N21.11 and lowering the expression of MCM8. Our research showed some SNPs in the m1A modification core genes are related to neuroblastoma.Clinical perspectives(i) Few reports have revealed the function of m1A modification core gene polymorphisms in neuroblastoma risk.(ii) After genotyping 12 SNPs with potential functions in four m1A modification core genes in children with neuroblastoma and healthy controls, we found several neuroblastoma predisposition loci, including TRMT6 rs236170, rs451571, rs236188, rs236110, and ALKBH1 rs6494, rs176942, and rs1048147. The eQTL assessment demonstrated that rs6494 T > A may be a potential functional variant by decreasing ALKBH1 mRNA expression.(iii) Our research is the first to reveal m1A modification core gene SNPs and neuroblastoma risk.

Microsatellite instability (MSI) serves as a crucial biomarker for immune checkpoint blockade therapy in colorectal cancer (CRC). However, only around 40% of MSI CRC patients benefit from ICB. Investigating the mechanisms underlying MSI CRC, particularly its association with cell death and the immune microenvironment, can provide insights to improve immunotherapy efficacy.

Chimeric antigen receptor T-cell (CAR T) therapy development represents a promising therapeutic strategy for HER2-positive non-small cell lung cancer (NSCLC), a subtype accounting for 1-5% of NSCLC cases. However, the clinical efficacy of CAR T cells remains limited by poor tumor infiltration. Here, we identify NSCLC-specific overexpression of the CXCL13 and CCL20 chemokines within the tumor microenvironment (TME) and develop a dual chemokine receptor strategy to overcome this barrier.

Growing evidence has revealed that N6-Methyladenosine (m6A) modification is crucial in cancer development, yet its role in hepatocellular carcinoma (HCC) remains unclear. To address this, we developed a novel m6A regulator-based prognostic signature (m6A-RPS) using comprehensive bioinformatics analysis of TCGA, GEO, and ICGC datasets. Our analysis revealed widespread dysregulation of m6A regulators in HCC tissues. Unsupervised consensus clustering further revealed distinct m6A methylation subtypes with significant survival differences, indicating the potential of m6A modification patterns in prognostic stratification for HCC. Using TCGA-LIHC cohort, LASSO Cox regression selected five key hub regulators (VIRMA, YTHDF1, YTHDF2, YTHDC1, IGF2BP3) to construct the m6A-RPS model.​​ This model proved to be a powerful and independent prognostic indicator (HR = 2.849 (1.819-4.461), P < 0.001), and validated in external cohort (ICGC-LIRI-JP). Patients with high m6A-RPS scores exhibited significantly poorer overall survival and progression-free interval, and the scores were positively correlated with adverse clinical characteristics (e.g., advanced stage, vascular invasion). ​ To facilitate clinical translation, we developed a nomogram that integrated the m6A-RPS with key clinical variables for individualized survival prediction.​​ Genomically, the high-risk group exhibited higher tumor mutation burden and mutation rates in hub regulators. Functional enrichment analyses implicated dysregulation in critical pathways like Wnt signaling, DNA replication, and cell cycle. Crucially, m6A-RPS stratified the tumor immune microenvironment: high-risk patients displayed an immunosuppressive phenotype characterized by enriched Th2 cells and higher potential for immune escape, whereas low-risk patients showed enhanced cytotoxic immune infiltration and elevated immunophenoscores, suggesting greater potential responsiveness to immune checkpoint inhibitors. Differential sensitivity to chemotherapy agents was also predicted. Finally, we constructed a regulatory network linking miRNAs, hub regulators, and 2 downstream target genes. Our study establishes m6A-RPS as a robust tool for prognosis prediction and immune landscape assessment in HCC, offering significant potential to guide personalized therapeutic strategies, particularly immunotherapy selection.

Kaposiform haemangioendothelioma (KHE) research faces challenges due to the lack of established cell lines and suitable animal models. Our study aimed to establish KHE cell lines, spheroids and refine murine models to mimic disease characteristics, advancing our understanding of KHE pathogenesis and exploring novel therapies. Primary KHE cells were sorted using CD31 antibodies and cultured into spheroids. These cells were then injected into mice, and the resulting tumours were analysed using immunohistochemistry. Preliminary exploration of the potential mechanisms of sirolimus action on KHE was conducted through transcriptome sequencing. CD31+ KHE cells were isolated and characterised from three out of six patients. The CD31+ KHE cells demonstrated positive expression of essential markers such as CD31, Ki67 and LYVE1, consistent with the profiles observed in KHE tumours. Additionally, subcutaneous tumours displayed similar positive expression of key markers, reminiscent of KHE tumours. Transcriptome sequencing revealed downregulation of ATG9B after sirolimus treatment in CD31+ KHE cells. CD31+ KHE cells can replicate human KHE in murine models, offering a valuable tool for studying pathogenesis. Our findings also suggest a potential mechanism of sirolimus action in treating KHE, warranting further investigation into novel therapeutic strategies.

