Background/Aims: Cholangiocarcinoma (CCA) is a primary malignant neoplasm with an extremely poor prognosis. While combined chemoradiotherapy has been demonstrated to delay CCA progression to a certain extent, the absence of specific molecular biomarkers or targets significantly hinders the diagnosis and treatment of CCA. Methods: Through cross-analysis of proteomics and ADMA modificationomics, we identified DDX1 overexpressed in CCA with elevated R602-ADMA modifications. HPLC-MS/MS identified PRMT1 as the methyltransferase and USP10 as the deubiquitinating enzyme for DDX1. Immunofluorescence and nuclear-cytoplasmic partitioning experiments confirmed DDX1’s nuclear localization. GO and KEGG analyses clarify the biological functions of DDX1 in response to hypoxia. RNA-seq transcriptomics analyzed key pathways influenced by DDX1. A hydrodynamic in situ CCA mouse model was established to validate the chemopreventive effects of the PRMT1-specific inhibitor GSK715 on CCA development. Results: DDX1 promotes CCA progression both in vivo and in vitro and can be inhibited by GSK715. Mechanistically, PRMT1 mediates ADMA modification at position R602 of DDX1. This modification promotes DDX1 nuclear localization by recruiting USP10 to deubiquitinate DDX1, while simultaneously inhibiting PRMT1 degradation. DDX1 promotes the transcription of PRMT1 and USP10 by binding to the mRNA 3’UTR region, establishing a positive feedback regulatory pathway. This mechanism promotes the occurrence and development of CCA and can serve as a target for the inhibitor GSK715 to suppress CCA progression. Conclusions Our study identified DDX1-R602-ADMA modification as a novel ADMA modification in CCA. It further confirmed its pivotal role in CCA progression. Targeting the USP10-PRMT1-DDX1 axis may represent a significant therapeutic approach for CCA.

Objective:To retrospectively analyze and explore the indications, methods and prognosis of optic nerve decompression (OND) in endoscopic surgery for benign fibro-osseous lesions (FOLs) of the nasal and skull base.Methods:Among 217 cases of craniofacial fibro-osseous lesions from July 2008 to January 2025 who were treated in the Otolaryngology Head and Neck Surgery Department of Beijing Tongren Hospital Affiliated to Capital Medical University, 14 patients (6.45%, 14/217) who underwent endoscopic resection of the lesion and OND under image navigation were included in this study, including 8 males and 6 females, aged from 4 to 28 years old. Among the 14 patients, 8 had fibrous dysplasia, 5 had ossifying fibroma, and 1 had osteoma. Clinical data, imaging data, surgical data and follow-up results were collected. Best corrected visual acuity (BCVA) and other indicators before and after treatment were recorded for analysis. Statistical analysis was conducted using SPSS 26.0 software.Results:Among 14 patients, preoperative visual decline involved 17 eyes (all 8 fibrous dysplasia cases, 2/5 ossifying fibroma cases, and 1 osteoma case). Surgical approaches included: partial resection for fibrous dysplasia (8 cases; bilateral decompression in 5, unilateral in 3); total resection for ossifying fibroma (3 cases; bilateral decompression in 2, unilateral in 1) or partial resection with bilateral decompression (2 cases, including 1 aneurysmal bone cyst); and total resection with unilateral decompression for osteoma (1 case). After the operation, the vision of 10 eyes (58.82%, 10/17) had been improved. Among the 5 eyes with severe visual impairment before the operation (no light perception/light perception/exponential vision), 2 eyes improved (1 eye from no light perception to light perception, and 1 eye from visual perception to exponential vision). Eight cases (10 eyes) of patients with proptosis improved after the operation. The proptosis before and after the operation were (16.60±1.71) mm and (13.60±1.35) mm ( P<0.05). Conclusions:For patients with benign FOLs involving the optic canal at the nasal and skull base who have visual impairment, OND via endoscopic endonasal approach can achieve visual salvage effects. Those with better preoperative residual vision have significant improvement in BCVA, so the operation should be performed as early as possible.

Body weight abnormalities, including overweight, obesity, and underweight, have become a dual public health challenge in Chinese adults: overweight and obesity lead to a variety of chronic complications, while underweight increases the risks of malnutrition, sarcopenia, and organ dysfunction. To systematically address these issues, multidisciplinary experts in endocrinology, sports science, nutrition, and psychiatry from various regions have held multiple weight management seminars. Based on the latest epidemiological data and clinical evidence, they expanded the guideline to include assessment and intervention strategies for underweight, in addition to the core content of obesity management. This guideline outlines the etiological mechanisms, evaluation methods, and multidimensional management strategies for overweight and obesity, covering key areas such as diagnosis and assessment, medical nutrition therapy, exercise prescription, pharmacological intervention, and psychological support. It is intended to provide a scientific and standardized approach to weight management across the adult population, aiming to curb the rising prevalence of obesity, mitigate complications associated with abnormal body weight, and improve nutritional status and overall quality of life.

