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Abstract Background and purpose Research shows that people with multiple sclerosis (MS) are more likely to experience cardiovascular complications. However, the precise mechanisms underlying this association remain unclear. This study investigated the causal relationship between MS and coronary heart disease (CHD) using Mendelian randomization (MR) techniques to clarify direct effects and identify relevant target genes. Methods We conducted various methods, including two-sample MR. method, reverse, and multivariable MR analyses, to examine the causal relationship between MS and CHD. These. methodologies effectively mitigate confounding variables and neutralize adverse causal effects. Additionally, the study explored the involvement of social factors through a two-step MR analysis. The research team performed a thorough screening of differentially expressed genes in MS based on GEO database, identifying potential target genes that may be associated with genetic risk of CHD. Enrichment analyses and protein-protein interaction studies were used to elucidate biological functions associated with these genes. We included colocalization analysis and summary data-based Mendelian randomization (SMR) method for further screening of core genes to obtain target genes.Finally, we investigated how these genes might affect health by conducting a phenome-wide MR analysis. Results Our findings revealed that genetic predisposition to MS significantly increases the risk of CHD, with an IVW-MR analysis yielding an odds ratio of 1.091 (95% CI: 1.030, 1.155, P = 0.0029). Mediation analysis revealed that frailty mediated 20.2% of the effect of MS on CHD (P = 0.026), suggesting that frailty is a critical pathway in this relationship. Additionally, low-density lipoprotein (LDL) is associated with an increased risk of developing both MS and CHD. We identified 3025 differentially expressed genes and 130 genes causally linked to CHD. Protein-protein interaction network analysis identified 77 interacting genes, with core genes such as SREBF1 involved in organelle regulation and nucleic acid metabolism. Colocalization analysis further supported the presence of shared genetic variants between IL6R and SREBF1 associated with CHD, with posterior probabilities (PPH4) of 90.2% and 92.3%, respectively. Interestingly, summary mendelian randomization (SMR) analysis revealed that SREBF1 may be a target gene for MS(bSMR=-0.174,PSMR = 0.0218, PHEIDI = 0.2806, topSNP: rs12951376). Further analysis of the phenome-wide MR did not find significant evidence of side effect associated with targeted therapy against SREBF1. Conclusion This study provided genetic evidence indicating that indivduals with MS face higher risk of coronary heart disease. Furthermore, SREBF1 maybe a critical target gene which would significantly contribute to drug development.

Abstract Ferroptosis plays a critical role in myocardial ischemia-reperfusion injury (MIRI), posing a significant clinical challenge. Nanoenzymes like cerium oxide (CeO2) hold promise for mitigating oxidative damage and inhibiting ferroptosis, but their delivery efficiency and biological activity require optimization. This study aims to develop a targeted nanozyme delivery system for MIRI treatment by integrating CeO2 with mesoporous polydopamine (mPDA) and dexrazoxane (DXZ) to achieve synergistic therapeutic effects. A biomineralization technique was used to synthesize CeO2 nanoparticles (2–3 nm) within mPDA, forming ~ 130 nm composite nanoparticles (Ce@mPDA). Surface modifications with cardiac homing peptide (CHP) and triphenylphosphine (TPP) enabled hierarchical targeting to injured myocardium and mitochondria. DXZ-loaded Ce@mPDA-C/P nanoparticles (D/Ce@mPDA-C/P) were evaluated in vitro and in a MIRI mouse model for their effects on oxidative stress, ferroptosis, apoptosis, inflammation, and cardiac function. D/Ce@mPDA-C/P nanoparticles exhibited robust ROS scavenging, sustained DXZ release, and efficient myocardial and mitochondrial targeting. The D/Ce@mPDA-C/P system significantly reduced oxidative stress, upregulated GPX4 expression, inhibited ferroptosis, and modulated the inflammatory microenvironment. Long-term studies in a MIRI mouse model demonstrated reductions in myocardial fibrosis and improvements in cardiac function, including enhanced fractional shortening and ejection fraction. This hierarchical targeting delivery system effectively combines the antioxidant properties of CeO2 with the iron-chelating effects of DXZ, providing a promising therapeutic strategy for MIRI. This approach may expand the clinical use of DXZ and advance nanomedicine-based interventions for myocardial repair. Graphical Abstract

In order to preliminarily explore the structure, immune and anti-aging activity of capsular polysaccharide (CPS) produced by Lactobacillus plantarum W1. In this study, CPS was extracted and prepared by enzymatic hydrolysis. The absolute molecular weight, functional groups and monosaccharide composition of CPS were analyzed by gel permeation chromatography system, Fourier transform infrared spectroscopy and high performance liquid chromatography. The immune and anti-aging activities of CPS were investigated using RAW264.7 cells and Caenorhabditis elegans (C. elegans) models. The results showed that CPS was a heteropolysaccharide with an average molecular weight of 5.49×104 Da, consisting of glucose and galactose in a molar ratio of 3.12:1. Furthermore, CPS had been found to enhance the proliferation and phagocytosis of RAW264.7 cells, as well as promote the secretion of NO and cytokines, thereby exerting an immunomodulatory effect. At a concentration of 125 μg/mL, the secretion levels of TNF-α, IL-6 and IL-1β in RAW264.7 cells reached their maximum values, which were 1.26 times, 1.11 times and 1.96 times higher than those in the control group, respectively. Concurrently, CPS significantly enhanced the antioxidant system of C. elegans (P

Abstract Ultralow-absorption laser films have critical applications in high-power continuous-laser and gravitational-wave-detection systems. During film deposition, the ionic oxygen concentration significantly affects the absorption loss of the film. In this study, Ta2O5 monolayers were deposited using an ion-assisted electron beam evaporation technique, and the weak absorption at 1064 nm, temperature rise, optical band gap, element content, and binding energy were tested and analyzed. The band structure and microdefects of the Ta2O5 films were characterized, and their correlation with the absorption properties was established. The analyses revealed that the primary mechanism responsible for reducing the absorption loss in Ta2O5 films was an appropriate ionic oxygen concentration, which improved the optical band gap and stoichiometric ratio and reduced oxygen vacancy defects. For Ta2O5 monolayers deposited with the optimal ionic oxygen concentration, the weak absorption was approximately 7.2 ppm and the temperature rise was approximately 0.6 °C, 1/4 and 1/3 of the values of those deposited with an excessive concentration, respectively—an important finding in the preparation of ultralow-absorption laser films.

Abstract Background Those who have severe fibrosis (F2 ≥ 2 stage) are at the greatest risk for the advancement of the illness among non-alcoholic fatty liver patients. To forecast the non-alcoholic steatohepatitis (NASH) probability accompanied by significant fibrosis, we propose to develop and validate a nomogram liver imaging reporting and data system, providing robust evidence for preventing and treating clinical liver diseases. Methods The study used SD rats to create a model of hepatic steatosis and fibrosis by feeding them a high-fat diet and injecting Ccl4 subcutaneously. Radiomics characteristics were derived from two-dimensional liver ultrasound images of the rats, and a radiomics model was constructed, with rad-scores calculated accordingly. Univariate and multivariate logistic regression was employed to ascertain the clinical characteristics of rats and liver elasticity values, aiming to establish a clinical model. Ultimately, a clinical radiomics model was created by integrating the rad-score from the radiomics model with independent clinical characteristics from the clinical model. A forest plot was generated to depict this integration. The forest plot's performance was assessed by the use of the area under the receiver operating characteristic (ROC) curve (AUC), decision curve analysis, and calibration curve. Results The areas under the receiver operating characteristic curve (AUC) for the training set and validation set of the clinical radiomics model were 0.986 and 0.971, respectively. Decision curve analysis showed that the clinical radiomics model had the highest net benefit across most threshold probability ranges. Conclusion The nomogram and clinical radiomics model, which consists of clinical characteristics, real-time shear wave elastography, and radiomics, provide excellent predictive capability in assessing the likelihood of fibrotic NASH.

