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Abstract Kinematic alignment (KA) in the short to medium term clinical outcomes is superior to the mechanical alignment (MA), but whether it will improve patients’ postoperative gait is still controversial. Understanding whether and how KA influences postoperative gait mechanics could provide insights into optimizing alignment philosophy to improve functional outcomes. To investigate the impact of KA versus MA in total knee arthroplasty (TKA) on the operated and contralateral native lower limbs by analyzing plantar pressure distribution during walking gait. This study was designed as a secondary analysis from a randomized controlled trial. Thirty-seven patients were included, nineteen underwent KA-TKA and eighteen underwent MA-TKA, each with a native knee in the contralateral limb. Pressure-sensitive insoles were used to collect plantar pressure distribution of both limbs simultaneously during walking defined as medial-lateral load ratio (MLR). Perioperative characteristics including radiographic metrics (Hip-Knee-Ankle angle (HKA), mechanical lateral distal femoral angle (mLDFA), and mechanical medial proximal tibial angle (mMPTA) and clinical outcomes (Oxford Knee Scores (OKS)) were compared between the two groups pre-operatively and 2-year postoperatively. Significant differences were found in postoperative radiographic metrics, with KA showing better OKS 1 year postoperatively (p = 0.021), lower mean HKA (p = 0.009) and mMPTA (p

Abstract Background Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide, with death rates increasing by approximately 2–3% per year. The high mortality and poor prognosis of HCC are primarily due to inaccurate early diagnosis and lack of monitoring when liver transplantation is not feasible. Fatty acid (FA) metabolism is a critical metabolic pathway that provides energy and signaling factors in cancer, particularly in HCC, and promotes malignancy. Therefore, it is essential to explore specific FA metabolism-related diagnostic and prognostic signatures that can enable the effective early diagnosis and monitoring of HCC. Methods In this study, we used genes associated with FA metabolism pathway and weighted gene co-expression network analysis (WGCNA) to establish a gene co-expression network and identify hub genes related to HCC (disease WGCNA) and FA clusters (cluster WGCNA). A diagnostic model was constructed using data downloaded from the Gene Expression Omnibus database (GSE25097), and a prognostic model was established using The Cancer Genome Atlas cohort, in which Univariate Cox regression analysis, multivariate Cox risk model, and LASSO Cox regression analysis were applied. The immune infiltration of HCC cells was evaluated using CIBERSORT. The function of the key SLC22A1 gene was experimentally verified in vitro and in vivo. Results Twelve overlapping genes (CPEB3, ASPDH, DEPDC7, ETFDH, UGT2B7, GYS2, F11, ANXA10, CYP2C8, GLYATL1, C6, and SLC22A1) from disease and cluster WGCNA were identified as key genes and used in the construction of the diagnostic and prognostic models. The RF model had the highest area under the ROC curve (AUC) of 0.994 was identified as the most effective for distinguishing patients with HCC with different features. The top five important genes (C6, UGT2B7, SLC22A1, F11, and CYP2C8) from the RF model were selected as diagnostic genes for further analysis (ROC curves: AUC value = 0.986, 95% confidence interval [95% CI] = 0.967–0.999). Moreover, a risk score formula consisting of four genes (GYS2, F11, ANXA10 and SLC22A1) was established and its independent prognostic ability was further demonstrated (univariate Cox regression analysis: hazard ratio [HR] = 3.664%, 95% CI = 2.033–6.605, P

Abstract Background Femoral head necrosis is a common orthopedic disease that results in significant physical disability in patients. Early prediction and diagnosis of steroid-induced osteonecrosis of the femoral head (SONFH) are crucial for the prevention and treatment of this condition. Methods In this study, initial CT images and clinical data of patients with SONFH, admitted from January 2019 to December 2022, were collected. Patients were grouped as follows: (1) those diagnosed with SONFH at the initial diagnosis (control group), and (2) those with high-risk factors but no symptoms at first diagnosis, who developed SONFH two years later (experimental group). CT imaging histological features, clinical characteristics, and transcriptome screening for differentially expressed genes, pathway enrichment, and immune infiltration analyses were performed. Results Significant differences were found in triglyceride (TG) levels between the training and validation groups. Age, sex, alkaline phosphatase (ALP), and hemoglobin levels differed between the training and internal validation groups, while HDL and red blood cell counts varied between the training and external validation groups. Univariate analysis showed that age, TG, HDL, and Radiomics scores influenced SONFH, while multivariate analysis revealed TG, HDL, and Radiomics scores were closely related to SONFH. Transcriptomic analysis showed associations with sphingolipid and adipocyte signaling pathways, along with immune cell involvement, linking SONFH to lipid metabolism and atherosclerosis. Conclusions These findings indicate a significant association between steroid-induced osteonecrosis of the femoral head and age, with TG and HDL serving as indicators of lipid metabolism closely correlated with the occurrence of SONFH. Radiomics scores were also found to correlate with SONFH occurrence, supported by transcriptomic and CT imaging findings. However, this study has limitations, including its retrospective design and a relatively limited sample size, which may impact the generalizability of the results. Further prospective studies with larger, more diverse populations are needed to validate and enhance the predictive model.

Abstract The Leshan Giant Buddha’s ushnisha (Head Bun) has suffered from loss of lime plaster, cracks, and biological damage, compromising its structural integrity and reducing the effectiveness of the drainage system in the Buddha's head. The infiltration of moisture has led to water damage within the statue, significantly accelerating its weathering. This situation urgently requires protection and reinforcement measures. Detecting deterioration in the ushnisha is a crucial step in the preservation process. In this study, we utilized two deep learning models for pixel-level semantic segmentation of the damage. Due to the small size of the cracks, a weighted loss function was applied to improve both the training speed of the model and the efficiency of crack identification. This weighting strategy proved effective for both models. The weighted K-Net model achieved a mean accuracy (mAcc) of 90.23% and a mean intersection-over-union (mIoU) of 69.55%, with a damage segmentation speed of 7 images per second, which is 1309 times faster than manual segmentation. By applying the trained deep learning models to re-examine the ushnisha, we successfully identified damage that had been overlooked during manual annotation. Using the model’s enhanced results, we conducted a comprehensive quantification of the damage across all ushnisha and identified the most severely affected areas. Additionally, we performed a model interpretability analysis to explain the decision-making process and principles of the deep learning models. This research provides significant practical value for detecting and quantifying damage in the Leshan Giant Buddha.

Abstract Background Bone fractures are a global public health issue and a major source of significant illness and financial hardship. However, to date, there is limited research on patella, tibia or fibula, or ankle fractures (FPTFA) disease burden. Methods Using the framework of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019, we conducted temporal trends of disease burden, effects of sex and socio-demographic index (SDI) on age standardized prevalence rate (ASPR) and age-period-cohort model. Machine learning models were built to predict the ASPR of FPTFA in 2035. Results In 1990 and 2019, the top three of all fractures with the highest ASPR was FPTFA. Globally, in 2019, there were 13529.45 million (95%UI: 11811.02, 15642.25), 9198.67 million (95%UI: 8518.9, 10009.91) and 77.54 million (95%UI: 34.09, 149.9) prevalent cases of fracture attributable to fall, transport injury and mechanical external force, respectively. The number of fracture prevalence and years lived with disability (YLDs), and ASPR were higher in males than in females. From 1990 to 2019, most of GBD regions showed a downward trend in average annual percent change (AAPC) of ASPR attributable to transport injuries, High-income Asia Pacific had the highest decline (AAPC= -1.81%, 95%CI: -1.89% to -1.74%). However, an upward trend in East Asia was observed (AAPC = 1.60%, 95%CI: 1.48-1.73%). With increasing SDI, the ASPR for FPTFA attributed to the fall and mechanical external force slowly increased and then turned downward, especially in high-income and high-SDI countries. The longitudinal age curve suggested that the attributed rate was increased for the three sites of lower limb fractures. The best predictive models for FPTFA caused by falls, transport injuries and mechanical external force were autoregressive integrated moving average model (ARIMA) (0,2,1), ARIMA (2,0,1) and ARIMA (0,2,2), with R2 of 0.96, 0.78 and 0.94, respectively. By 2035, ASPR for the fall-related FPTFA will continue to rise rapidly, whereas the ASPR of the transport injury-related FPTFA will gradually decrease. Conclusion FPTFA attributed to the falls is the dominant type and the burden and trends of the fall-related FPTFA are substantial. Fall prevention and access to treatment are crucial for reducing FPTFA burden.

