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Abstract Smartphone addiction, emerging from excessive use of smartphones, poses a challenge to inhibitory control functions within society. This research employed transcranial direct current stimulation (tDCS) as an intervention alongside the stop signal task (SST) to explore behavioral distinctions between individuals with smartphone addiction and a non-addicted control group, focusing on the efficacy of tDCS intervention. The participant cohort comprised 80 individuals, divided into an addiction group (39 participants, with 19 receiving active tDCS and 20 receiving sham tDCS) and a control group (41 participants, with 20 receiving active tDCS and 21 receiving sham tDCS), with anodal stimulation applied over the right dorsolateral prefrontal cortex (dlPFC) and cathodal placement over the left arm. The findings indicate that university students struggling with smartphone addiction exhibit reduced inhibitory control compared to their non-addicted peers, while maintaining similar levels of general cognitive control. Remarkably, tDCS interventions were observed to enhance inhibitory control in both groups. Although the improvement in the addiction group appeared more pronounced numerically than in the control group, no significant interaction with group was noted. However, a higher percentage of participants in the smartphone addiction (SA) group exhibited enhanced response inhibition under active tDCS. This study demonstrates the inhibitory control deficits in individuals addicted to smartphones and underscores the potential of tDCS in enhancing response inhibition. It provides a valuable reference for future tDCS research targeting smartphone addiction and highlights the importance of developing healthier smartphone usage habits.

Abstract Pseudouridine widely affects the stability and function of RNA. However, our knowledge of pseudouridine properties in tumors is incomplete. We systematically analyzed pseudouridine synthases (PUSs) expression, genomic aberrations, and prognostic features in 10907 samples from 33 tumors. We found that the pseudouridine-associated pathway was abnormal in tumors and affected patient prognosis. Dysregulation of the PUSs expression pattern may arise from copy number variation (CNV) mutations and aberrant DNA methylation. Functional enrichment analyses determined that the PUSs expression was closely associated with the MYC, E2F, and MTORC1 signaling pathways. In addition, PUSs are involved in the remodeling of the tumor microenvironment (TME) in solid tumors, such as kidney and lung cancers. Particularly in lung cancer, increased expression of PUSs is accompanied by increased immune checkpoint expression and Treg infiltration. The best signature model based on more than 112 machine learning combinations had good prognostic ability in ACC, DLBC, GBM, KICH, MESO, THYM, TGCT, and PRAD tumors, and is expected to guide immunotherapy for 19 tumor types. The model was also effective in identifying patients with tumors amenable to etoposide, camptothecin, cisplatin, or bexarotene treatment. In conclusion, our work highlights the dysregulated features of PUSs and their role in the TME and patient prognosis, providing an initial molecular basis for future exploration of pseudouridine. Studies targeting pseudouridine are expected to lead to the development of potential diagnostic strategies and the evaluation and improvement of antitumor therapies.

Abstract Existing strategies use bifunctional chimaeras to mediate extracellular protein degradation. However, these strategies rely on specific lysosome-trafficking receptors to facilitate lysosomal delivery, which may raise resistance concerns due to intrinsic cell-to-cell variation in receptor expression and mutations or downregulation of the receptors. Another challenge is establishing a universal platform applicable in multiple scenarios. Here, we develop MONOTAB (MOdified NanOparticle with TArgeting Binders), a plug-and-play monofunctional degradation platform that can drag extracellular targets into lysosomes for degradation. MONOTAB harnesses the inherent lysosome-targeting ability of certain nanoparticles to obviate specific receptor dependency and the hook effect. To achieve high modularity and programmable target specificity, we utilize the streptavidin-biotin interaction to immobilize antibodies or other targeting molecules on nanoparticles, through an antibody mounting approach or by direct binding. Our study reveals that MONOTAB can induce efficient degradation of diverse therapeutic targets, including membrane proteins, secreted proteins, and even extracellular vesicles.