Abstract This open-label phase II trial (NCT04542837) aimed to evaluate the efficacy and safety of KN046 combined with lenvatinib in patients with advanced hepatocellular carcinoma (HCC), and explore the potential response biomarkers. Participants received KN046 5 mg/kg every 3 weeks and lenvatinib 12 or 8 mg once daily. The primary endpoints were safety, tolerability, dose-limiting toxicity (DLT), and objective response rate (ORR) according to RECIST v1.1. A total of fifty-five participants were enrolled. The results meet the pre-specified primary endpoints. No DLT was observed in the safety run-in period. The incidence of serious adverse events and grade ≥3 treatment-related adverse events (TRAEs) was 30.9% and 47.3%, respectively. Grade ≥3 immunotherapy-related adverse events occurred in 3 (5.5%) participants. Five (9.1%) participants discontinued treatment due to TRAEs, all of which were grade 1-2. The ORR was 45.5% (95% CI, 31.97-59.45). The median progression-free survival was 11.0 (95% CI, 8.21-15.24) months. The median overall survival (OS) was 16.4 (95% CI, 11.20-not estimable) months, and 12-month OS rate was 60.0% (95% CI, 45.87-71.55). Circulating tumor DNA status before the third cycle of treatment was associated with prognosis. In conclusion, First-line KN046 plus lenvatinib shows promising efficacy for advanced unresectable or metastatic HCC.

ABSTRACT Objective Gap balancing is a vital process during mobile‐bearing unicompartmental knee arthroplasty (MB‐UKA). However, this process commonly depends on the surgeon's experience and lacks specific unified standards. This study aimed to propose and evaluate a novel “measured resection” method for gap balance in MB‐UKA. Methods This prospective study included 49 consecutive patients (52 knees) who underwent MB‐UKA from February 1, 2023, to September 1, 2023. Gap balance was achieved by the traditional “two‐finger” method (Group 1, 26 knees) or the measured resection method (Group 2, 26 knees). The novel “measured resection” method was performed by measuring the thickness of the resected posterior femoral condyle and resected medial posterior tibial plateau to assess proper meniscal bearing thickness. Data were collected at baseline and the 6‐month follow‐up. Prosthetic angles, range of motion (ROM), visual analog scale (VAS) score, Oxford knee score (OKS), and Global Perceived Scale (GPE) were used to evaluate clinical outcomes. Independent samples t‐test and Mann–Whitney U test were used to compare the differences. Results There were significant improvements in all measured outcomes at the 6‐month follow‐up from baseline in both groups (p 0.05). Conclusions The measured resection method is a reliable method for assisting surgeons in choosing the ideal meniscal bearing thickness in MB‐UKA to achieve proper gap balance and gain better clinical outcomes. Trial Registration ClinicalTrials.gov (NCT03815448)

Background: Numerous clinical studies have demonstrated that the therapeutic efficacy of combining nifedipine and enalapril in treating hypertension with coronary heart disease surpasses that of nifedipine as a stand-alone treatment. However, the current evidence is not yet sufficient due to limitations in the sample size, and further validation is needed. To analyze and assess the clinical impact of nifedipine combined with enalapril on hypertension complicated with coronary heart disease, and provide evidence for rational drug use in clinic. Methods: We employed a revised version of the Jadad scale to assess the quality of the research literature following a rigorous screening process. The statistical analysis was performed utilizing the software RevMan 5.4.1 for data analysis. Heterogeneity in the studies was evaluated based on the results of the Q test (P value), and the OR value of the combined effect was calculated using either the model with fixed effects or the one with random effects, with the results presented in a forest plot. Furthermore, a sensitivity analysis was conducted by excluding articles with the highest impact, and potential bias in publication was assessed through the utilization of a funnel plot. Results: A total of 183 articles were initially identified, and after a comprehensive review, 14 clinical randomized controlled trials were chosen for analysis. The meta-analysis findings revealed that the trial group displayed a significantly higher overall effectiveness rate compared to the control group (OR=3.47, 95%CI 2.40-5.03). Additionally, the trial group exhibited a more pronounced reduction in blood pressure and greater enhancement in cardiac function (OR=5.55, 95%CI). Conversely, the control group had a lower occurrence of ischemic events compared to the trial group (OR=0.35, 95%CI 0.24-0.50). Sensitivity analysis confirmed the stability and reliability of the combined effect size results (OR=3.91, 95%CI 2.51-6.09, P

Abstract Background and objective While the connection between the Triglyceride glucose-waist circumference (TyG-WC) index and the risk of diabetes remains understudied, this particular research delves into the potential predictive value of the TyG-WC index within a significant Japanese population. Methods This retrospective cohort study encompassed a comprehensive analysis of 15,413 Japanese adults, all of whom were diabetes-free at the outset of the study period from 2004 to 2015. Comprehensive medical records were obtained for all participants who underwent physical examinations. The study employed Cox proportional-hazards regression, smooth curve fitting, various sensitivity, and subgroup analyses to explore the association between TyG-WC and the development of diabetes. Furthermore, a Receiver Operating Characteristic (ROC) curve was created to detect the predictive capability of TyG-WC for diabetes risk. Results After a maximum of 13.0 years of follow-up, 358 people finally developed diabetes. Upon adjusting for covariates, the result showed TyG-WC was positively and independently associated with incident Diabetes Mellitus (DM) (Hazard Ratio (HR): 1.004, 95%C: 1.001–1.006). Furthermore, ROC curve analysis demonstrated that TyG-WC outperformed both the triglycerides-glucose index and triglyceride glucose-body mass index in predicting the onset of diabetes. Conclusion High levels of TyG-WC are autonomously linked to a heightened risk of diabetes in the Japanese demographic, indicating its potential as a dependable predictive indicator for diabetes mellitus in individuals at elevated risk.

Abstract Background Neuroimmune interaction is an underestimated mechanism for lung diseases, and cryoablation is a competitive advantageous technique than other non-pharmacologic interventions for peripheral nerve innervating the lung. However, a lack of cryodenervation model in laboratory rodents leads to the obscure mechanisms for techniques used in clinic. Method Herein, we developed a novel practical method for mouse peripheral nerve cryoablation, named visualized and simple cryodenervation (VSCD). We first estimated the feasibility, safety and effectiveness of the technique via haematoxylin-eosin staining, histochemistry or immunofluorescence staining and immunoblotting assay. We then constructed the acute lung injury (ALI) model triggered by lipopolysaccharide (LPS) to verify the effect of VSCD in the resolution of pulmonary inflammation. Besides, the IL-10 knockout mice were also applied to explain the underlying mechanism of the protective activity of VSCD in ALI mice. Result We demonstrated that VSCD was able to induce a reliable and stable blockade of innervation, but reversible structural damage of mouse vagus nerve without detectable toxicity to lung tissues. Cholinergic parasympathetic nerve in the mouse lung coming from vagus nerve was activated at the initial stage (1 week) after VSCD, and blocked 3 weeks later. By use of the ALI mouse model, we found that VSCD effectively decreased pulmonary inflammation and tissue damage in the ALI mice. Moreover, the activated cholinergic anti-inflammatory pathway (CAP) and elevated IL-10 expression might explain the protective action of VSCD following LPS challenge. Conclusion This study fills the gap in the cryoablation for mouse vagus nerve, thereby guiding the application of cryodenervation in clinical management of pulmonary diseases. It also offers evidence of anti-inflammatory potential of VSCD in ALI mouse model and opens therapeutic avenues for the intervention of acute lung inflammation.

Abstract Objective In clinical practice, diagnosing the benignity and malignancy of solid-component-predominant pulmonary nodules is challenging, especially when 3D consolidation-to-tumor ratio (CTR) ≥ 50%, as malignant ones are more invasive. This study aims to develop and validate an AI-driven radiomics prediction model for such nodules to enhance diagnostic accuracy. Methods Data of 2,591 pulmonary nodules from five medical centers (Zhengzhou People’s Hospital, etc.) were collected. Applying exclusion criteria, 370 nodules (78 benign, 292 malignant) with 3D CTR ≥ 50% were selected and randomly split 7:3 into training and validation cohorts. Using R programming, Lasso regression with 10-fold cross-validation filtered features, followed by univariate and multivariate logistic regression to construct the model. Its efficacy was evaluated by ROC, DCA curves and calibration plots. Results Lasso regression picked 18 non-zero coefficients from 108 features. Three significant factors—patient age, solid component volume and mean CT value—were identified. The logistic regression equation was formulated. In the training set, the ROC AUC was 0.721 (95%CI: 0.642–0.801); in the validation set, AUC was 0.757 (95%CI: 0.632–0.881), showing the model’s stability and predictive ability. Conclusion The model has moderate accuracy in differentiating benign from malignant 3D CTR ≥ 50% nodules, holding clinical potential. Future efforts could explore more to improve its precision and value. Clinical trial number Not applicable.