Abstract Background Astragalus membranaceus (Fisch.) Bunge is one of the most well-known tonic herbs in traditional Chinese medicine, renowned for its remarkable medicinal value in various clinical contexts. The corresponding chloroplast (cp) and nuclear genomes have since been accordingly sequenced, providing valuable information for breeding and phylogeny studies. However, the mitochondrial genome (mitogenome) of A. membranaceus remains unexplored, which hinders comprehensively understanding the evolution of its genome. Results For this study, we de novo assembled the mitogenome of A. membranaceus (Fisch.) Bunge var. mongholicus (Bunge) P. K. Hsiao using a strategy integrating Illumina and Nanopore sequencing technology and subsequently performed comparative analysis with its close relatives. The mitogenome has a multi-chromosome structure, consisting of two circular chromosomes with a total length of 398,048 bp and an overall GC content of 45.3%. It encodes 54 annotated functional genes, comprising 33 protein-coding genes (PCGs), 18 tRNA genes, and 3 rRNA genes. An investigation of codon usage in the PCGs revealed an obvious preference for codons ending in A or U (T) bases, given their high frequency. RNA editing identified 500 sites in the coding regions of mt PCGs that exhibit a perfect conversion of the base C to U, a process that tends to lead to the conversion of hydrophilic amino acids into hydrophobic amino acids. From the mitogenome analysis, a total of 399 SSRs, 4 tandem repeats, and 77 dispersed repeats were found, indicating that A. membranaceus possesses fewer repeats compared to its close relatives with similarly sized mitogenomes. Selection pressure analysis indicated that most mt PCGs were purifying selection genes, while only five PCGs (ccmB, ccmFc, ccmFn, nad3, and nad9) were positive selection genes. Notably, positive selection emerged as a critical factor in the evolution of ccmB and nad9 in all the pairwise species comparisons, suggesting the extremely critical role of these genes in the evolution of A. membranaceus. Moreover, we inferred that 22 homologous fragments have been transferred from cp to mitochondria (mt), in which 5 cp-derived tRNA genes remain intact in the mitogenome. Further comparative analysis revealed that the syntenic region and mt gene organization are relatively conserved within the provided legumes. The comparison of gene content indicated that the gene composition of Fabaceae mitogenomes differed. Finally, the phylogenetic tree established from analysis is largely congruent with the taxonomic relationships of Fabaceae species and highlights the close relationship between Astragalus and Oxytropis. Conclusions We provide the first report of the assembled and annotated A. membranaceus mitogenome, which enriches the genetic resources available for the Astragalus genus and lays the foundation for comprehensive exploration of this invaluable medicinal plant.

Abstract Tumor-infiltrating lymphocyte (TIL) therapy in adoptive T-cell therapy (ACT) has already caused durable regression in a variety of cancer types due to T-cell persistence, clinical activity, and duration of objective response and safety. TILs are composed of polyclonal effector T-cells specific to heterogenetic tumor antigens, reasonably providing a promising means for tumor therapy. In addition, their expansion in vitro can release them from the suppressive tumor microenvironment. Even though significant advances have been made in the procedure of TIL therapy, from TIL isolation, modification, expansion, and infusion back to the patient to target the tumor, strategy optimization is always ongoing to overcome drawbacks such as a complex process, options for the lineage differentiation status of TILs, and sufficient trafficking of TILs to the tumor. In this review, we summarize the current advances of TIL therapy, raise problem-based optimization strategies, and provide future perspectives on next-generation TIL therapy as a potential avenue for enhancing cell-based immunotherapy.

Abstract Background The current treatment strategies for borderline resectable esophageal squamous cell carcinoma remain controversial. This study aimed to evaluate the efficacy and safety of programmed cell death 1 inhibitors combined with chemotherapy, followed by conversion surgery, for borderline resectable esophageal squamous cell carcinoma. Methods Patients with borderline resectable esophageal squamous cell carcinoma treated with induction immunochemotherapy from January 1, 2020 to July 1, 2023 at our hospital were retrospectively analyzed. The primary study outcome was the R0 resection rate. Secondary study outcomes included progression-free survival (PFS), overall survival (OS), pathological complete remission (pCR) rate, and safety. Results Forty patients with borderline resectable esophageal squamous cell carcinoma were included in the analysis. The R0 resection rate was 23/40 (57.5%); the conversion success rate was 27/40 (67.5%), and the pCR rate was 11/40 (27.5%). The median follow-up was 23.6 months (95% CI, 19.1–28.2). One-year OS and PFS rates were 77.7% and 71.8%, respectively. The incidence rate of Grade 3–4 adverse events was 10%. There was a significant difference in PFS between patients who underwent surgery and those who did not (P = 0.008, HR: 0.144 95%CI: 0.034–0.606). However, the difference in OS was not significant (P = 0.128, HR: 0.299 95%CI: 0.063–1.416). Patients who achieved clinical downstaging after induction therapy had significantly better OS (P = 0.004 h: 0.110 95%CI: 0.025–0.495) and PFS (P = 0.0016, HR: 0.106 95%CI: 0.026–0.426) compared to those who did not. Conclusions Conversion surgery after induction immunochemotherapy is a promising new strategy with a high conversion rate, inspiring R0 resection rate, significant pathological remission rate, and mild toxicity for borderline resectable esophageal squamous cell carcinoma.

Abstract Victims of explosive events frequently suffer from blast lung injuries. Immune system has been implicated in the pathogenesis of this disease. However, systemic immune responses underlying the progression and recovery of injury repair remain poorly understood. Here, we depict the systemic landscape of immune dysregulation during blast lung injury and uncover immune recovery patterns. Single-cell analyses reveal dramatic changes in neutrophils, macrophages, monocytes, dendritic cells, and eosinophils after a gas explosion, along with early involvement of CD4 T, CD8 T, and Th17 cells. We demonstrate that myeloid cells primarily exert functions during the acute phase, while the spleen serves as an alternative source of granulocytes. Granulopoiesis is initiated in the bone marrow at a later stage during blast lung injury recovery, rather than at the acute stage. These findings contribute to a better understanding of the pathogenesis and provide valuable insights for potential immune interventions in blast lung injury.

This paper proposes a novel vibration fatigue testing methodology of thin-walled specimens in the very high cycle fatigue (VHCF) regime, with the lifetime up to 109 cycles. A series of novel thin-walled specimens for the single crystal superalloy DD6 are designed, considering the thickness range from 0.5 to 1.5 mm. And the influences of the wall thickness on the S–N relations are obtained at RT and 760 °C, respectively. Subsequently, the thickness debit effect of the superalloy in terms of VHCF is presented and the relevant mechanism is discussed finally. The results show the proposed fatigue testing methodology is feasible and efficient for the thin-walled specimens. It is revealed the thickness debit effect of the superalloy at 760 °C, which shows the fatigue strengths of the 0.5 mm specimens are remarkably lower than those of other thicker specimens, especially in the VHCF regime. The thickness debit effect is mainly attributed to the fatigue crack initiation assisted by oxide penetration.