Abstract Background We aimed to investigate the post-cessation T2DM risk in male NAFLD and NAFLD-free smokers in a 7-year cohort study. Methods The study population was male adults who underwent annual health checkups in a 7-year cohort study. Recent quitters were categorized into four groups based on their weight gain during follow-up:

Abstract Background Proper control of the lineage bias of megakaryocytic and erythroid progenitor cells (MEPs) is of significant importance, the disorder of which will lead to abnormalities in the number and function of platelets and erythrocytes. Unfortunately, the signaling pathways regulating MEP differentiation largely remain to be elucidated. This study aimed to analyze the role and the underlying molecular mechanism of miR-1915-3p in megakaryocytic and erythroid differentiation. Methods We utilized miRNA mimics and miRNA sponge to alter the expression of miR-1915-3p in megakaryocytic and/or erythroid potential cells; siRNA and overexpression plasmid to change the expression of SOCS4, a potential target of miR-1915-3p. The expression of relevant surface markers was detected by flow cytometry. We scanned for miR-1915-3p target genes by mRNA expression profiling and bioinformatic analysis, and confirmed the targeting by dual-luciferase reporter assay, western blot and gain- and lost-of-function studies. One-way ANOVA and t-test were used to analyze the statistical significance. Results In this study, overexpression or knockdown of miR-1915-3p inhibited or promoted erythroid differentiation, respectively. Accordingly, we scanned for miR-1915-3p target genes and confirmed that SOCS4 is one of the direct targets of miR-1915-3p. An attentive examination of the endogenous expression of SOCS4 during megakaryocytic and erythroid differentiation suggested the involvement of SOCS4 in erythroid/megakaryocytic lineage determination. SOCS4 knockdown lessened erythroid surface markers expression, as well as improved megakaryocytic differentiation, similar to the effects of miR-1915-3p overexpression. While SOCS4 overexpression resulted in reversed effects. SOCS4 overexpression in miR-1915-3p upregulated cells rescued the effect of miR-1915-3p. Conclusions miR-1915-3p acts as a negative regulator of erythropoiesis, and positively in thrombopoiesis. SOCS4 is one of the key mediators of miR-1915-3p during the differentiation of MEPs.

Abstract. Background:. Carotid intima-media thickness (IMT) and diameter, stiffness, and wave reflections, are independent and important clinical biomarkers and risk predictors for cardiovascular diseases. The purpose of the present study was to establish nationwide reference values of carotid properties for healthy Chinese adults and to explore potential clinical determinants. Methods:. A total of 3053 healthy Han Chinese adults (1922 women) aged 18–79 years were enrolled at 28 collaborating tertiary centers throughout China between April 2021 and July 2022. The real-time tracking of common carotid artery walls was achieved by the radio frequency (RF) ultrasound system. The IMT, diameter, compliance coefficient, β stiffness, local pulse wave velocity (PWV), local systolic blood pressure, augmented pressure (AP), and augmentation index (AIx) were then automatically measured and reported. Data were stratified by age groups and sex. The relationships between age and carotid property parameters were analyzed by Jonckheere–Terpstra test and simple linear regressions. The major clinical determinants of carotid properties were identified by Pearson’s correlation, multiple linear regression, and analyses of covariance. Results:. All the parameters of carotid properties demonstrated significantly age-related trajectories. Women showed thinner IMT, smaller carotid diameter, larger AP, and AIx than men. The β stiffness and PWV were significantly higher in men than women before forties, but the differences reversed after that. The increase rate of carotid IMT (5.5 μm/year in women and 5.8 μm/year in men) and diameter (0.03 mm/year in both men and women) were similar between men and women. For the stiffness and wave reflections, women showed significantly larger age-related variations than men as demonstrated by steeper regression slopes (all P for age by sex interaction