Objective:To investigate the application of the conjugate gradient (CG) algorithm to treatment plan optimization for intensity-modulated brachytherapy (IMBT).Methods:The general Monte Carlo software TOPAS was utilized to simulate the 192Ir source of IMBT, and the unit dose contribution matrix was calculated. An objective function was established using the weighted least squares method and was solved using the CG algorithm to achieve optimized IMBT treatment plans. The optimization was validated using five clinical cervical cancer cases under modulation width 60°. The dose distributions of IMBT treatment plans under 45°, 60°, 90°, 120°, and 180° modulation widths were compared using the Wilcoxon test to determine the optimal IMBT treatment plan for cervical cancer treatment. Results:The CG algorithm successfully optimized IMBT treatment plans under modulation width 60° for five cases within 22.2 s on average. On the premise of sufficient target dose coverage, the average D2 cm 3 values of the bladder and rectum in IMBT treatment plans were 3.66 and 1.97 Gy, respectively, representing reductions of 0.54 and 0.69 Gy compared to traditional brachytherapy plans. For the five modulation widths, the D90% values of all IMBT treatment plans reached 6 Gy, without statistically significant differences ( P > 0.05). The average D2 cm 3 values of the bladder in IMBT treatment plans were significantly lower than those in the traditional brachytherapy plans( P<0.05), with modulation width 60° associated with the greatest reduction of 0.61 Gy. In contrast, the average D2 cm 3 values of the rectum under 45°, 60°, and 90° modulation widths decreased by 0.63, 0.54, and 0.45 Gy, respectively, compared to traditional plans, with statistically significant differences( P<0.05). Conclusions:The CG method enables rapid achievement of optimized IMBT treatment plans that meet clinical requirements, and modulation width 60° contributes to valid dosimetric optimization. This study can serve as a guide for the clinical implementation of IMBT.

Primary ciliary dyskinesia (PCD) is a genetically heterogeneous disorder characterized by impaired motility of cilia and flagella. Mutations in cilia- and flagella-associated protein 300 ( CFAP300 ) are associated with human PCD and male infertility; however, the underlying pathogenic mechanisms remain poorly understood. In a consanguineous Chinese family, we identified a homozygous CFAP300 loss-of-function variant (c.304delC) in a proband presenting with classical PCD symptoms and severe sperm abnormalities, including dynein arm deficiency and acrosomal malformation, as confirmed by transmission electron microscopy (TEM). Histological analysis revealed multiple morphological abnormalities of the sperm flagella in CFAP300 -mutant individual, whereas immunofluorescence demonstrated markedly reduced CFAP300 expression in the spermatozoa of the proband. Furthermore, tandem mass tag (TMT)-based quantitative proteomics showed that the CFAP300 mutation reduced key spermatogenesis proteins (e.g., sperm flagellar 2 [SPEF2], solute carrier family 25 member 31 [SLC25A31], and A-kinase anchoring protein 3 [AKAP3]) and mitochondrial ATP synthesis factors (e.g., SLC25A31, cation channel sperm-associated 3 [CATSPER3]). It also triggered abnormal increases in autophagy-related proteins and signaling mediator phosphorylation. These molecular alterations are likely to contribute to progressive deterioration of sperm ultrastructure and function. Notably, successful pregnancy was achieved via intracytoplasmic sperm injection (ICSI) using the proband's sperm. Overall, this study expands the known CFAP300 mutational spectrum and offers novel mechanistic insights into its role in spermatogenesis.
Humans ; Male ; Infertility, Male/pathology* ; Acrosome/pathology* ; Sperm Tail/pathology* ; Pedigree ; Spermatozoa ; Adult ; Loss of Function Mutation ; Ciliary Motility Disorders/genetics* ; Spermatogenesis/genetics* ; Female