Nanocellulose (CNF) was obtained from carrots using a combination of chemical treatment, mechanical milling, and ultrasonic treatment. Ultrafast preparation of maleic anhydride esterified nanocellulose was achieved by a hydrated hydrogen ion-driven dissociation, chemical cross-linking strategy based on a “one-pot” reaction method. Esterification modification with maleic anhydride reduced the crystallinity of nanocellulose and enhanced its thermal stability. High-strength drug-carrying hydrogels (MACNF/SA) with different drug loading capacities were prepared using cefixime (CFX) as a drug model and maleic anhydride esterified nanocellulose (MACNF) and sodium alginate (SA) as the main raw materials. The compressive strength of MACNF/SA hydrogels made from MACNF reached a maximum of 80.3 kPa when the mass ratio of CNF to MA was 2.5:12. Rheological property tests showed that the MACNF/SA hydrogels were pseudoplastic fluids with shear thinning. The drug release from the drug-carrying hydrogels followed non-Fickian diffusion.

Abstract Background Chronic obstructive pulmonary disease (COPD) is a prevalent chronic disorder in China, impacting a significant proportion of individuals aged > 40 years. In China, the prevalence of and risk factors for COPD among non-smokers remain largely unexplored. In this study, we aimed to determine the prevalence of COPD in non-smokers within the Chinese population and identify potential risk factors associated with COPD in non-smokers. Methods Web of Science, PubMed, Embase, Chinese WanFang, Chinese China National Knowledge Infrastructure, and Weipu databases from inception to August 5, 2024, were searched. Studies reporting the percentage of never-smokers among those diagnosed with COPD and investigations exploring the risk factors associated with COPD in never-smokers in China were examined. Summary proportions and odds ratios (OR), along with their corresponding 95% confidence intervals (95% CI), were measured. Results In total, 112 investigations with 491,812 participants were included. The percentage of never-smokers in people with COPD was 41.1% (95% CI: 37.5–44.6%). The prevalence of never-smokers among males diagnosed with COPD was 22.3% (95% CI: 18.8–25.7%), which differed from that among women (81.3%, 95% CI: 75.3–87.2%). The results showed an association between the utilization of biomass fuel and the occurrence of COPD in never-smokers (OR: 1.25, 95% CI: 1.06–1.44). Among never-smokers, the data showed a close association between being underweight (OR: 1.89, 95% CI: 1.78–2.00), tuberculosis history (OR: 1.71, 95% CI: 1.53–1.88) and COPD. Never-smokers living in rural areas or those with low educational status were more susceptible to COPD. Conclusion This review confirmed the highly different proportions of never-smokers among male and female patients with COPD. Trial registration PROSPERO: CRD42023420786.

Theoretical research on betavoltaic batteries require calculating characteristic parameters of the radiation-voltage conversion device，in order to predict the output characteristics under irradiation. Through the calculated output characteristics，important theoretical references for the design of betavoltaic batteries are provided. Our algorithm calculates the characteristic parameters of the radiation-voltage conversion device based on the tested dark current-voltage curve and evaluates the quality of the characteristic parameters by statistical methods. To prove the effectiveness of the algorithm，the current-voltage curves under irradiation were predicted，and compared with those obtained by exposing to a real radioactive source. Calculation results achieved good results in both curve fitting and output characteristic prediction of the radiation-voltage conversion device. The results show our algorithm can predict the output of betavoltaic battery through the dark current-voltage curve without irradiation and provide guidance for the design of batavoltaic batteries.

Abstract Stress grading systems using non‐linear resistive coatings are a key component to suppress surface corona in the end‐windings of rotating machine. Compared to a sinusoidal‐fed motor, the high slew rate of the voltage at the flanks of the repetitive square voltages from the inverter cause large capacitive currents to flow in the main wall insulation. These large currents, if not properly considered in the design phase, lead to severe electrothermal stress of the grading system. Experiments and simulations were conducted on a stress grading system whose structure arises from limitation posed by the motor structure. Measurements performed with different rise times show that the maximum potential along the conductive armour tape (CAT) increases non‐linearly with increasing axial distance, and the potential at the edge of the CAT reached nearly twice the peak‐to‐peak voltage at 500 ns rise time, leading to corona inception. As metal plates are used in the machine to dampen vibrations in the end‐winding, similar plates were also fastened to the stress grading system, worsening the already inadequate corona suppression performance. The stress grading system was therefore modified, avoiding the surface corona while, at the same time, reducing the temperature in the grading system to acceptable levels.

Abstract In this work, four mainstream machine learning (ML) techniques are used to evaluate the bulk porosity and static elastic modulus of weathered Yungang Grottoes sandstone. Datasets are gathered from the experiments, which includes 432 groups effective experimental data including 8 inputs features. bulk porosity and static elastic modulus were considered as outputs to determine the weathering degrees of Yungang Grottoes sandstone. The 4 performance criteria were used to evaluate the ML models. Results demonstrate that the Artificial Neural Network (ANN) is the best-fitted models for estimating the bulk porosity and static elastic modulus compared to Multiple Linear Regression (MLR), Support Vector Regression (SVR), Gaussian Process Regression (GPR). The accuracy of the trained model for static elastic modulus is slightly higher than that of bulk porosity. The GPR and ANN model can accurately predict the bulk porosity and static elastic modulus in training stages. The ANN with multi-hidden layers developed is competent with high degree of precision and generalization ability for bulk porosity and static elastic modulus compared to other selected regression-based ML models (MLR, SVR, and GPR). The coefficient of determinations of ANN in the range of (0.9537–0.9641) during the testing stages is more stable and higher than that of (0.8883–0.9453) other built ML models. The prediction efficiency of pretrained ANN model was well adjusted for the actual and forecast datasets at the training and testing stages, and the error range was no more than 0.7% and 0.15 GPa at both stages of prediction for bulk porosity and static elastic modulus respectively. And the ANN based static elastic modulus prediction model’s error proportions significantly decreased and were confined to a modest range between + 10% and − 10%. The proposed surrogate models are valid for the bulk porosity ranging from 7 to 14% and the static elastic modulus ranging from 0.7 to 1.4 Gpa, which can be utilized for the accurate and fast prediction of the weathering degrees of Yungang Grottoes sandstone.

Abstract Background Physical activity and sleep are established modifiable lifestyle factors, but the optimal time of the day of these behaviours for health is unknown. This study examined the independent and joint associations of diurnal patterns of physical activity and sleep with all-cause mortality. Methods This prospective cohort study included 6,673 participants who have attended the accelerometer assessment in the 2011–2014 National Health and Nutrition Examination Surveys (NHANES). Diurnal patterns of accelerometer-measured physical activity and sleep were identified using K-means clustering analysis. All-cause mortality was ascertained from the accelerometer measurement to December 31, 2019 (median follow-up 6.8 years). Survey-weighted Cox proportional hazard models were performed to estimate the independent and joint associations of diurnal patterns of physical activity and sleep with all-cause mortality. Results Diurnal patterns identified were: early-morning (32.4%), midday (42.5%), and late-afternoon (25.1%) for physical activity; and irregular sleep (37.4%), morning lark (33.6%), and night owl (29.0%) for sleep. After adjusting for volume of physical activity, sleep duration and other potential covariates, the early-morning physical activity pattern (hazard ratio 1.36, 95% confidence interval 1.13–1.64) and irregular sleep pattern (1.42, 1.01–1.99) were independently associated with higher risk of all-cause mortality, compared with midday physical activity and morning lark sleep patterns, respectively. In addition, participants with the combined pattern of early-morning physical activity and irregular sleep had higher risk of all-cause mortality compared to those with midday physical activity combined with a morning lark sleep pattern (1.92, 1.33–2.78). Several sociodemographic differences were observed in the strength of these associations. Conclusions Wearable activity-rest monitoring data showed that peak physical activity in the early morning and irregular sleep diurnal patterns are associated with increased mortality risk, and the combination of these patterns further exaggerated the risk. Public health program should acknowledge that the diurnal patterns of physical activity and sleep, in addition to their duration and frequency, may play a crucial role in lifestyle-based health promotion and management strategies.