Peroxisome proliferator-activated receptor α (PPARα) is a crucial transcription factor in regulating brown adipose tissue (BAT) physiological function. However, the mechanisms of enhancer-promoter chromatin interactions that control transcription regulation of Pparα in BAT remain unclear. In this study, we used circularized chromosome conformation capture coupled with next-generation sequencing (4C-seq) to reveal distinct differences in Pparα-associated chromatin interactions between intrascapular BAT (iBAT) and epididymal white adipose tissue (eWAT). In addition, we identified an iBAT-specific active enhancer (Pparα-En4) that was activated by cold stimulation. Functional assays demonstrated that targeted repression of Pparα-En4 region significantly decreased Pparα expression and impaired brown adipocyte differentiation and thermogenesis. Moreover, the transcription factor CREB regulated Pparα-En4 activity and increased Pparα expression in cooperation with the acetyltransferase CBP. Repression of Pparα-En4 using a lentiviral system in iBAT resulted in reduced thermogenic capacity and mitochondrial damage during cold acclimation conditions in vivo. These findings reveal that Pparα-En4 is a critical regulatory element in thermogenesis and mitochondrial function, and provide important insights into enhancer-mediated transcriptional regulation of Pparα expression in BAT.

Consolidative thoracic radiotherapy (RT) following chemo-immunotherapy is increasingly used in extensive-stage small cell lung cancer (ES-SCLC). This study investigates the prognostic value of the estimated radiation dose to immune cells (EDRIC) and its determinants in these patients.

Tuberculosis (TB), resulting from the bacterial pathogen Mycobacterium tuberculosis (Mtb), continues to be a leading cause of death and illness globally. Mtb employs secretory proteins to avoid host immune responses during the infection process and is able to survive, spread and replicate within the hostile micro-environment. Early secreted antigenic target 6 kDa (ESAT-6), the major virulence factor of Mtb, plays an important role in Mtb-induced macrophage apoptosis, which could benefit the dissemination of Mtb. However, the underlying mechanism of ESAT-6 in macrophage apoptosis still unclear.

Messenger RNA (mRNA) vaccines have demonstrated significant potential in cancer immunotherapy by activating both innate and adaptive immunity. However, the detailed cellular and molecular dynamics underpinning these systemic immune responses remain incompletely understood. In this study, we characterized the systemic immune landscape following human papillomavirus (HPV)-targeted mRNA-lipid nanoparticle (LNP) vaccination using single-cell RNA sequencing (scRNA-seq) in a murine model of HPV-positive head and neck squamous cell carcinoma (HNSCC). Our study revealed a coordinated remodeling of the systemic immune landscape, involving the tumor microenvironment (TME), tumor-draining lymph nodes (TDLNs), spleen, and blood. Notably, we pioneered a distinct interferon-stimulated gene (ISG) signature across multiple lymphoid subsets in TDLNs, driven by the LNP component, which contributed to rapid, non-antigen-specific immune activation. Additionally, HPV mRNA-LNP vaccination induced an antigen-specific cycling burst of immune cells that mediated tumor control through a systemic coordination of multi-directional differentiation into anti-tumor cell compositions. These findings enhance our understanding of how mRNA-LNP vaccination orchestrates systemic anti-tumor responses and highlight the therapeutic potential of targeting ISG-expressing and cycling immune cells to improve vaccine efficacy, paving the way for future clinical applications in HPV-related cancers.

Balance is a fundamental quality for trampoline athletes, the basis for completing complex skills. We aimed to compare balance control strategies between elite trampolinists (ETs) and sub-elite trampolinists (Sub-ET) by integrating linear and nonlinear center of pressure (COP) measures across stable and unstable surfaces. Twenty-four male athletes (12 ET, 12 Sub-ET) participated. Each participant performed 15-s static standing trials with eyes closed on a firm surface (FI) and a foam surface (FO). COP parameters were extracted, including ellipse area, sway velocity, sway range, and sample entropy (SampEn) in the medio-lateral (ML) and antero-posterior (AP) directions. Repeated-measures ANOVA was applied to examine the effects of group and surface condition. Linear analyses indicated that ET athletes exhibited greater sway amplitudes and faster velocities than Sub-ET athletes, with both groups showing larger sway on FO compared with FI. Nonlinear analyses revealed that ET athletes demonstrated lower SampEn, suggesting more structured and automatized control strategies. ET athletes maintained consistent entropy across both conditions, reflecting stronger adaptability to unstable surfaces. These results emphasize the importance of combining linear and nonlinear measures in balance assessment and suggest that incorporating unstable or trampoline-like surfaces into training may enhance adaptability, improve performance, and reduce injury risk.