Abstract Background Jianwei Xiaoshi oral liquid (JWXS), a classical traditional prescription comprising various edible medicinal plants, has demonstrated significant efficacy in treating paediatric indigestion. It originates from Jianpi Pill, which is developed in the Ming Dynasty and nourishes the spleen and regulates gastrointestinal function. However, the specific molecular mechanisms involved remain unclear. Methods To elucidate the material base of JWXS and its underlying mechanism in treating dyspepsia, the UHPLC–Q–Orbitrap HRMS method and network pharmacology were utilized. This was followed by pharmacological experiments, transcriptomics analyses and gut microbiota studies to further investigate the effects of JWXS on dyspepsia. Results A total of 105 compounds, mainly flavonoids, alkaloids, organic acids and cyclic peptides, were identified. According to the five principles of generic drug properties, 43 candidate compounds were screened out. Their efficacy was verified through gastric emptying and intestinal propulsion experiments. Transcriptomic analysis revealed that JWXS primarily alleviated dyspepsia symptoms by regulating the secretion of 8 key proteins in the pancreatic secretion pathway. The differences in the gut microbiota, as identified through 16S rRNA and ITS2 sequencing, were subsequently more pronounced than those observed in the bacterial microbiota of the model group. In total, 15 differential bacteria and 16 differential fungi were identified. Targeted metabolomics analysis of SCFAs revealed a significant decrease in valeric acid (VA), acetic acid (AA), and isovaleric acid (IVA) levels in the model group, which were restored to the corresponding levels after the administration of JWXS. Correlation analysis revealed that VA, AA, and IVA were positively correlated with Lactobacillus and Bacteroides, and negatively correlated with Aspergillus and Candida. This further suggested that JWXS might alleviate symptoms of indigestion by regulating the composition of the microbiota, increasing the variety and quantity of beneficial bacteria, reducing fungal contamination, and further increasing the levels of SCFAs in the body. Conclusion JWXS improved functional dyspepsia in immature rats via a mechanism involving the regulation of the secretion of 8 key proteins in the pancreatic secretion pathway and the amelioration of flora disorders. Graphical Abstract

The combination of reversible angular dispersion-induced microbunching (ADM) and the rapid damping storage ring provides a storage-ring-based light source with the capability to produce longitudinal coherent radiation with a high repetition rate. This paper presents a prototype design for a test facility based on the study by Jiang et al. [Sci. Rep. (2022), 12, 3325]. The modulation–demodulation section is inserted into a long straight section of the storage ring instead of a bypass line, which poses great challenges for the optimization of the nonlinear dynamics of the storage ring. However, this design avoids the challenging injection and extraction system connecting to the bypass line. To utilize mature laser technology and reduce the difficulty of the reversible ADM lattice design, we use a long-wavelength 1030 nm seed laser. In the simulation, we achieved 20th harmonic radiation with a bunching factor of about 7.2%. The growth rate of vertical emittance and energy spread of the electron beam for a single pass are about 11% and 0.02%, respectively. When the energy of the electron beam is 800 MeV and two sets of damping wigglers are employed, the damping time in the vertical plane is reduced to 8.31 ms. This results in a 438 kHz repetition rate of the coherent radiation at the new equilibrium state.

In order to explore the preparation and purification process of polyphenols from purple flower kidney bean skins and their anti-lipid oxidation effect, this study investigated the effects of solvent concentration, extraction temperature, extraction time, solid-liquid ratio and number of extraction on extraction amount of polyphenols from purple flower kidney bean skins by single factor experiments. Purified the crude extraction with HPD600 macroporous resin, and analyzed the phenolic composition using liquid chromatography-mass spectrometer. Shelf life predication model of peanut oil was established with peroxide value as the indicator using the Arrhenius equation. The experimental results showed that the optimal extraction conditions for kidney bean skin polyphenols were: ethanol concentration of 60%, extraction temperature of 70 ℃, extraction time of 40 min, solid-to-liquid ratio of 1:60 (g:mL), and 4 times of extraction, under these conditions, the extraction amount of polyphenols was 0.18±0.49 g/g. HPD600 had the highest static adsorption capacity and desorption rate, making it suitable for purifying polyphenols from purple kidney bean skins. The optimal purification conditions were: loading flow rate of 1.0 mL/min, ethanol concentration of 60%, elution flow rate of 1.0 mL/min, and the maximum purity of polyphenols was 54.68%±1.97%. Kidney bean skins contained 19 types of monomer phenols, with the highest catechin content at 425.952±7.652 µg/g. Adding kidney bean skin polyphenols or antioxidants could effectively delay the increase in peroxide value of edible oil. Using a model, it was calculated that peanut oil mixed with polyphenols-vitamin C had a maximum shelf life of 193.4 d at 20 ℃, control group was 150.3 d, with a maximum relative error of 8.7% compared to measured values, accurately predicting the shelf life of the edible oil. In conclusion, kidney bean skin polyphenols had strong antioxidant properties and potential as a safe natural food antioxidant.

Introduction: Bisphenol A (BPA) is a widespread environmental pollutant which has serious toxic effects on organisms. One of the crucial trace elements is selenium (Se), whose shortage can harm biological tissues and enhance the toxicity of contaminants, in which apoptosis and autophagy are core events. Objectives: An in vivo model was established to investigate the effects of BPA and low-Se on chicken pancreatic tissue, and identify the possible potential molecular mechanism. Methods: A total of 80 1-day-old broiler chickens (Xinghua Chicken Farm, Harbin, China) were stochastically divided into 4 groups (n = 20/group): Control group, BPA group, low-Se group, and low-Se + BPA group. Pancreatic tissue was collected at day 42 to detect changes in markers. Results: First, the data showed that BPA and low-Se exposure gave rose to structural abnormalities in pancreatic tissue, oxidative stress, mitochondrial dysfunction and homeostasis imbalance, apoptosis and mitophagy. In addition, the co-exposure of BPA and low-Se caused the most serious damage to pancreatic tissue. In terms of mechanism, it was found that apoptosis and mitophagy induced by BPA and low-Se were related to the activation of PTEN/PI3K/AKT/mTOR pathway. Conclusion: In summary, the study found that BPA and low-Se exacerbated mitochondria damage, apoptosis and mitophagy by regulating the PTEN/PI3K/AKT/mTOR pathway.

Abstract The identification of ferroptosis represents a pivotal advancement in the field of cell death research, revealing an entirely novel mechanism of cellular demise and offering new insights into the initiation, progression, and therapeutic management of various diseases. Ferroptosis is predominantly induced by intracellular iron accumulation, lipid peroxidation, or impairments in the antioxidant defense system, culminating in membrane rupture and consequent cell death. Studies have associated ferroptosis with a wide range of diseases, and by enhancing our comprehension of its underlying mechanisms, we can formulate innovative therapeutic strategies, thereby providing renewed hope for patients.

Abstract Objective By comparing the differences in pre-competition state anxiety, inter-competition heart rate variability (HRV), and shooting performance of young athletes of different grades, and revealing the correlation between these variables, it provides a potential basis for improving athletes’ shooting performance. Methods A total of 45 adolescent shooters were selected in Chongqing, China, and completed 40 effective shots at self-pace in real shooting scenes. The pre-competition state anxiety, inter-competition HRV, and shooting performance of the athletes were monitored and evaluated respectively. Results (1) There was a significant difference in the pre-match state anxiety of the adolescent shooters, which showed that the cognitive state anxiety and physical state anxiety of the first-level athletes were significantly lower than those of the second-level athletes, while the state confidence was significantly higher than that of the second-level athletes. (2) There were significant differences in HRV of athletes with different sports levels during the competition, showing that the root mean square differences of the standard deviation (RMSSD), total power (TP), and high-frequency of normal (HFn) of the first-level athletes were significantly higher than those of second-level athletes, while low-frequency of normal (LFn) was significantly lower than the latter. (3) The shooting performance of first-level athletes was significantly better than that of second-level athletes. (4) Among adolescent shooters of different grades, there was a significant correlation between pre-competition state anxiety, inter-competition HRV, and shooting performance. The negative dimension of state anxiety was positively correlated with sympathetic activity in HRV, negatively correlated with parasympathetic activity, and negatively correlated with shooting performance. The positive dimension of state anxiety was negatively correlated with sympathetic activity in HRV, positively correlated with parasympathetic activity, and significantly positively correlated with motor performance. Conclusion Adolescent shooters with higher sports levels usually have better pre-competition mental state and emotional regulation ability, and could better maintain autonomic nerve dynamic balance and focus attention resources on shooting tasks during the competition, so it was easier to achieve good shooting performance. Meanwhile, pre-competition state anxiety and HRV during competition could be used as objective indicators to monitor and evaluate the competitive state of young shooters.