Abstract The Rho GTPase signaling pathway is responsible for cell-specific processes, including actin cytoskeleton organization, cell motility, cell division, and the transcription of specific genes. The implications of RhoA and the downstream effector ROCK2 in cancer epithelial-mesenchymal transition, migration, invasion, and therapy resistance associated with stem cells highlight the potential of targeting RhoA/ROCK2 signaling in therapy. Tumor relapse can occur due to cancer cells that do not fully respond to adjuvant chemoradiotherapy, targeted therapy, or immunotherapy. Rho signaling-mediated mitotic defects and cytokinesis failure lead to asymmetric cell division, allowing cells to form polyploids to escape cytotoxicity and promote tumor recurrence and metastasis. In this review, we elucidate the significance of RhoA/ROCK2 in the mechanisms of cancer progression and summarize their inhibitors that may improve treatment strategies.

Abstract Telomerase reverse transcriptase promoter (TERTp) mutations are associated with non-radioiodine avidity. However, the role of these mutations in the clinical outcomes of patients with radioiodine-refractory differentiated thyroid cancer (RAIR-DTC) remains unknown. Herein, we aim to analyze gene mutations and clinical manifestations to verify TERTp’s role in driving disease progression to RAIR-DTC and clinical outcomes. Next-generation sequencing data and clinical data were obtained from 243 patients with DTC. Of the 25 patients with TERTp mutations, 80% (20/25) had RAIR-DTC. RAIR-DTC was significantly less prevalent in patients with BRAF V600E (9/143, 6.3%) than those with both BRAF V600E and TERTp mutations (14/17, 82.4%). Patients with RAIR-DTC harboring both BRAF V600E and TERTp mutations were more likely to have > 3 distant metastatic sites (85.7%, 12/14) than those with BRAF V600E alone (33.3%, 3/9). Only one patient with both BRAF V600E and TERTp mutations had non-RAIR-DTC. The time from initial radioactive iodine therapy to RAIR-DTC diagnosis was significantly shorter in patients with TERTp mutations than in those without. Patients with BRAF V600E and TERTp mutations progressed faster to RAIR-DTC than those with BRAF V600E alone (p

Abstract Colorectal cancer (CRC) ranks as the second most lethal cancer worldwide because of its high rate of metastasis, and approximately 20% of CRC patients have metastases at initial diagnosis. Metabolic reprogramming, a hallmark of cancer cells, has been implicated in the process of metastasis. We previously demonstrated that fucosyltransferase 2 (FUT2) promotes the malignancy of CRC cells, however, the underlying mechanisms remain unclear. Here, bioinformatic analysis revealed that FUT2 is associated with the malignant phenotype and fatty acid metabolism in CRC. FUT2 knockdown decreased glucose uptake and de novo fatty acid synthesis, which in turn inhibited the proliferation and metastasis of CRC cells. Mechanistically, FUT2 promotes YAP1 nuclear translocation and stabilizes mSREBP-1 by fucosylation, thus promoting de novo fatty acid synthesis in CRC cells. In summary, this study demonstrates that FUT2 promotes the proliferation and metastasis of CRC cells by reprogramming fatty acid metabolism via YAP/TAZ signaling and SREBP-1, indicating that FUT2 might be a potential target for developing therapeutic strategies against CRC.

Abstract The gut microbiome has been implicated in various human diseases, though findings across studies have shown considerable variability. In this study, we reanalyzed 6314 publicly available fecal metagenomes from 36 case-control studies on different diseases to investigate microbial diversity and disease-shared signatures. Using a unified analysis pipeline, we observed reduced microbial diversity in many diseases, while some exhibited increased diversity. Significant alterations in microbial communities were detected across most diseases. A meta-analysis identified 277 disease-associated gut species, including numerous opportunistic pathogens enriched in patients and a depletion of beneficial microbes. A random forest classifier based on these signatures achieved high accuracy in distinguishing diseased individuals from controls (AUC = 0.776) and high-risk patients from controls (AUC = 0.825), and it also performed well in external cohorts. These results offer insights into the gut microbiome’s role in common diseases in the Chinese population and will guide personalized disease management strategies.

One of the most prevalent disorders that cause blindness worldwide is cataract, and its essence is the visual disorder caused by the opacity of the lens. The significant degree of variation in cataracts and the fact that a variety of factors can impact a patient's lens transparency make it especially crucial to investigate the pathogenesis of cataracts at the molecular level. It has been found that more than 60 genes are linked to the formation of cataracts, and the construction of a transgenic mouse model of cataract similar to the selection of human lens clouding due to a variety of causes has become an important means of studying the pathogenesis of cataract. Therefore, the research on the application of transgenic mice to the molecular pathogenesis of cataracts will be the main topic of this review of the literature.

Abstract Silicone rubber (SiR) is commonly used in reinforced insulation parts for high‐voltage direct current (HVDC) cable accessories due to its excellent insulation, elasticity, and high‐temperature resistance. HVDC cable accessories always suffer from the local electric field concentration due to the electrical conductivity mismatch between reinforced insulation and main insulation, which can ultimately lead to electric breakdown. The non‐linear conductive composites based on SiR have the ability to adaptively adjust the distribution of the electric field in cable accessories. This is expected to solve the problem of localised electric field concentration. The zinc oxide (ZnO) and glycidyl methacrylate (GMA) are used as fillers and grafted modifier respectively to improve the non‐linear electrical conductivity of ZnO/SiR‐GMA composites. The results indicate that grafting GMA can increase electrical conductivity of SiR, while doping ZnO filler enables SiR to have non‐linear conductivity characteristics. The combination of doping and grafting modification of the composites achieves excellent non‐linear conductive properties at lower ZnO filler content. Additionally, the mechanical properties of the modified composites are enhanced. The simulation results indicate that ZnO/SiR‐GMA is the most effective material for homogenising the electric field when used as reinforced insulation for cable intermediate joints.

Abstract For individuals with hearing loss, even successful speech communication comes at a cost. Cochlear implants transmit degraded information, specifically for voice pitch, which demands extra and sustained listening effort. The current study hypothesized that abnormal pitch patterns contribute to the additional listening effort, even in non-tonal language native speaking normally hearing listeners. We manipulated the fundamental frequency (F0) within and across words, while participants listen and repeat (simple intelligibility task), or listen, repeat, and later recall (concurrent encoding task) the words. In both experiments, the F0 manipulations resulted in small changes in intelligibility but no difference in free recall or subjective effort ratings. Pupillary metrics were yet sensitive to these manipulations: pupil dilations were larger when words were monotonized (flat contour) or inverted (the natural contour flipped upside-down), and larger when successive words were organized into a melodic pattern. The most likely interpretation is that the natural or expected F0 contour of a word contributes to its identity and facilitate its matching and retrieval from the phonological representation stored in long-term memory. Consequently, degrading words’ F0 contour can result in extra listening effort. Our results call for solutions to improve pitch saliency and naturalness in future development of cochlear implants’ signal processing strategies, even for non-tonal languages.