OBJECTIVES: To investigate the molecular epidemiology of children with phenylketonuria (PKU) in Gansu, China, providing foundational data for intervention strategies. METHODS: A retrospective analysis was conducted on 1 159 PKU families who attended Gansu Provincial Maternity and Child Care Hospital from January 2012 to December 2024. Sanger sequencing, multiplex ligation-dependent probe amplification, whole exome sequencing, and deep intronic variant analysis were used to analyze the PAH gene. RESULTS: For the 1 159 children with PKU, 2 295 variants were identified in 2 318 alleles, resulting in a detection rate of 99.01%. The detection rates were 100% (914/914) in 457 classic PKU families, 99.45% (907/912) in 456 mild PKU families, and 96.34% (474/492) in 246 mild hyperphenylalaninemia families. The 2 295 variants detected comprised 208 distinct mutation types, among which c.728G>A (14.95%, 343/2 295) had the highest frequency, followed by c.611A>G (4.88%, 112/2 295) and c.721C>T (4.79%, 110/2 295). The cumulative frequency of the top 23 hotspot variants reached 70.28% (1 613/2 295), and most variant alleles were detected in exon 7 (29.19%, 670/2 295). CONCLUSIONS Deep intronic variant analysis of the PAH gene can improve the genetic diagnostic rate of PKU. The development of targeted detection kits for PAH hotspot variants may enable precision screening programs and enhance preventive strategies for PKU.
Humans ; Phenylketonurias/epidemiology* ; Female ; Male ; Retrospective Studies ; Phenylalanine Hydroxylase/genetics* ; Mutation ; Child, Preschool ; China/epidemiology* ; Child ; Infant

Idiopathic pulmonary fibrosis (IPF), a chronic interstitial lung disease, is characterized by aberrant wound healing, excessive scarring and the formation of myofibroblastic foci. Although the role of alternative splicing (AS) in the pathogenesis of organ fibrosis has garnered increasing attention, its specific contribution to pulmonary fibrosis remains incompletely understood. In this study, we identified an up-regulation of serine/arginine-rich splicing factor 7 (SRSF7) in lung fibroblasts derived from IPF patients and a bleomycin (BLM)-induced mouse model, and further characterized its functional role in both human fetal lung fibroblasts and mice. We demonstrated that enhanced expression of Srsf7 in mice spontaneously induced alveolar collagen accumulation. Mechanistically, we investigated alternative splicing events and revealed that SRSF7 modulates the alternative splicing of pyruvate kinase (PKM), leading to metabolic dysregulation and fibroblast activation. In vivo studies showed that fibroblast-specific knockout of Srsf7 in conditional knockout mice conferred resistance to bleomycin-induced pulmonary fibrosis. Importantly, through drug screening, we identified lomitapide as a novel modulator of SRSF7, which effectively mitigated experimental pulmonary fibrosis. Collectively, our findings elucidate a molecular pathway by which SRSF7 drives fibroblast metabolic dysregulation and propose a potential therapeutic strategy for pulmonary fibrosis.

BACKGROUND: Gluconeogenesis is a critical metabolic pathway for maintaining glucose homeostasis, and its dysregulation can lead to glycometabolic disorders. This study aimed to identify hub biomarkers of these disorders to provide a theoretical foundation for enhancing diagnosis and treatment. METHODS: Gene expression profiles from liver tissues of three well-characterized gluconeogenesis mouse models were analyzed to identify commonly differentially expressed genes (DEGs). Weighted gene co-expression network analysis (WGCNA), machine learning techniques, and diagnostic tests on transcriptome data from publicly available datasets of type 2 diabetes mellitus (T2DM) patients were employed to assess the clinical relevance of these DEGs. Subsequently, we identified hub biomarkers associated with gluconeogenesis-related glycometabolic disorders, investigated potential correlations with immune cell types, and validated expression using quantitative polymerase chain reaction in the mouse models. RESULTS: Only a few common DEGs were observed in gluconeogenesis-related glycometabolic disorders across different contributing factors. However, these DEGs were consistently associated with cytokine regulation and oxidative stress (OS). Enrichment analysis highlighted significant alterations in terms related to cytokines and OS. Importantly, osteomodulin ( OMD ), apolipoprotein A4 ( APOA4 ), and insulin like growth factor binding protein 6 ( IGFBP6 ) were identified with potential clinical significance in T2DM patients. These genes demonstrated robust diagnostic performance in T2DM cohorts and were positively correlated with resting dendritic cells. CONCLUSIONS Gluconeogenesis-related glycometabolic disorders exhibit considerable heterogeneity, yet changes in cytokine regulation and OS are universally present. OMD , APOA4 , and IGFBP6  may serve as hub biomarkers for gluconeogenesis-related glycometabolic disorders.
Machine Learning ; Humans ; Computational Biology/methods* ; Biomarkers/metabolism* ; Diabetes Mellitus, Type 2/genetics* ; Animals ; Mice ; Gluconeogenesis/physiology* ; Gene Expression Profiling ; Transcriptome/genetics* ; Gene Regulatory Networks/genetics* ; Clinical Relevance