Objective Numerous iron deposits hosted in Carboniferous marine volcanic rocks occurred in the Beishan Orogenic Belt, Eastern Tianshan.The Biyushan iron deposit, located at the northwestern margin of Inner Mongolia, is a typical iron deposit hosted in Carboniferous marine volcanic rocks. Methods In this study, we utilized field observation, microscope imaging, and scanning electron microscopy to charaterize the mineral assemblages of iron ores and microtextures of magnetite and apatite, in order to decipher the genesis of iron ores. Results Our preliminary work has revealed that iron ores in the Biyushan deposit commonly have a mineral assemblage of magnetite-apatite, with apatite having abundant monazite inclusions due to the dissolution-reprecipitation processes.In addition, magnetite grains commonly have high Ti contents with ilmenite exsolution.Thus, the mineral assemblage of iron ores and mineralogical features of apatite and magnetite are similar to these of typical Kiruna-type deposits. Conclusion Based on our preliminary analysis of geological characteristics, we suggest that the Biyushan iron deposit in Inner Mongolia is likely a Kiruna-type iron deposit hosted in submarine volcanic rocks that has not yet been documented.Therefore, these findings can guide future exploration of iron oxide-apatite deposits in this region.

Abstract Background Sodium–Glucose Cotransporter-2 Inhibitor (SGLT2i) is a novel oral drug for treating type 2 diabetes mellitus (T2DM) with demonstrated cardiovascular benefits. Previous studies in apolipoprotein E knockout mice have shown that SGLT2i is associated with attenuated progression of atherosclerosis. However, whether this effect extends to T2DM patients with coronary atherosclerosis in real-world settings remains unknown. Methods In this longitudinal cohort study using coronary computed tomography angiography (CCTA), T2DM patients who underwent ≥ 2 CCTA examinations at our center between 2019 and 2022 were screened. Eligible patients had multiple study plaques, defined as non-obstructive stenosis at baseline and not intervened during serial CCTAs. Exclusion criteria included a CCTA time interval 0.05). Conclusions In this longitudinal CCTA cohort of T2DM patients, SGLT2i therapy markedly regressed coronary overall PV and PAV, mainly result from a significant reduction in non-calcified plaque. Graphical abstract

Objective: To validated a classifier to distinguish the status of rotator cuff tear and predict post-operative re-tear by utilizing magnetic resonance imaging (MRI) markers. Methods: This retrospective study included patients with healthy rotator cuff and patients diagnosed as rotator cuff tear (RCT) by MRI. Radiomics features were identified from the pre-operative shoulder MRI and selected by using maximum relevance minimum redundancy (MRMR) methods. A radiomics model for diagnosis of RCT was constructed, based on the 3D volume of interest (VOI) of supraspinatus. Another model for the prediction of rotator re-tear after rotator cuff repair (Re-RCT) was constructed based on VOI of humerus, supraspinatus, infraspinatus and other clinical parameters. Results: The model for diagnosing the status of RCT produced an area under the receiver operating characteristic curve (AUC) of 0.989 in the training cohort and 0.979 for the validation cohort. The radiomics model for predicting Re-RCT produced an AUC of 0.923 ± 0.017 for the training dataset and 0.790 ± 0.082 for the validation dataset. The nomogram combining radiomics features and clinical factors yielded an AUC of 0.961 ± 0.020 for the training dataset and 0.808 ± 0.081 for the validation dataset, which displayed the best performance among all models. Conclusion: Radiomics models for the diagnosis of rotator cuff tear and prediction of post-operative Re-RCT yielded a decent prediction accuracy.