Abstract Background Abnormal expression of six-transmembrane epithelial antigen of prostate 4 (STEAP4) has been implicated in the carcinogenesis of hepatocellular carcinoma (HCC). However, the biological role and regulatory mechanisms of STEAP4 in HCC remain unclear. Methods and Results Here, we analyzed STEAP4 expression levels and differentially expressed genes (DEGs) between STEAP4 high- and low-expression groups using multiple databases. Proliferation assays, 5-ethynyl-2’-deoxyuridine (EdU) assays, propidium iodide (PI) flow cytometry, and colony formation assays were conducted to assess the effects of STEAP4 on HCC cell proliferation, cell cycle progression, and clonogenic capacity. STEAP4 was downregulated in HCC tumor tissues, with lower expression associated with poorer overall survival (OS) and disease-free survival (DFS) in patients. Functional network analysis suggested that STEAP4 regulates cell cycle signaling, with tumor sections showing a negative correlation between STEAP4 and cell cycle proteins. Overexpression of STEAP4, combined with non-cytotoxic copper exposure in the HepG2 cell line, reduced proliferation and clonogenicity, induced cell cycle arrest, and downregulated the mRNA and protein levels of cell cycle-regulating genes. A predictive model based on STEAP4 and cell cycle gene demonstrated prognostic value in HCC patients. Conclusions Our results lay a foundation for further study of the cell cycle regulatory role of STEAP4 with Cu2+ reductase activity in HCC, indicating that STEAP4 may be a promising therapeutic target for HCC.

Abstract Cardiovascular diseases (CVDs) and cerebrovascular diseases (CeVDs) are closely related vascular diseases, sharing common cardiometabolic risk factors (RFs). Although pleiotropic genetic variants of these two diseases have been reported, their underlying pathological mechanisms are still unclear. Leveraging GWAS summary data and using genetic correlation, pleiotropic variants identification, and colocalization analyses, we identified 11 colocalized loci for CVDs-CeVDs-BP (blood pressure), CVDs-CeVDs-LIP (lipid traits), and CVDs-CeVDs-cIMT (carotid intima-media thickness) triplets. No shared causal loci were found for CVDs-CeVDs-T2D (type 2 diabetes) or CVDs-CeVDs-BMI (body mass index) triplets. The 11 loci were mapped to 12 genes, namely CASZ1, CDKN1A, TWIST1, CDKN2B, ABO, SWAP70, SH2B3, LRCH1, FES, GOSR2, RPRML, and LDLR, where both GOSR2 and RPRML were mapped to one locus. They were enriched in pathways related to cellular response to external stimulus and regulation of the phosphate metabolic process and were highly expressed in endothelial cells, epithelial cells, and smooth muscle cells. Multi-omics analysis revealed methylation of two genes (CASZ1 and LRCH1) may play a causal role in the genetic pleiotropy. Notably, these pleiotropic loci are highly enriched in the targets of antihypertensive drugs, which further emphasizes the role of the blood pressure regulation pathway in the shared etiology of CVDs and CeVDs.

Abstract Background With the rising incidence of pulmonary nodules (PNs), lung adenocarcinoma in situ (AIS) is a critical early stage of lung cancer, necessitating accurate diagnosis for early intervention. This study applies artificial intelligence (AI) for quantitative imaging analysis to differentiate AIS from atypical adenomatous hyperplasia (AAH) and minimally invasive adenocarcinoma (MIA), aiming to enhance clinical diagnosis and prevent misdiagnosis. Methods The study analyzed 1215 PNs with confirmed AAH, AIS, and MIA from six centers using the Shukun AI diagnostic module. Parameters evaluated included demographic data and various CT imaging metrics to identify indicators for clinical application, focusing on the mean CT value's predictive value. Results Significant differences were found in several parameters between AAH and AIS, with nodule mass showing the highest predictive value. When comparing AIS to MIA, total nodule volume was the best predictor, followed by the maximum CT value. Conclusion The mean CT value has limited discriminative power for AIS diagnosis. Instead, the maximum CT value and maximum 3D diameter are recommended for clinical differentiation. Nodule mass and volume of solid components are strong indicators for differentiating AIS from AAH and MIA, respectively.

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.

Collagen XVII (COL17) is a transmembrane protein that mediates skin homeostasis. Due to expression of full length collagen was hard to achieve in microorganisms, arising the needs for selection of collagen fragments with desired functions for microbial biosynthesis. Here, COL17 fragments (27–33 amino acids) were extracted and replicated 16 times for recombinant expression in Escherichia coli. Five variants were soluble expressed, with the highest yield of 223 mg/L. The fusion tag was removed for biochemical and biophysical characterization. Circular dichroism results suggested one variant (sample-1707) with a triple-helix structure at >37 °C. Sample-1707 can assemble into nanofiber (width, 5.6 nm) and form hydrogel at 3 mg/mL. Sample-1707 was shown to induce blood clotting and promote osteoblast differentiation. Furthermore, sample-1707 exhibited high capacity to induce mouse hair follicle stem cells differentiation and osteoblast migration, demonstrating a high capacity to induce skin cell regeneration and promote wound healing. A strong hydrogel was prepared from a chitosan and sample-1707 complex with a swelling rate of >30 % higher than simply using chitosan. Fed-batch fermentation of sample-1707 with a 5-L bioreactor obtained a yield of 600 mg/L. These results support the large-scale production of sample-1707 as a biomaterial for use in the skin care industry.

The development of green transportation is crucial for creating a low-carbon roadmap in the transportation sector. We calculate the efficiency of green transportation in China and then examine its effect on carbon lock-in. The asymmetric nexus between green transportation efficiency and carbon lock-in is investigated, and the moderating and mediating effects are also examined. Our results indicate that (1) green transportation efficiency is effective in reducing carbon lock-in and promoting a low-carbon transition; (2) The relationship between green transportation efficiency and carbon lock-in is asymmetric, with green transportation efficiency having a stronger effect in areas with lower levels of carbon lock-in. (3) Environmental regulation can contribute to the eradication of carbon lock-in and strengthen the effect of green transportation efficiency, showing significant a moderating effect. (4) Green transportation efficiency indirectly affects carbon lock-in by promoting energy consumption efficiency and renewable energy development.

Introducing CO2 during the mixing process of filling slurry for wet carbonation enables simultaneous carbonation and hydration reactions of the carbonated filling slurry (CSL). This study evaluates the microstructural evolution and strength development of carbonated cemented paste backfill (CCPB) under different carbonation times, and discusses the carbonation products and carbon sequestration of CCPB. The results reveal that introducing 99% pure CO2 at a flow rate of 1 L/min for 10 min into the filling slurry in a non-sealed container effectively optimizes the microscopic pore structure and mechanical properties of CCPB, achieving a carbon sequestration rate of 6.42%. Short-term carbonation leads to a continuous decrease in the T2 relaxation signal of CSL in the early hydration stage, enhancing pore structure by converting secondary pores to micropores. The main carbonation product is calcite crystalline CaCO3, which forms a dense carbonation layer on the surface of the tailings particles. However, prolonged carbonation results in the formation of microscopic pore encapsulation layer, hindering further CO2 diffusion, reducing carbonation efficiency, and deteriorating the mechanical properties of CCPB. With a carbonation time of 10 min, the UCS and EM of CCPB with different cement-to-tailings ratios show significant improvement, and the specimens exhibit lower fragmentation and fewer secondary cracks, maintaining better integrity after failure. In conclusion, the wet carbonation of filling slurry not only enhances the strength of the filling material but also achieves the reutilization of gaseous and solid wastes through carbon sequestration filling method, providing an efficient and eco-friendly solution for mine backfilling.