Premature ovarian insufficiency (POI) is a major cause of infertility and endocrine dysfunction, in which chronic inflammation plays a critical role. The homeostasis of tissue-resident macrophages and monocyte-differentiated macrophages from peripheral blood serves as a key mechanism of inflammation across organs, yet their phenotypic plasticity in ovarian pathologies, including POI, remains poorly understood. Here, we identify that SIRT5 deficiency decreases macrophage count by attenuating monocyte-macrophage differentiation. SIRT5 deficiency markedly attenuated follicular depletion and granulosa cell apoptosis, coinciding with reduced M1 macrophage infiltration and cytokine expression in the POI model. Mechanistically, we uncovered RAC2 as a novel succinylation substrate of SIRT5. SIRT5 deficiency elevated RAC2 succinylation, promoting its proteasomal degradation and thereby impairing CSF1R-driven macrophage differentiation and M1 polarization. Pharmacological inhibition of SIRT5 recapitulated these protective effects, preserving follicular integrity and suppressing macrophage-mediated inflammation. Our findings identify the SIRT5-RAC2 axis as a key regulator of ovarian immune homeostasis and establish SIRT5 as a proof-of-concept therapeutic target for POI.

This study aimed to identify the candidate genes of dihydroartemisinin (DHA) in acting against hepatocellular carcinoma (HCC), as well as its association with lipid metabolism-related genes (LMRGs), thereby providing a basis for the application of DHA in anti-HCC therapy.

The objective of this study is to evaluate perioperative fertility-related stress and identify its correlative factors among women of childbearing age undergoing salpingectomy for ectopic pregnancy (EP).

4-Borono-L-phenylalanine (BPA) is a key 10B carrier used in boron neutron capture therapy (BNCT), while its PET tracer analogue, 4-borono-2-18F-fluoro-L-phenylalanine (18F-BPA), enables non-invasive visualization of tumour boron uptake. Since BNCT efficacy depends on precise tumour boron accumulation, we evaluated whether 18F-BPA mirrors BPA's transport and biodistribution. In vitro, BPA exhibited a highly consistent uptake profile with its non-radioactive fluorinated analogue, 2-19F-4-borono-L-phenylalanine (19F-BPA), across nine cancer cell lines (r = 0.9455, P < 0.001) and tri-iodothyronine (T3)-mediated LAT-1 inhibition markedly reduced the uptake of both BPA and 19F-BPA. In vivo, BPA and 18F-BPA showed predominant accumulation in the kidneys and pancreas in Sprague-Dawley rats, with substantially lower levels detected in other organs. Importantly, in tumour-bearing mice, the time-concentration curve of BPA and the time-activity curve of 18F-BPA in tumours were found to be highly consistent, and showed a corresponding relationship between BPA concentration and 18F-BPA activity in terms of accumulation in tumour, blood, and muscle (r = 0.9623, P < 0.0001). Collectively, these findings confirm that BPA and 18F-BPA not only share LAT-1-mediated transport mechanisms, but also exhibit similar pharmacokinetics and tumour-specific accumulation. This substantiates the use of 18F-BPA as a reliable surrogate for visualizing BPA biodistribution and optimizing patient-specific BNCT treatment planning.

Hypertensive nephropathy (HN) is a common complication of hypertension. Clinically, there is an urgent need for new HN treatment strategies. Sijunzitang (SJZT) is widely used in clinical practice, but its therapeutic effects and pharmacological mechanisms in the treatment of HN remain unclear.

Mycoplasma pneumoniae pneumonia (MPP) is a common respiratory infection, yet its molecular mechanisms remain incompletely understood. Long non-coding RNAs (lncRNAs) play critical roles in various diseases, but their regulatory functions in MPP require further investigation. This study aimed to investigate the expression profile and clinical significance of NFYC-AS1 in MPP and analyze its interaction with miR-1323 in modulating cellular functions.

Colorectal cancer (CRC) is a significant public health concern, highlighting the critical need for identifying novel intervention targets for its prevention.