Abstract Background The role of Mediator complex subunit 1 (MED1), a pivotal transcriptional coactivator implicated in diverse biological pathways, remains unexplored in the context of oral squamous cell carcinoma (OSCC). This study aims to elucidate the contributory mechanisms and potential impact of MED1 on the progression of OSCC. Methods The expression and clinical significance of MED1 in OSCC tissues were evaluated through the bioinformatics analyses. The effects of MED1 on the biological behavior of OSCC cancer cells were assessed both in vitro and in vivo. Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP) assay, bioinformatic analysis, CD8+ T cell isolation experiment, coculture experiment, enzyme-linked immunosorbent assay (ELISA), and flow cytometric analysis were employed to elucidate the underlying mechanism through which MED1 operates in the progression of OSCC. Results MED1 exhibited upregulation in both OSCC tissues and multiple OSCC cell lines, which correlated with decreased overall survival in patients. In vitro experiments demonstrated that knockdown of MED1 in metastatic OSCC cell lines SCC-9 and UPCI-SCC-154 hindered cell migration and invasion, while overexpression of MED1 promoted these processes. Whereas, MED1 knockdown had no impact on proliferation of cell lines mentioned above. In vivo studies further revealed that downregulation of MED1 effectively suppressed distant metastasis in OSCC. Mechanistically, MED1 enhanced the binding of transcription factors c-Jun and c-Fos to the matrix metalloprotein 9 (MMP9) promoters, resulting in a significant upregulation of MMP9 transcription. This process contributes to the migration and invasion of SCC-9 and UPCI-SCC-154 cells. Furthermore, MED1 modulated the expression of programmed death-ligand 1 (PD-L1) through the Notch signaling pathway, consequently impacting the tumor-killing capacity of CD8+ T cells in the tumor microenvironment. Conclusions Our findings indicate that MED1 plays a pivotal role in OSCC progression through the activation of MMP9 transcription and suppression of CD8+ T cell antitumor immunity, suggesting that MED1 may serve as a novel prognostic marker and therapeutic target in OSCC.

Abstract Tibetan Buddhist monasteries constitute significant cultural heritages of ethnic minorities, evolving into the Principal-Subordinate Monastery System (PSMS) with profound historical and cultural significance. This system exhibits an integrated hierarchical structure in terms of religious dominance, political administration, and cultural diffusion. Existing research primarily focuses on internal humanistic factors such as governance patterns, while there is not any research focused on its patterns and manifestations in spatial distribution. This study aims to elucidate the spatial distribution characteristics of the PSMS in Hehuang region, including the Tibetan Buddhist monasteries from all sects in the Hehuang region since the Song Dynasty It establishes a hierarchical PSMS database based on the affiliation relationships, aimed at storing spatial and property information related to PSMS. The database standardizes the naming and coding of monasteries, and classifies them through hierarchical relationships to ensure data consistency and usability. Finally, the classified and coded monastery data were analyzed by GIS tools to form the PSMS spatial distribution characterisation framework. Results reveal that (1) Monasteries demonstrate notable spatial clustering patterns from both holistic and sectarian perspectives, with density being influenced by the principal monastery’s position. (2) Almost every PSMS exhibits a spatial pattern centered around the principal monastery, with subordinate monasteries clustering within a defined range correlated with the administrative region of the principal monastery. (3) PSMS scale variations are controlled by principal monasteries, exhibiting positive correlations in hierarchical structure, control quantity, and distribution range. (4) The spatial orientation of PSMS correlates with river distribution, while the relationships among mountain ranges require further investigation. These findings provide initial insights into the spatial distribution characteristics of PSMS, confirming the spatial influence of the principal monastery. Besides, this study established an innovative spatial research framework for heritage clusters with multiple types and hierarchies. Thus, this study offers new insights into the spatial distribution of Tibetan Buddhist monastery heritage and presents a framework for further examining the spatial distribution of the Tibetan Buddhist monastery heritage in other regions, as well as other heritage clusters where connected and clustered through religious and cultural ties.

Abstract Background Bed rest during pregnancy can lead to reduced physical activity, impairing lower limb venous blood flow and increasing the risk of deep vein thrombosis (DVT) and muscle atrophy. We investigated the clinical efficacy of foam rolling intervention (FRI) in enhancing lower limb venous blood flow, mitigating the risk of DVT and muscle atrophy in pregnant women on bed rest. Methods This single-blind, randomised controlled trial enrolled 86 pregnant women with long-term bed rest for foetal protection (≥ 7 days), gestational age ≥ 20 weeks, and maternal age 0.05), however, the peak blood velocities of the popliteal veins were significantly higher in the control group (P = 0.031). On the seventh day post-intervention, the experimental group had significantly higher mean and peak blood velocities in femoral and popliteal veins, significantly (P

Abstract Vigorous CD8+ T cells play a crucial role in recognizing tumor cells and combating solid tumors. How T cells efficiently recognize and target tumor antigens, and how they maintain the activity in the “rejection” of solid tumor microenvironment, are major concerns. Recent advances in understanding of the immunological trajectory and lifespan of CD8+ T cells have provided guidance for the design of more optimal anti-tumor immunotherapy regimens. Here, we review the newly discovered methods to enhance the function of CD8+ T cells against solid tumors, focusing on optimizing T cell receptor (TCR) expression, improving antigen recognition by engineered T cells, enhancing signal transduction of the TCR-CD3 complex, inducing the homing of polyclonal functional T cells to tumors, reversing T cell exhaustion under chronic antigen stimulation, and reprogramming the energy and metabolic pathways of T cells. We also discuss how to participate in the epigenetic changes of CD8+ T cells to regulate two key indicators of anti-tumor responses, namely effectiveness and persistence.

Abstract Weathering features of sandstone heritage can be recognized by using artificial intelligence (AI) based surrogate models, and most models perform classification tasks for types based on precise labels. But there are lack of prior validated knowledge of the weathering or untagged historical data for complex weathering conditions in many cases. To this aim, a unsupervised graph neural network (GNN) based on the statistical features of the acoustic emission (AE) signals is constructed. Firstly, taking unweathered sandstone as a reference, we define 4 weathering levels of sandstone ranging from I to IV based on pore indicators. We selected 11 statistical features that are high correlated with pore of sandstone. Then, this GNN is constructed and trained by 2880 sets of statistical measured AE signals. Compared with AEs, LOF and IF models, GNN achieves the best identification performance among the four evaluation criteria. Each iteration of the GNN network is fitting the feature information of the signals and their neighbors. By data dimensionality reduction techniques, when the GNN stops iterating, it will be easy to distinguish unweathered AE signals from weathered one by comparing the reconstruction error of each signal. Furthermore, when the nearest neighbor’s k gradually increases, the AUC of GNN also gradually increases and then tend to stable when k equals to 50–100. While the hidden layers of the network aggregates less information about the neighborhood features of the signals and cannot distinguish significantly between unweathered and weathered signals when the value of k is small. As the depth of the network deepens, the feature values between signals become more and more similar, their reconstruction errors in the output layer of the network to become more similar, making it difficult to distinguish unweathered AE signals from weathered AE signals via GNN. Meanwhile, GNN adopts more AE features and considers the similarity between each features. This can greatly eliminate various errors caused by wave velocity measurement, greatly improving the robustness of AE detection. Hence, the GNN model presented addresses the limitations of relying solely on P-wave velocity measurements to assess the degree of sandstone weathering at stone cultural heritage.

Abstract Brachial artery access for coronary diagnostic or therapeutic procedures is associated with a greater risk of vascular complications. To determine whether 3D printing of a novel elbow joint fixation device could reduce postoperative complications after percutaneous coronary diagnostic or therapeutic procedures through the brachial artery. Patients who underwent percutaneous coronary diagnostic or therapeutic procedures by brachial access were randomly assigned to receive either a 3D-printed elbow joint fixation device (brace group) or traditional compression (control group) from March 2023 to December 2023. The severity of puncture site-related discomfort at 24 h postsurgery was significantly lower in the brace group (P = 0.014). Similarly, the upper arm calibration rate at 24 h postsurgery was significantly lower in the brace group [0.024 (0.019–0.046) vs. 0.077 (0.038–0.103), P

Upon 98% reduction cold-rolling, a single layer AA3003 foil material of 115 μm thick was intermediately annealed at 300–420 °C/1-8 h, and the preferred temperature and time of the intermediate annealing for the laminated AA4343/AA3003/AA4343 composite foil material were determined. All of these samples were cold rolled by 40% to 70 μm thick and finally annealed at a temperature in the range of 300–550 °C for 1–9 h. Their sagging resistance and microstructure were investigated using simulated brazing treatment, optical microscopy (OM), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). For the single layer AA3003 foil, the sagging distance decreased first and then increased with increasing intermediate annealing temperature, and the lowest sagging distance corresponds to the coarsest grain in the recrystallized sample. After the final annealing for the single layer, the sagging distance decreased monotonously. For the laminated foil subjected to the final annealing, the sagging distance curves decreased first and then increased with increasing annealing temperature and time. The improvement of sagging resistance was attributed to the recovery of two types of materials during annealing process. The deterioration of the sagging resistance in the laminated foils was due to the corrosion in the brazing process, resulted from the Si diffusion from the cladding layer into the core layer. It is the coarse grains, few dislocations and minimal diffusion of Si that are crucial for improving the sagging resistance of the laminated foils.