Abstract Recent research suggested that mental toughness might play a mediating role in the relationship between multidimensional perfectionism and sleep quality. This study sought to examine the associations between multidimensional perfectionism, mental toughness, and sleep quality in young Chinese athletes, with a particular focus on investigating the potential mediating role of mental toughness in the relationship between multidimensional perfectionism and sleep quality. A total of 208 Chinese athletes (129 females and 79 males) aged from 15 to 29 (Mage = 19.9, SD = 2.52) were included. Structural equation modeling (SEM) was used to analyze the potential mediating effect. The results revealed that perfectionism striving was not associated with sleep quality, whereas perfectionism concerning emerged as a negative predictor of sleep quality. Mental toughness could positively predict sleep quality. The mediation analysis demonstrated that mental toughness partially mediated the relationship between perfectionism concerning and sleep quality. This study revealed that perfectionism concerning can reduce sleep quality, and mental toughness played a partial mediating role in the relationship between perfectionism concerning and sleep quality among Chinese young athletes. These findings suggest that enhancing athletes’ mental toughness and reducing perfectionism concerning may be effective strategies for improving sleep quality.

Abstract Anatomy-based guidelines for shoulder surgery have established the routine preoperative evaluation of the humeral head. Despite recognized sex differences in humeral head size, there has been limited investigation into sex-specific variations in acromiohumeral contact surface (AHCS) arc length. This study aims to assess sex differences in the AHCS arc length within a sample of the Chinese population. We retrospectively analyzed 169 normal shoulder CT images from a single medical center, collected between 2011 and 2021. The AHCS arc length was defined as the distance from the superior glenoid tubercle to the lateral edge of the greater tuberosity, measured using a three-dimensional reconstruction algorithm. Physiological reference values for the AHCS arc length were determined at three abduction angle intervals. Linear regression analysis was used to assess the correlation between the AHCS arc length and abduction angle in both sexes. The reference values for AHCS arc length were significantly lower in women across three abduction angle intervals (male 48.07 ± 3.37 mm vs. female 43.54 ± 2.54 mm, (0–10] °, p 20 °, p = 0.001, respectively). Additionally, the AHCS arc length was linearly and negatively correlated with the abduction angle (male R2 = 0.436, p

Abstract Objective To investigate the relationship between internet use, physical activity, social adaptability, and depressive tendencies of college students, and to reveal the “advantages” and “disadvantages” of internet use around the “dose-effect”. Method The Revised Chinese Internet Addiction Scale (CIAS-R), Physical Activity Rating Scale (PARS-3), Chinese College Student Social Adjustment Scale (CCSAS), and Self-rating Depression Scale (SDS) were used to conduct a random sampling survey among 3008 college students in China. Results (1) Internet use could directly and positively predict the depressive tendencies of college students. (2) Physical activity and social adaptability have a significant chain mediating effect between internet use and depressive tendencies. (3) There was a “U-shaped” dose-effect relationship between internet use and depression tendencies, indicating that normal internet use could directly and negatively predict depressive tendencies, and through the chain mediating effect of physical activity and social adaptability negatively predict depressive tendencies. In contrast, internet use dependence and addiction could directly predict depressive tendencies, and through the chain mediating effect of physical activity and social adaptability positively predict it. Conclusion Therefore, normal or moderate internet use has potential protective benefits on the physical and mental health of college students and can promote the positive development of physical activity and social adaptability to a certain extent, and prevent or reduce depressive tendencies, otherwise, it is not conducive to the healthy development of related behaviors and psychology.

Abstract Foxtail millet is an important minor cereal crop rich in nutrients. Due to the small size of its seeds, there is little information on the diversity of its seed structure among germplasms, limiting the identification of genes controlling seed development and germination. This paper utilized X-ray computed tomography (CT) scanning technology and deep learning models to reveal the microstructure of foxtail millet seeds, gaining insights into their internal features, distribution, and composition. A total of 100 foxtail millet varieties were scanned with X-ray computed tomography to obtain 3D reconstruction images and slices. Pre-processing steps were adopted to improve image segmentation accuracy, including noise reduction, rotation, contrast enhancement, and brightness enhancement. The experiment revealed that traditional OpenCV image processing methods failed to achieve precise segmentation, whereas deep learning models exhibited outstanding performance in segmenting seed CT slice images. We compared UNet, PSPNet, and DeepLabV3 models, selected different backbones and optimizers based on the dataset, and continuously adjusted learning rates and maximum training epochs to train the models. Results demonstrated that VGG16-UNet achieved an accuracy of 99.19% on the foxtail millet seed CT slice image dataset, outperforming PSPNet and DeepLabV3 models. Compared to ResNet-UNet, VGG16-UNet shows an improvement of approximately 3.18% in accuracy, demonstrating superior performance in accurately segmenting the inner glume, outer glume, embryo, and endosperm under various adhesion conditions. Accurate segmentation of foxtail millet CT images enables analysis of embryo size, endosperm size, and glume thickness, which impact germination, growth, and nutrition. This study fills a gap in small grain structure research, offering insights to optimize agriculture and molecular breeding for improved yield and quality.

The cracking issue at the bonded interface due to the differing shrinkage performances of newly poured concrete and existing concrete poses a significant threat to the safe service of composite structures. Inspired by the musculoskeletal system, we propose the use of multiscale hybrid reinforced concrete materials, incorporating basalt fiber (BF), polypropylene (PP) fiber, and cellulose nanofiber (CNF), for bridge widening structures. Experimental investigations were carried out to assess the bond splitting tensile strength, diagonal shear strength, crack resistance, development of drying shrinkage deformation, and the propagation behavior of restrained shrinkage-induced cracks in both new and old concrete reinforced with single and hybrid combinations of BF, PP fiber, and CNF. The microstructure, phase composition, and pore structure evolution of BF, PP fiber, and CNF-reinforced concrete were observed and analyzed using scanning electron microscopy, thermogravimetric and derivative thermogravimetric analysis, nuclear magnetic resonance, and mercury intrusion porosimetry. The results indicate that the incorporation of BF, PP fiber, and CNF exhibits excellent synergistic effects, improving the bond and shrinkage performance of the concrete interface. As the CNF content increases, the macro fiber–matrix interface improves. This bio-inspired work will contribute to the development of strong, tough, and sustainable concrete for bridge widening structures.

Soft tissue integration around titanium (Ti) implants is weaker than that around natural teeth, compromising long-term success of Ti implants. Carbon monoxide (CO) possesses distinctive therapeutic properties, rendering it as a highly promising candidate for enhancing STI. However, achieving controlled CO generation at the STI interface remains challenging. Herein, a controlled CO-releasing dual-function coating was constructed on Ti surfaces. Under near-infrared (NIR) irradiation, the designed surface could actively accelerate CO generation for antibiosis against both aerobic and anaerobic bacteria. More importantly, in the absence of NIR, the slow release of CO induces macrophage polarization from pro-inflammatory phenotype towards pro-regenerative phenotype. In a rat implantation model with induced infection, the designed surface effectively controlled the bacterial infection, alleviates accompanying inflammation and modulated immune microenvironment, leading to enhanced STI. Single-cell sequencing revealed that the coating alters the cytokine profile within the soft tissue, thereby influencing cellular functions. Differentially expressed genes in macrophages are highly enriched in the PIK3-Akt pathway. Furthermore, the cellular communication between fibroblasts and macrophages was significantly enhanced through the CXCL12/CXCL14/CXCR4 and CSF1-CSF1R ligand-receptor pair. These findings indicate that our coating showed an appealing prospect for enhancing STI around Ti implants, which would ultimately contribute to the improved long-term success of Ti implants.

Abstract Immune checkpoint blockade (ICB) is a promising cancer therapy; however, resistance frequently develops. To explore ICB resistance mechanisms, we develop Immunotherapy Resistance cell-cell Interaction Scanner (IRIS), a machine learning model aimed at identifying cell-type-specific tumor microenvironment ligand-receptor interactions relevant to ICB resistance. Applying IRIS to deconvolved transcriptomics data of the five largest melanoma ICB cohorts, we identify specific downregulated interactions, termed resistance downregulated interactions (RDI), as tumors develop resistance. These RDIs often involve chemokine signaling and offer a stronger predictive signal for ICB response compared to upregulated interactions or the state-of-the-art published transcriptomics biomarkers. Validation across multiple independent melanoma patient cohorts and modalities confirms that RDI activity is associated with CD8 + T cell infiltration and highly manifested in hot/brisk tumors. This study presents a strongly predictive ICB response biomarker, highlighting the key role of downregulating chemotaxis-associated ligand-receptor interactions in inhibiting lymphocyte infiltration in resistant tumors.