Objective:To explore the intervention effects of the "four-steps tendon resetting and collaterals dredging manipulation" on the symptoms and muscle status of calf muscle group of patients with chronic ankle sprains.Methods:This study was a prospective self-controlled clinical trial. A total of 39 patients with chronic ankle sprains who sought treatment at the basic units from April to September 2023 and Rehabilitation Medicine Center of Characteristic Medical Center of PLA Rocket Force from February to October 2023 were recruited. The "four-steps tendon resetting and collaterals dredging manipulation" was employed for treatment, with two sessions conducted per patient and one session per week. Pain levels were assessed using the Visual Analog Scale (VAS), ankle joint function was evaluated using the Ankle Osteoarthritis Scale and Function Assessment (AOFAS) score, and MyotonPRO digital palpation instrument was used to measure bilateral triceps and peroneal longus muscles and evaluate muscle status.Results:Compared with before treatment, VAS scores decreased ( t values were 5.85, 5.97, respecively, P<0.001) and AOFAS scores increased ( Z values were -4.59, -4.68, respecively, P<0.001). Before the first treatment and after the second treatment, the damping vibration frequency (Freq) of the affected and healthy triceps and peroneal muscles increased ( t values were -3.09,-2.92,-2.97,-2.28, respecively, P<0.05), the muscle stiffness (Stiff) increased ( t values were -3.12, -2.99, -2.88, -2.15, respecively, P<0.05), and the logarithmic attenuation value (Decr) of the damping vibration of the healthy calf triceps muscle decreased ( t=-2.31, P<0.05); Compared before and after the first treatment, the Decr value ( t=-2.51, P<0.05) and Stiff value ( t=-2.05, P<0.05) of the affected fibular longus muscle increased, while the Ferq, Decr, and Stiff values of the healthy calf triceps muscle increased before and after treatment ( t values were -2.92, -2.13, -2.64, respecively, P<0.05); before and after the second treatment, the Freq values of the triceps and peroneal longus muscles on the affected and healthy sides increased ( t values were -4.28, -2.67, -2.69, -2.38, respecively, P<0.05) and Stiff values increased ( t values were -4.24, -3.43, -3.87, -2.33, respecively, P<0.05); there was no statistical significance in Ferq, Decr, and Stiff values between the affected and healthy sides before and after the first and second treatments ( P>0.05). Conclusion:The "four-steps tendon resetting and collaterals dredging manipulation" can improve the symptoms of chronic ankle sprains and significantly change the muscle condition of the affected and healthy sides of the calf. The mechanism may be related to the neuromuscular control mechanism.

To determine the optimal cultivation duration and harvest period for cultivated Notopterygium incisum and promote its industrial development, this study established a characteristic chromatographic profile of cultivated N. incisum and employed chemometrics combined with entropy-weighted grey correlation analysis to assess differences in agronomic traits and quality indicators across different cultivation years and harvest periods. By comparing with reference substances, ten common peaks were identified, including chlorogenic acid, p-coumaric acid, ferulic acid, marmesinin, nodakenin, isochlorogenic acid B, notopterol, phenethyl ferulate, isoimperatorin, and falcarindiol. The similarity between the characteristic chromatographic profiles of N. incisum at different cultivation years and the reference profile was all above 0.932. Principal component analysis(PCA) and orthogonal partial least squares discriminant analysis(OPLS-DA) revealed that the quality of 1-to 3-year-old cultivated N. incisum was highly dispersed and unstable, whereas the quality of 4-year-old cultivated N. incisum remained relatively stable across different harvest periods. This suggests that the accumulation of relevant compounds in the medicinal material had reached a plateau, confirming that the optimal cultivation period for N. incisum is four years. Entropy-weighted grey correlation analysis indicated that the quality of 4-year-old cultivated N. incisum across different harvest periods ranked from highest to lowest as follows: November, December, October, August, July, and September, demonstrating that November is the optimal harvest time. The findings of this study establish the suitable cultivation duration and optimal harvest period for N. incisum, providing a scientific basis for cultivation guidance and quality standardization.
Chromatography, High Pressure Liquid/methods* ; Apiaceae/chemistry* ; Entropy ; Chemometrics/methods* ; Drugs, Chinese Herbal/chemistry* ; Principal Component Analysis ; Quality Control