Local defects in coatings allow aggressive electrolytes penetrate to the coating/substrate interface, accelerating the corrosion of the exposed Mg substrate and compromising its biocompatibility. In this work, self-healing calcium hydrogen phosphate dihydrate (DCPD) coating incorporated with 3,5-dinitrosalicylic acid (3,5-D) or 5-amino salicylic acid (5-A) is designed on Mg. The results reveal that the self-healing and corrosion resistance performance of DCPD improves after adding 3,5-D/5-A. Namely, incorporating 3,5-D/5-A into DCPD accelerates the self-healing process and repair the coating at the initial stage. The released 3,5-D/5-A additives could adsorb on the exposed Mg surface and combine with the Ca2+ ions to precipitate. The interfacial adsorption mechanism of 3,5-D/5-A additives is disclosed by quantum chemical calculation. The simultaneously responsive adsorption and deposition of additives during coating degradation increase the thickness and compactness of the deposition layer at the coating defects, further inhibiting corrosion and stabilizing pH. These findings suggest taking biocompatibility recovery into consideration of preparing self-healing coating for biomedical applications.

Aluminum (Al) and its alloys have been widely used in daily life, but the absence of antibacterial properties makes them potential vectors for bacterial transmission. In this study, an Ag-doped TiO2 coating was successfully prepared on the porous surface of etched Al foil using the sol-gel method. The results indicated that the porous layer allowed the gel to permeate through the holes, thereby forming an interface carrying these antibacterial agents with a thickness of about 10 μm. The Ag dopant promoted the transformation of titania from rutile to anatase during the calcination process, with the rutile being absent when the atomic ratio of Ag to Ti reached 0.10. Meanwhile, the doped Ag+ was thermally decomposed into metallic Ag0. As a result, doping Ag enhanced the photocatalytic efficacy of TiO2 coating. Moreover, the antibacterial rate of this coating against Escherichia coli and Staphylococcus aureus under dark conditions could reach more than 99%, and the corrosion resistance of the Al foil was also slightly improved by it.

Myeloid-derived suppressor cells (MDSCs) are closely related to the occurrence and development of many cancers, but the specific mechanism is not fully understood. It has been found that N6-methyladenosine (m6A) plays a key role in RNA metabolism, but its function in MDSCs has yet to be revealed. In this study, we found that MDSCs in mice with colorectal cancer (CRC) have significantly elevated levels of m6A, while ALKBH5 expression is decreased. Overexpression of ALKBH5 can reduce the immunosuppressive function of MDSCs in vivo and in vitro, and attenuates the protumorigenic ability of MDSCs. Mechanism study found that the overexpression of ALKBH5 in MDSCs reduced the m6A modification level of Arg-1 mRNA, and then weakened the stability of Arg-1 mRNA and protein expression. These data suggest that the decreased expression of ALKBH5 in CRC tumor mice may promote the expression of Arg-1, enhance the immunosuppressor function of MDSCs, and promote tumor growth. These findings highlight that ALKBH5 may regulate the function of MDSCs in tumor-bearing mice and may be a new target for immunotherapy. This research provides a new perspective for our understanding of the role of MDSCs in cancer development, and also brings new hope for cancer treatment.

Abstract Background Lasianthus species are widely used in traditional Chinese folk medicine with high medicinal value. However, source materials and herbarium specimens are often misidentified due to morphological characteristics and commonly used DNA barcode fragments are not sufficient for accurately identifying Lasianthus species. To improve the molecular methods for distinguishing among Lasianthus species, we report the complete chloroplast (CP) genomes of Lasianthus attenuatus, Lasianthus henryi, Lasianthus hookeri, Lasianthus sikkimensis, obtained via high-throughput Illumina sequencing. Results These showed CP genomes size of 160164-160246 bp and a typical quadripartite structure, including a large single-copy region (86675–86848 bp), a small single-copy region (17177–17326 bp), and a pair of inverted repeats (28089–28135 bp). As a whole, the gene order, GC content and IR/SC boundary structure were remarkably similar among of the four Lasianthus CP genomes, the partial gene length and IR, LSC and SSC regions length are still different. The average GC content of the CP genomes was 36.71–36.75%, and a total of 129 genes were detected, including 83 different protein-coding genes, 8 different rRNA genes and 38 different tRNA genes. Furthermore, we compared our 4 complete CP genomes data with publicly available CP genome data from six other Lasianthus species, and we initially screened eleven highly variable region fragments were initially screened. We then evaluated the identification efficiency of eleven highly variable region fragments and 5 regular barcode fragments. Ultimately, we found that the optimal combination fragment' ITS2 + psaI-ycf4' could authenticated the Lasianthus species well. Additionally, the results of genome comparison of Rubiaceae species showed that the coding region is more conservative than the non-coding region, and the ycf1 gene shows the most significant variation. Finally, 49 species of CP genome sequences belonging to 16 genera of the Rubiaceae family were used to construct phylogenetic trees. Conclusions Our research is the first to analyze the chloroplast genomes of four species of Lasianthus in detail and we ultimately determined that the combination fragment' ITS2 + psaI-ycf4' is the optimal barcode combination for identifying the genus of Lasianthus. Meanwhile, we gathered the available CP genome sequences from the Rubiaceae and used them to construct the most comprehensive phylogenetic tree for the Rubiaceae family. These investigations provide an important reference point for further studies in the species identification, genetic diversity, and phylogenetic analyses of Rubiaceae species.

Four new N-acylated aminoalkanoic acids, namely clonoroseins E−H (1−4), together with three previously identified analogs, clonoroseins A, B, and D (5−7), were identified from the endophytic fungus Clonostachys rosea strain 15020 (CR15020), using Feature-based Molecular Networking (FBMN). The elucidation of their chemical structures, including their absolute configurations, was achieved through spectroscopic analysis combined with quantum chemical calculations. Bioinformatics analyses suggested that an iterative type I HR-PKS (CrsE) generates the polyketide side chain of these clonoroseins. Furthermore, a downstream adenylate-forming enzyme of the PKS (CrsD) was suspected to function as an amide synthetase. CrsD potentially facilitates the transformation of the polyketide moiety into an acyl-AMP intermediate, followed by nucleophilic substitution with either β-alanine or γ-aminobutyric acid to produce amide derivatives. These findings significantly expand our understanding of PKS-related products originating from C. rosea and also underscore the powerful application of FBMN analytical methods in characterization of new compounds.