Abstract Background Pulmonary embolism (PE) is life-threatening and requires timely and accurate diagnosis, yet current imaging methods, like computed tomography pulmonary angiography, present limitations, particularly for patients with contraindications to iodinated contrast agents. We aimed to develop a quantitative texture analysis pipeline using machine learning (ML) based on non-contrast thoracic computed tomography (CT) scans to discover intensity and textural features correlated with regional lung perfusion (Q) physiology and pathology and synthesize voxel-wise Q surrogates to assist in PE diagnosis. Methods We retrospectively collected 99mTc-labeled macroaggregated albumin Q-SPECT/CT scans from patients suspected of PE, including an internal dataset of 76 patients (64 for training, 12 for testing) and an external testing dataset of 49 patients. Quantitative CT features were extracted from segmented lung subregions and underwent a two-stage feature selection pipeline. The prior-knowledge-driven preselection stage screened for robust and non-redundant perfusion-correlated features, while the data-driven selection stage further filtered features by fitting ML models for classification. The final classification model, trained with the highest-performing PE-associated feature combination, was evaluated in the testing cohorts based on the Area Under the Curve (AUC) for subregion-level predictability. The voxel-wise Q surrogate was then synthesized using the final selected feature maps (FMs) and model score maps (MSMs) to investigate spatial distributions. The Spearman correlation coefficient (SCC) and Dice similarity coefficient (DSC) were used to assess the spatial consistency between FMs or MSMs and Q-SPECT scans. Results The optimal model performance achieved an AUC of 0.863 during internal testing and 0.828 on the external testing cohort. The model identified a combination containing 14 intensity and textural features that were non-redundant, robust, and capable of distinguishing between high- and low-functional lung regions. Spatial consistency assessment in the internal testing cohort showed moderate-to-high agreement between MSMs and reference Q-SPECT scans, with median SCC of 0.66, median DSCs of 0.86 and 0.64 for high- and low-functional regions, respectively. Conclusions This study validated the feasibility of using quantitative texture analysis and a data-driven ML pipeline to generate voxel-wise lung perfusion surrogates, providing a radiation-free, widely accessible alternative to functional lung imaging in managing pulmonary vascular diseases. Clinical trial number Not applicable.

Infections with the coronavirus disease 2019 (COVID-19) and disorders of the heart and blood vessels are causally related. To ascertain the causal relationship between COVID-19 and cardiovascular disease (CVD), we carried out a Mendelian randomization (MR) study through a method known as inverse variance weighting (IVW). When analyzing multiple SNPs, MR can meta-aggregate the effects of multiple loci by using IVW meta-pooling method. The weighted median (WM) is the median of the distribution function obtained by ranking all individual SNP effect values according to their weights. WM yields robust estimates when at least 50% of the information originates from valid instrumental variables (IVs). Directed gene pleiotropy in the included IVs is permitted because MR–Egger does not require a regression straight line through the origin. For MR estimation, IVW, WM and MR-Egger were employed. Sensitivity analysis was conducted using funnel plots, Cochran's Q test, MR–Egger intercept test, MR–PRESSO, and leave-one-out analysis. SNPs related to exposure to COVID-19 and CVD were compiled. CVD for COVID-19 infection, COVID-19 laboratory/self-reported negative, and other very severe respiratory diagnosis and population were randomly assigned using MR. The COVID-19 laboratory/self-reported negative results and other very severe respiratory confirmed cases versus MR analysis of CVD in the population (p ​> ​0.05); COVID-19 infection to CVD (p ​= ​0.033, OR ​= ​1.001, 95%CI: 1.000–1.001); and the MR–Egger results indicated that COVID-19 infection was associated with CVD risk. This MR study provides preliminary evidence for the validity of the causal link between COVID-19 infection and CVD.

Abstract As the first identified multidrug efflux pump in Mycobacterium tuberculosis (Mtb), EfpA is an essential protein and promising drug target. However, the functional and inhibitory mechanisms of EfpA are poorly understood. Here we report cryo-EM structures of EfpA in outward-open conformation, either bound to three endogenous lipids or the inhibitor BRD-8000.3. Three lipids inside EfpA span from the inner leaflet to the outer leaflet of the membrane. BRD-8000.3 occupies one lipid site at the level of inner membrane leaflet, competitively inhibiting lipid binding. EfpA resembles the related lysophospholipid transporter MFSD2A in both overall structure and lipid binding sites and may function as a lipid flippase. Combining AlphaFold-predicted EfpA structure, which is inward-open, we propose a complete conformational transition cycle for EfpA. Together, our results provide a structural and mechanistic foundation to comprehend EfpA function and develop EfpA-targeting anti-TB drugs.

The calculation method for negative skin friction of a single pile has not been unified yet. To improve the design and calculation level of the single pile under vertical load considering negative skin friction, the threshold limit value of pile skin friction was determined based on the effective stress method. The effects of relative displacement of pile-soil and pile depth on pile skin friction were analyzed, and a nonlinear calculation model for pile skin friction was established. The pile skin friction was divided into elastic and plastic states. In the elastic range, the friction is a quadratic function with the depth of the pile body; while in the plastic range, the friction is distributed linearly along the pile body, and the slope is the product of the effective weight of the soil around the pile and the negative friction coefficient. Consequently, the analytical solution of the pile skin friction for the corresponding pile section was acquired. Based on the theory of pile axial force calculation, a formula for calculating the axial force of a single pile under different distribution forms of pile lateral friction was obtained. The reliability, applicability, and practicality of this model were verified by measured data. Based on the calculated pile shaft axial force, the axial force of single pile with different distributions of skin friction was analyzed. This study has practical significance for fully utilizing the performance of pile foundations and improving the level of pile foundation design.

Background: The causal associations and potential mechanisms between prostatic diseases, the predominant male urological disorders, and the course of COVID-19 remain unclear. Methods: A two-sample Mendelian randomization (MR) analysis was performed to evaluate causal associations between prostate cancer, benign prostatic hyperplasia, and prostatitis and different COVID-19 outcomes (SARS-CoV-2 infection, hospitalized COVID-19, and severe COVID-19). Reverse MR, linkage disequilibrium score regression, and Bayesian colocalization analyses were subsequently performed to strengthen the identified causal relationships. Furthermore, immunome- and metabolome-wide MR analysis was conducted to prioritize COVID-19-associated immune characteristics and metabolites. Two-step MR analysis was performed to evaluate the mediating effects of the immunome and metabolome on the associations between prostatic diseases and COVID-19. Results: Genetically predicted prostatic diseases were not causally associated with severe COVID-19, while prostatitis was suggested to be an independent risk factor for SARS-CoV-2 infection (odds ratio (OR) = 1.11, 95% confidence interval (CI) 1.01 to 1.23; P = 0.03). Multiple sensitivity tests verified the reliability of the established causal relationships. Dozens of blood immune and metabolic features were identified to reveal the immune and metabolic profiles of different COVID-19 courses. Moreover, PDL-1 on monocyte was found to mediate the interaction between prostatitis and SARS-CoV-2 infection, with a mediation proportion of 9.2%. Conclusion: Our study identified the causal relationships of prostatic diseases with COVID-19 and suggested pathways explaining these associations through alterations in the blood immunome and metabolome.

Abstract As one of the most prevalent tumors, colorectal cancer (CRC) owns complex pathogenesis and the high recurrence rate significantly influence the prognosis of patients with KRAS mutant CRC, to discovery the crosstalk among KEAP1‐NFE2L2 and oncogenic KRAS as the potential prognostic biomarkers in CRC, which might be used to develop novel and effective therapeutics. By using bioinformatics analysis, we explored and identified key genes as the predicted targets in the crosstalk among KEAP1 oncogenic signatures of KRAS mutation that were linked with development, metastasis, and poor prognosis in CRC. We further investigated the correlations between the clinical characteristics and expressions of prognostic genes among the KRAS and KEAP1‐related key hub genes in CRC, which as predicted targets to find the potential herbal ingredients in HERB database, further to verify the active herbal ingredients could regulate the key targets that related to KEAP1‐NFE2L2 in KRAS mutant CRC. The newest TCGA data reveals that the mutation of KRAS is found in 44% of CRC patients. In total, 28 genes were identified as differentially expressed genes (DEGs), and the hub genes such as CDKN2A, SPP1, FOS, BCL2L11, and HPSE were verified. Results indicated that key genes (SOX9, SPP1) significant correlation with the target prediction of the active herbal ingredients by molecular docking analysis. Furthermore, KEAP1, NFE2L2, SOX9 expression were decreased significantly with the treatment of potential ingredients. Furthermore, cyclopamine could enhance the sensitivity of HCT116 cells, downregulated the expression of SPP1, and induced activation of KEAP1‐NFE2L2 pathway, which cell death are characteristic features of apoptosis, and enhanced anticancer effect. Therefore, KEAP1‐related genes might be important oncogenic signatures in KRAS mutant CRC cells and cyclopamine was identified as a potential ingredient and regulated the predict targets of SOX9 and SPP1, may be expand the efficacy and range of novel and effective therapeutics.

Abstract Stress can lead to gut dysbiosis in brain-gut axis disordered diseases as irritable bowel syndrome (IBS), yet the mechanisms how stress transfer from the brain to the gut and disrupt gut microbiota remain elusive. Here we describe a stress-responsive brain-to-gut axis which impairs colonocytes’ mitochondria to trigger gut dysbiosis. Patients with IBS exhibit significantly increased facultative anaerobes and decreased obligate anaerobes, related to increased serum corticotropin-releasing hormone (CRH) level and defected colonocytes’ mitochondria ultrastructure. Mice exposed to acute stress experienced enhanced CRH-CRH receptor type 1 (CRHR1) signaling, which impaired mitochondria and epithelium hypoxia in the colon, subsequently triggered gut dysbiosis. Antagonizing CRHR1 expression to inhibit cAMP/Ras/MAPK signaling or activating mitochondria respiration conferred resilience against stress-induced mitochondria damaging and epithelium hypoxia impairment, ultimately improving gut dysbiosis. These results suggest that the CRH-CRHR1-mitochondria pathway plays a pivotal role in stress-induced gut dysbiosis that could be therapeutically targeted for stress-induced gastrointestinal diseases. Yiming Zhang et.al report that psychological stress activated Corticotropin-releasing hormone (CRH)-CRH receptor type 1 (CRHR1)-mitochondria pathway to trigger gut dysbiosis and reveal CRHR1 upregulation damages mitochondria via cAMP/Ras/MAPK signaling in colonocytes.

Abstract Background Parathyroid adenoma is the primary cause of primary hyperparathyroidism, commonly presenting with elevated parathyroid hormone (PTH) and blood calcium levels. Chronic primary hyperparathyroidism often results in bone destruction, resulting in the formation of brown tumors. The preferred clinical treatment for parathyroid adenoma is parathyroidectomy. Postoperative pancytopenia, although rare, is a critical complication that warrants further investigation into its mechanisms and management strategies. Case presentation We present a case of a 59-year-old female patient who was admitted due to nausea and vomiting. Positron emission tomography-computed tomography (PET-CT) revealed a mass posterior to the left thyroid lobe and multiple areas of fibrocystic osteitis throughout the body. Hematological tests showed elevated serum calcium and parathyroid hormone (PTH) levels. The patient subsequently underwent parathyroidectomy, and pathological examination confirmed the presence of a parathyroid adenoma. Postoperatively, the patient developed pancytopenia and received symptomatic treatment such as correction of anemia and elevation of white blood. At the two-month follow-up, all indicators had returned to normal. Conclusions Pancytopenia is commonly seen in bone marrow diseases, infections and immune-related disorders, nutritional deficiencies, and metabolic diseases. This case confirms that pancytopenia can also occur postoperatively in patients with parathyroid adenoma. Therefore, Clinicians should be aware of the potential for postoperative pancytopenia following parathyroidectomy and the need for prompt management.

Abstract Retinopathy of prematurity (ROP) is a severe retinal disease in premature infants characterized by pathological neovascularization, obliteration of retinal vessels and increased vessel tortuosity. Currently, there are no completely satisfactory treatments for ROP. Pigment epithelium‐derived factor (PEDF), a potent inhibitor of angiogenesis, appears late in gestation and its deficiency may be linked to development of ROP. This study investigates the preclinical efficacy of PEDF protein alone or in combination with VEGF antagonists for treating ROP. The safety of PEDF protein in the rat eye was assessed using functional in vivo measurements and histology. The efficacy of intravitreal injections (IVI) of various treatments was evaluated in a rat oxygen‐induced retinopathy (OIR) model using in vivo imaging and flatmount analyses. No functional or histological side‐effects were found in rat eyes after intravitreal PEDF protein injection. PEDF protein alone or combined with anti‐VEGF drugs significantly reduced pathological neovascularization and vessel obliteration, comparable to the effects of anti‐VEGF drugs alone. Regarding arterial tortuosity, treatment with a combination of PEDF, and VEGF antagonist was more effective than treatment with anti‐VEGF alone. IVI of PEDF protein is safe. PEDF protein alone or combined with VEGF antagonists shows similar efficacy in reducing pathological neovascularization and vessel obliteration as anti‐VEGF agents. Furthermore, only treatments involving PEDF protein, alone or with VEGF antagonists, significantly improved the quality of retinal vasculature. Thus, PEDF protein alone or combined with anti‐VEGF agents presents a promising alternative to current anti‐VEGF treatments for ROP.

Labral tear of the hip joint is an important factor causing joint pain and locking, as well as mobility disturbance. Although femoroacetabular impingement syndrome often results in anterior labral tears, posterior labral tears are present in a subset of patients, especially those with a history of posterior hip dislocation. Posterior labral repair under arthroscopy usually requires switching between the viewing approach and the operating approach, but this undoubtedly increases the operative time and the destruction of soft tissue. This article introduces a technique for rapid posterior labral suture by rotating the arthroscopic camera without switching the surgical approach.

Cardiovascular diseases are the most lethal diseases worldwide, of which myocardial infarction is the leading cause of death. After myocardial infarction, in order to ensure normal blood supply to the heart, the remaining cardiomyocytes compensate for the loss of cardiomyocytes mainly by working at high capacity rather than by proliferating to produce new cardiomyocytes. This is partly due to the extremely limited ability of the adult heart to repair itself. A growing body of research suggests that the loss of cardiac regenerative capacity is closely related to metabolic shifts in energy sources. Currently, a large number of studies have focused on changes in metabolic levels before and after the proliferation window of cardiomyocytes, so it is crucial to search for relevant factors in metabolic pathways to regulate the cell cycle in cardiomyocyte progression. This paper presents a review of the role of myocardial energy metabolism in regenerative repair after cardiac injury. It aims to elucidate the effects of myocardial metabolic shifts on cardiomyocyte proliferation in adult mammals and to point out directions for cardiac regeneration research and clinical treatment of myocardial infarction.

The Jurassic Yan ’an Formation in the southwestern margin of Ordos Basin has developed many sets of coal-associated and non-associated mudstone as well as oil shale. Different analytical methods including total organic carbon (TOC), Rock-Eval pyrolysis, and conventional biomarker analyses were applied on the mudstone, the coal and the oil shale extracts to unravel their organic geochemical characteristics and the paleo depositional environment. Results reveal that all the source rock samples are immature to mature with good petroleum generation potentials. The redox environment is generally reducing. The organic matter input is mainly terrestrial higher plants. The low Ga/C30 hopane ratio of all the samples indicate the low salinity of the paleo-water column. The oil shale samples show much higher thermal maturity than the coals and mudstones as indicated by the higher C31 homohopane isomerization indexes, C32 homohopane isomerization indexes and the C29 sterane ααα20S/(S + R) ratios. The depositional environment of the oil shale is more reduced compared to the coals and mudstones as can be reflected by the low oxygen index and the higher C35 hopane/(C31-C35 homohopanes) ratios. Thus, the oil shale layers should be the target of the next exploration and development. And the Oil shale and coal can be exploited simultaneously in Pengyang area.