The effective promotion of wound healing poses a substantial challenge for clinical treatment. Despite evidence supporting the role of extracellular vesicles (EVs) in this process, their therapeutic potential is currently restrict by challenges in targeting and maintaining them. The manufacturing process for rhCol III, or recombinant human collagen III, is stable, and the rejection rate is low. We used a cross-linking method to prepare a rhCol III incorporated sodium alginate (SA) hydrogel, which enabled to accomplish an EV sustained release that was site-specific. Cell viability through MTT assay, proliferation and ROS generation were performed with MC3T3-E1cell lines. In addition, diabetic wounds are characterised by an environment of hyper-inflammation and elevated oxidative stress. The rhCol III/SA-EVs hydrogel, which is a delivery vehicle with anti-inflammatory and antioxidant characteristics, promotes wound healing in this setting. The In vivo effectiveness of the created wound dressing on a diabetic wound model was examined in this study. After 21 days of treatment, the wound dressing significantly (p

Utilizing standardized artificial regulatory sequences to fine-tuning the expression of multiple metabolic pathways/genes is a key strategy in the creation of efficient microbial cell factories. However, when regulatory sequence expression strengths are characterized using only a few reporter genes, they may not be applicable across diverse genes. This introduces great uncertainty into the precise regulation of multiple genes at multiple expression levels. To address this, our study adopted a fluorescent protein fusion strategy for a more accurate assessment of target protein expression levels. We combined 41 commonly-used metabolic genes with 15 regulatory sequences, yielding an expression dataset encompassing 520 unique combinations. This dataset highlighted substantial variation in protein expression level under identical regulatory sequences, with relative expression levels ranging from 2.8 to 176-fold. It also demonstrated that improving the strength of regulatory sequences does not necessarily lead to significant improvements in the expression levels of target proteins. Utilizing this dataset, we have developed various machine learning models and discovered that the integration of promoter regions, ribosome binding sites, and coding sequences significantly improves the accuracy of predicting protein expression levels, with a Spearman correlation coefficient of 0.72, where the promoter sequence exerts a predominant influence. Our study aims not only to provide a detailed guide for fine-tuning gene expression in the metabolic engineering of Escherichia coli but also to deepen our understanding of the compatibility issues between regulatory sequences and target genes.

AbstractAs a processed product of traditional Chinese medicine Curcumae Radix, Curcumae Radix Carbonisata (CRC) has been widely used in the treatment of liver diseases in ancient medical books. In this study, novel carbon dots (CDs) extending from 1.0 to 4.5 nm were separated from fluid extricates of CRC. Meanwhile, a liver fibrosis model induced by carbon tetrachloride (CCl4) was utilized to determine the inhibitory effects of CRC-CDs against liver fibrosis. The results exhibited the CRC-CDs with a quantum yield of 1.34% have a significant inhibitory effect on CCl4-induced liver fibrosis, as demonstrated by improving hepatocyte degeneration and necrosis, inflammatory cell infiltration and fibrotic tissue hyperplasia, downregulating the levels of alanine transaminase (ALT), aspartate aminotransferase (AST), total bilirubin (TBIL), direct bilirubin (DBIL), total bile acid (TBA), triglyceride (TG), tumour necrosis factor-α (TNF-α), interleukin (IL)-6 and IL-1β in the serum, upregulating the contents of superoxide dismutase (SOD), reduced glutathione (GSH), and downregulating the concentration of malondialdehyde (MDA), which lays an important foundation for the development of CRC-CDs as a novel drug for the treatment of liver fibrosis, and provide a certain experimental basis for the clinical application of CRC-CDs in the future.

AbstractChinese herbs contain substances that regulate female hormones. Our study confirmed that Zingiberis rhizoma carbonisata contains Zingiberis rhizoma-based carbon dots (ZR-CDs), which exert regulatory effects on serum oestradiol and FSH in mice and show impacts on endometrial growth and follicular development that potentially affect the ability of female fertility. ZR-CDs were characterized to clarify the microstructure, optical features, and functional group characteristics. It shows that ZR-CDs are spherical carbon nanostructures ranging from 0.97 to 2.3 nm in diameter, with fluorescent properties and a surface rich in functional groups. We further investigated the impact of ZR-CDs on oestradiol and FSH in serum, growth, and the development of ovarian and uterine using normal female mice and exogenous oestradiol intervention model. It was observed that ZR-CDs accelerated oestrogen metabolism and attenuated oestradiol-induced endometrial hyperplasia. Simultaneously, ZR-CDs triggered an increase in FSH, even in the presence of high-serum oestradiol that inhibits FSH secretion. Our findings suggest that ZR-CDs could be a potential therapeutic treatment for anovulatory menstruation.

Abstract The CLDN18-ARHGAP fusion gene is an oncogenic driver newly discovered in gastric cancer. It was detected in 9% (8/87) of gastric cancer patients in our center. An immunogenic peptide specifically targeting CLDN18-ARHGAP fusion gene was generated to induce neoantigen-reactive T cells, which was proved to have specific and robust anti-tumor capacity both in in vitro coculture models and in vivo xenograft gastric cancer models. Apart from the immunogenic potential, CLDN18-ARHGAP fusion gene was also found to contribute to immune suppression by inducing a regulatory T (Treg) cell-enriched microenvironment. Mechanistically, gastric cancer cells with CLDN18-ARHGAP fusion activate PI3K/AKT-mTOR-FAS signaling, which enhances free fatty acid production of gastric cancer cells to favor the survival of Treg cells. Furthermore, PI3K inhibition could effectively reverse Treg cells upregulation to enhance anti-tumor cytotoxicity of neoantigen-reactive T cells in vitro and reduce tumor growth in the xenograft gastric cancer model. Our study identified the CLDN18-ARHGAP fusion gene as a critical source of immunogenic neoepitopes, a key regulator of the tumor immune microenvironment, and immunotherapeutic applications specific to this oncogenic fusion.

Abstract Background Acute-on-chronic liver failure (ACLF) is characterized by a systemic inflammatory response, predominantly associated with hepatitis B virus in the Asia-Pacific region, with a high short-term mortality rate. The platelet to high-density lipoprotein ratio (PHR) has been used to predict the prognosis of patients with various inflammatory diseases. We aim to is to use the PHR to predict the short-term prognosis of patients with HBV-ACLF. Method In this study, we retrospectively analyzed clinical data from 270 HBV-ACLF patients. Using logistic regression, we identified independent risk factors for short-term mortality and developed a prognostic model. This model was then validated, compared, and its clinical utility assessed via decision curve analysis (DCA). Results Among the 270 HBV-ACLF patients, 98 patients died within 28 days. The deceased group exhibited a higher proportion of severe hepatic encephalopathy and ascites. Additionally, there was a statistically significant difference (P = 0.046) in the novel inflammation scoring system, PHR, between the two groups. Following stringent variable selection, PHR was identified as a predictive factor for short-term mortality in HBV-ACLF patients using logistic regression analysis (OR: 0.835 (0.756–0.999), P = 0.009), and it exhibited a synergistic effect with certain traditional scores. The prognostic model constructed based on PHR demonstrated a superior ability to predict short-term mortality compared to traditional scores such as Child-Turcotte-Pugh (AUC: 0.889). Evaluation using calibration curves and decision curve analysis (DCA) suggested its practical utility. Conclusion PHR can predict short-term mortality in patients, with a low PHR upon admission being associated with an increased risk of death.

Abstract Osteoclast is critical in skeletal development and fracture healing, yet the impact and underlying mechanisms of their metabolic state on these processes remain unclear. Here, by using osteoclast-specific small GTPase Rheb1-knockout mice, we reveal that mitochondrial respiration, rather than glycolysis, is essential for cathepsin K (CTSK) production in osteoclasts and is regulated by Rheb1 in a mechanistic target of rapamycin complex 1 (mTORC1)-independent manner. Mechanistically, we find that Rheb1 coordinates with mitochondrial acetyl-CoA generation to fuel CTSK, and acetyl-CoA availability in osteoclasts is the central to elevating CTSK. Importantly, our findings demonstrate that the regulation of CTSK by acetyl-CoA availability is critical and may confer a risk for abnormal endochondral ossification, which may be the main cause of poor fracture healing on alcohol consumption, targeting Rheb1 could successfully against the process. These findings uncover a pivotal role of mitochondria in osteoclasts and provide a potent therapeutic opportunity in bone disorders.