CD8 subunit alpha (CD8A) is an important gene in immunity and is involved in the functional regulation of T lymphocytes. However, the specific role and regulatory mechanism of CD8A in chicken T lymphocytes remain unknown. In this study, we overexpressed and interfered with CD8A in chicken T lymphocytes and found that interfering with CD8A expression inhibited the proliferation and induced the apoptosis of T lymphocytes and that the overexpression of CD8A promoted T lymphocyte activation. Additionally, transcriptomic and metabolomic analyses of chicken T lymphocytes with CD8A overexpression or interference were performed. The overexpression and interference of the CD8A gene caused widespread changes in gene and metabolite expression in chicken T cells. The results of the transcriptome analysis revealed that differentially expressed genes (DEGs) caused by altered expression of the CD8A gene were associated with multiple “neuroactive ligand-receptor interaction”, “cell adhesion molecules”, “calcium signaling pathway”, etc. The metabolome analysis results revealed that different metabolites (DMs) caused by altered CD8A gene expression were associated with “Glutathione metabolism”, “Arginine biosynthesis”, “D-amino acid metabolism”, etc. The combined transcriptional and metabolic analysis revealed one metabolically related pathway, “Glutathione metabolism”. Our findings further revealed that interference and overexpression of CD8A plays a role in the metabolism of Glutathione. Thus, CD8A may be a critical regulator of “Glutathione metabolism” and may subsequently affect T-cell function in chickens. These results provide an important reference for further research on the effect of CD8A on the immune performance of chickens.

Objective: Segmenting and reconstructing 3D models of bone tumors from 2D image data is of great significance for assisting disease diagnosis and treatment. However, due to the low distinguishability of tumors and surrounding tissues in images, existing methods lack accuracy and stability. This study proposes a U-Net model based on double dimensionality reduction and channel attention gating mechanism, namely the DCU-Net model for oncological image segmentation. After realizing automatic segmentation and 3D reconstruction of osteosarcoma by optimizing feature extraction and improving target space clustering capabilities, we built a mixed reality (MR) infrastructure and explored the application prospects of the infrastructure combining deep learning-based medical image segmentation and mixed reality in the diagnosis and treatment of bone tumors. Methods: We conducted experiments using a hospital dataset for bone tumor segmentation, used the optimized DCU-Net and 3D reconstruction technology to generate bone tumor models, and used set similarity (DSC), recall (R), precision (P), and 3D vertex distance error (VDE) to evaluate segmentation performance and 3D reconstruction effects. Then, two surgeons conducted clinical examination experiments on patients using two different methods, viewing 2D images and virtual reality infrastructure, and used the Likert scale (LS) to compare the effectiveness of surgical plans of the two methods. Results: The DSC, R and P values of the model introduced in this paper all exceed 90%, which has significant advantages compared with methods such as U-Net and Attention-Uet. Furthermore, LS showed that clinicians in the DCU-Net-based MR group had better spatial awareness of tumor preoperative planning. Conclusion: The deep learning DCU-Net algorithm model can improve the performance of tumor CT image segmentation, and the reconstructed fine model can better reflect the actual situation of individual tumors; the MR system constructed based on this model enhances clinicians’ understanding of tumor morphology and spatial relationships. The MR system based on deep learning and three-dimensional visualization technology has great potential in the diagnosis and treatment of bone tumors, and is expected to promote clinical practice and improve efficacy.

BackgroundAfter the successful reforms of drug pricing, China has implemented two significant reforms to reduce medical consumables expenses: the elimination of markup on prices (zero-markup policy) and the implementation of centralized procurement of high-value medical consumables (national procurement policy). The public hospitals in Guangdong province had implemented the zero-markup policy and national procurement policy for coronary stents. Currently, research on the zero-markup consumable policy and national procurement of coronary stents for medical consumables at the hospital level lacks analysis of changes in cost structures (other expenses) and studies on hospital response strategies.ObjectiveThis study aims to examine the effects of these reforms on hospitalization expenses for patients undergoing coronary stent implantation, including the specific changes in total hospitalization expenses, the component of total expenses, and the proportion of each expense category following the implementation of the reforms.MethodsData were obtained from the case management system of Guangdong Provincial Second People’s Hospital in China. An interrupted time series design was employed to assess the impact of the reforms on inpatient expenses.ResultsBefore the reforms, the median total hospitalization expense was 63,124.98 CNY, which decreased to 58,332.50 CNY during the zero-markup consumable policy period and further decreased to 48,266.34 CNY during the national centralized procurement policy period. The median expenses for western drugs, diagnostic tests, treatment, surgery, medical consumables, and other categories also displayed varying patterns. The expenses for medical consumables notably decreased from 39,119.52 CNY to 785.79 CNY after the implementation of the national procurement policy. The slope change of medical consumables expenses decreased by 600.81 CNY per month after the zero-markup policy, and the immediate effect of the national procurement policy resulted in a decrease of 32,160.81 CNY in median medical consumables expenses. Other expense categories experienced notable changes, with a substantial increase in the median of other expenses by 28,350.39 CNY during the national procurement policy period.ConclusionThe reforms in medical consumables pricing and procurement have effectively reduced the cost of consumables for inpatients undergoing coronary stent plantation. The analysis of interrupted time series revealed that the elimination of the consumable markup policy had a limited effect on the level and trend of total hospitalization expenses. However, the implementation of the national procurement policy for coronary stents led to a significant reduction in medical consumables expenses. The study found that after the reform, hospitals mitigated revenue losses by increasing ambiguous other expenses, which may involve the shifting of medical consumable expenses in their accounting records.

Laser speckle contrast imaging (LSCI) is a noninvasive, label-free technique that allows real-time investigation of the microcirculation situation of biological tissue. High-quality microvascular segmentation is critical for analyzing and evaluating vascular morphology and blood flow dynamics. However, achieving high-quality vessel segmentation has always been a challenge due to the cost and complexity of label data acquisition and the irregular vascular morphology. In addition, supervised learning methods heavily rely on high-quality labels for accurate segmentation results, which often necessitate extensive labeling efforts. Here, we propose a novel approach LSWDP for high-performance real-time vessel segmentation that utilizes low-quality pseudo-labels for nonmatched training without relying on a substantial number of intricate labels and image pairing. Furthermore, we demonstrate that our method is more robust and effective in mitigating performance degradation than traditional segmentation approaches on diverse style data sets, even when confronted with unfamiliar data. Importantly, the dice similarity coefficient exceeded 85% in a rat experiment. Our study has the potential to efficiently segment and evaluate blood vessels in both normal and disease situations. This would greatly benefit future research in life and medicine.

Background Chordoma is a slow-growing, primary malignant bone tumor that arises from notochordal tissue in the midline of the axial skeleton. Surgical excision with negative margins is the mainstay of treatment, but high local recurrence rates are reported even with negative margins. High-dose radiation therapy (RT), such as with proton or carbon ions, has been used as an alternative to surgery, but late local failure remains a problem. B7-H3 is an immune checkpoint, transmembrane protein that is dysregulated in many cancers, including chordoma. This study explores the efficacy of B7-H3 chimeric antigen receptor T (CAR-T) therapy in vitro and in vivo.Methods Chordoma cancer stem cells (CCSCs) were identified using flow cytometry, sphere formation, and western blot analysis. The expression of B7-H3 in paraffin-embedded chordoma tissue was determined by immunohistochemical staining, and the expression of B7-H3 in chordoma cells was measured by flow cytometry. Retroviral particles containing either B7-H3 or CD19 CAR-expressing virus were transduced into T cells derived from peripheral blood mononuclear cells isolated from healthy human donor blood to prepare CAR-T cells. Animal bioluminescent imaging was used to evaluate the killing effect of CAR-T cells on chordoma cells in vivo. An irradiator was used for all irradiation (IR) experiments.Results The combination of B7-H3 CAR-T cell therapy and IR has a greater killing effect on killing radiation-resistant CCSCs and bulk chordoma cells compared with CAR-T cell or IR monotherapy. Additionally, increased expression of B7-H3 antigens on CCSCs and bulk tumor cells is associated with enhanced CAR-T cell killing in vitro and in vivo xenograft mouse models. Upregulation of B7-H3 expression by IR increases CCSCs sensitivity to B7-H3 CAR-T cell-mediated killing.Conclusions Our preliminary data show that IR and B7-H3 CAR-T cell therapy is synergistically more effective than either IR or CAR-T cell monotherapy in killing chordoma cells in vitro and in a xenograft mouse model. These results provide preclinical evidence for further developing this combinatorial RT and B7-H3 CAR-T cell therapy model in chordoma