Abstract In view of the cracking, sag, and damage of sheath caused by the load effect and external force impact of power cable, the echo parameters of cable sheath damage detection based on the characteristics of torsional guided wave propagation are studied in this work. According to the Navier displacement equilibrium equation, the dispersion curve of a magnetostrictive guided wave of the cable sheath was solved, and the T(0,1) mode with a group velocity of 1198.8 m/s and no dispersion was selected. Furthermore, while considering the excitation frequency, loss rate, and direction of the damaged section, the displacement field and the echo characteristic parameters of guided wave in the cable sheath were solved. Moreover, by analyzing the time-domain signals of damaged section echo, the cubic fitting function for the loss rate of the damaged section and the damaged section echo coefficient were obtained, which can effectively characterize the quantitative relationship between the damaged location, size, and guided wave echo of the cable sheath.

Abstract Background Leukocyte immunoglobulin-like receptor B4 (LILRB4) plays a significant role in regulating immune responses. LILRB4 in microglia might influence the infiltration of peripheral T cells. However, whether and how LILRB4 expression aggravates brain damage after acute ischemic stroke remains unclear. This study investigates the role of LILRB4 in modulating the immune response and its potential protective effects against ischemic brain injury in mice. Methods and results Microglia-specific LILRB4 conditional knockout (LILRB4-KO) and overexpression transgenic (LILRB4-TG) mice were constructed by a Cre-loxP system. Then, they were used to investigate the role of LILRB4 after ischemic stroke using a transient middle cerebral artery occlusion (tMCAO) mouse model. Spatial transcriptomics analysis revealed increased LILRB4 expression in the ischemic hemisphere. Single-cell RNA sequencing (scRNA-seq) identified microglia-cluster3, an ischemia-associated microglia subcluster with elevated LILRB4 expression in the ischemic brain. Flow cytometry and immunofluorescence staining showed increased CD8+ T cell infiltration into the brain in LILRB4-KO-tMCAO mice. Behavioral tests, cortical perfusion maps, and infarct size measurements indicated that LILRB4-KO-tMCAO mice had more severe functional deficits and larger infarct sizes compared to Control-tMCAO and LILRB4-TG-tMCAO mice. T cell migration assays demonstrated that LILRB4-KD microglia promoted CD8+ T cell recruitment and activation in vitro, which was mitigated by CCL2 inhibition and recombinant arginase-1 addition. The scRNA-seq and spatial transcriptomics identified CCL2 was predominantly secreted from activated microglia/macrophage and increased CCL2 expression in LILRB4-KD microglia, suggesting a chemokine-mediated mechanism of LILRB4. Conclusion LILRB4 in microglia plays a crucial role in modulating the post-stroke immune response by regulating CD8+ T cell infiltration and activation. Knockout of LILRB4 exacerbates ischemic brain injury by promoting CD8+ T cell recruitment. Overexpression of LILRB4, conversely, offers neuroprotection. These findings highlight the therapeutic potential of targeting LILRB4 and its downstream pathways to mitigate immune-mediated damage in ischemic stroke.

Abstract Background Ulcerative colitis (UC) is a chronic intestinal inflammation, resulting in a global healthcare challenge with no real specific medicine. Natural medicines are recognized as a potential clinical alternative therapy, but their applications are limited by poor solubility and low bioavailability. Results In this work, inspired by the natural medicines of ancient China, novel functional carbon dots derived from Magnetite and Medicated Leaven (MML-CDs) were synthesized by hydrothermal method, and confirmed their ultrasmall nano-size (3.2 ± 0.6 nm) and Fe doped surface structure, thereby with excellent gastrointestinal stability, remarkable capabilities in eliminating ROS, and highly biocompatibility. With no external stimuli, the oral administration of MML-CDs demonstrated obvious alleviation to UC. Further experiments pointed that MML-CDs could improve hemostasis capability, suppress inflammation reactions and oxidative stress, and up-regulate the expression of tight junction proteins. Furthermore, MML-CDs also showed well regulation in the dysbiosis of intestinal flora. Conclusion Overall, above evidence reveals that green-synthesized MML-CDs can significantly alleviate intestinal bleeding, inhibit colon inflammation, and repair colonic barrier damage, further regulating intestinal flora and intestinal inflammation microenvironment. Our findings provide an efficient oral administration of MML-CDs as a novel therapy strategy for ulcerative colitis. Graphical Abstract

Abstract Primary liver cancer (PLC) is one of the most common malignant gastrointestinal tumors worldwide. Limited by the shortage of liver transplantation donors and the heterogeneity of tumors, patients with liver cancer lack effective treatment options, which leads to rapid progression and metastasis. Currently, preclinical models of PLC fall short of clinical reality and are limited in their response to disease progression and the effectiveness of drug therapy. Organoids are in vitro three-dimensional cultured preclinical models with a high degree of heterogeneity that preserve the histomorphological and genomic features of primary tumors. Liver cancer organoids have been widely used for drug screening, new target discovery, and precision medicine; thus representing a promising tool to study PLC. Here, we summarize the progress of research on liver cancer organoids and their potential application as disease models. This review provides a comprehensive introduction to this emerging technology and offers new ideas for researchers to explore in the field of precision medicine.

Abstract Background Prior antibiotic exposure has been identified as a risk factor for VAP occurrence, making it a growing concern among clinical practitioners. But there is a lack of systematic research on the types of antibiotics and the duration of exposure that influence VAP occurrence in children at current. Methods We retrospectively reviewed 278 children admitted to the Pediatric Intensive Care Unit (PICU) and underwent invasive mechanical ventilation (MV) between January 2020 and December 2022. Of these, 171 patients with MV duration ≥ 48 h were included in the study, with 61 of them developing VAP (VAP group) and the remaining 110 as the non-VAP group. We analyzed the relationship between early antibiotic exposure and VAP occurrence. Results The incidence of VAP was 21.94% (61/278). The VAP group had significantly longer length of hospital stay (32.00 vs. 20.00 days, p

Abstract Background and purpose Ir192 vaginal brachytherapy (IBT) is commonly used for patients with postoperative endometrial cancer (EC). We devised a novel multichannel vaginal applicator that could be equipped with an electronic brachytherapy (EBT) device. We aimed to explore the differences in physical parameters between the EBT and IBT. Materials and methods This retrospective study included 20 EC patients who received adjuvant IBT from March 1, 2023, to May 1, 2023. Multichannel vaginal cylinders were used, and three-dimensional plans were generated. We designed an electronic multichannel vaginal applicator model and simulated a three-dimensional EBT plan. In order to ensure comparability, D90 of the CTV for the EBT plan was normalized to be equivalent to that of the IBT plan for the same patient. Results Twenty EBT plans were compared with 20 IBT plans. Results showed, the mean D90 value of clinical target volume (CTV) was 536.1 cGy for both treatment plans. For the mean dose of CTV, the EBT was significantly greater (738.3 vs. 684.3 cGy, p = 0.000). There was no significant difference in CTV coverage between the EBT and IBT plans. For high-dose areas (V200% and V150%), the EBTs were significantly greater. There were no significant differences in the maximum doses to the vaginal mucosa between the EBT and IBT, whether at the apex or in the middle segment. For the bladder and rectum, both the low-dose area and high-dose area were significantly lower in the EBT plans. For the conformity index, there was no significant difference between the EBT and IBT plans. For the dose homogeneity index, the EBT value was lower. Conclusion In conclusion, under the premise of a three-dimensional brachytherapy plan, for patients receiving multichannel vaginal applicator brachytherapy, compared with IBT, EBT could reduce the dose to the surrounding organs at risk while maintaining the dose in the target area.