Abstract Background Metastasis is the major cause of colorectal cancer (CRC) mortality. Emerging evidence suggests that long noncoding RNAs (lncRNAs) drive cancer metastasis and that their regulatory pathways could be targeted for preventing metastasis. However, the underlying mechanisms of lncRNAs in CRC metastasis remain poorly understood. Methods Microarray analysis was used to screen for differentially expressed lncRNAs. Transwell assays, fibronectin cell adhesion assays, and mouse metastasis models were utilized to evaluate the metastatic capacities of CRC in vitro and in vivo. Chromatin isolation by RNA purification, chromatin immunoprecipitation and chromosome conformation capture were applied to investigate the underlying mechanism involved. qRT‒PCR and transmission electron microscopy were performed to confirm macrophage polarization and the presence of cancer-derived exosomes. Results The lncRNA RP11-417E7.1 was screened and identified as a novel metastasis-associated lncRNA that was correlated with a poor prognosis. RP11-417E7.1 enhances the metastatic capacity of CRC cells in vivo and in vitro. Mechanistically, RP11-417E7.1 binding with High mobility group A1 (HMGA1) promotes neighboring thrombospondin 2 (THBS2) transcription via chromatin loop formation between its promoter and enhancer, which activates the Wnt/β-catenin signaling pathway and facilitates CRC metastasis. Furthermore, exosomes derived from CRC cells transport THBS2 into macrophages, thereby inducing the M2 polarization of macrophages to sustain the prometastatic microenvironment. Notably, netropsin, a DNA-binding drug, suppresses chromatin loop formation mediated by RP11-417E7.1 at the THBS2 locus and significantly inhibits CRC metastasis in vitro and in vivo. Conclusions This study revealed the novel prometastatic function and mechanism of the lncRNA RP11-417E7.1, which provides a potential prognostic indicator and therapeutic target in CRC.

Abstract Background This study is to propose a clinically applicable 2-echelon (2e) diagnostic criteria for the analysis of thyroid nodules such that low-risk nodules are screened off while only suspicious or indeterminate ones are further examined by histopathology, and to explore whether artificial intelligence (AI) can provide precise assistance for clinical decision-making in the real-world prospective scenario. Methods In this prospective study, we enrolled 1036 patients with a total of 2296 thyroid nodules from three medical centers. The diagnostic performance of the AI system, radiologists with different levels of experience, and AI-assisted radiologists with different levels of experience in diagnosing thyroid nodules were evaluated against our proposed 2e diagnostic criteria, with the first being an arbitration committee consisting of 3 senior specialists and the second being cyto- or histopathology. Results According to the 2e diagnostic criteria, 1543 nodules were classified by the arbitration committee, and the benign and malignant nature of 753 nodules was determined by pathological examinations. Taking pathological results as the evaluation standard, the sensitivity, specificity, accuracy, and area under the receiver operating characteristic curve (AUC) of the AI systems were 0.826, 0.815, 0.821, and 0.821. For those cases where diagnosis by the Arbitration Committee were taken as the evaluation standard, the sensitivity, specificity, accuracy, and AUC of the AI system were 0.946, 0.966, 0.964, and 0.956. Taking the global 2e diagnostic criteria as the gold standard, the sensitivity, specificity, accuracy, and AUC of the AI system were 0.868, 0.934, 0.917, and 0.901, respectively. Under different criteria, AI was comparable to the diagnostic performance of senior radiologists and outperformed junior radiologists (all P 0.05). Conclusions The proposed 2e diagnostic criteria are consistent with real-world clinical evaluations and affirm the applicability of the AI system. Under the 2e criteria, the diagnostic performance of the AI system is comparable to that of senior radiologists and significantly improves the diagnostic capabilities of junior radiologists. This has the potential to reduce unnecessary invasive diagnostic procedures in real-world clinical practice.

Abstract Objectives To quantify the relationship between abdominal computed tomography (CT)-based body composition parameters and renal function in systemic lupus erythematosus (SLE) patients and evaluate the potential effect of insulin resistance on this relationship. Methods SLE patients from institutions A and B between January 2017 and August 2023 were enrolled. Areas and attenuation values of subcutaneous adipose tissue, visceral adipose tissue, intermuscular adipose tissue (IMAT), and skeletal muscle index on CT images were measured at the L3 vertebral level. Logistic regression analysis was used to identify risk factors associated with decreased renal function. Linear regression models were used to describe the relationships between body composition parameters and estimated glomerular filtration rate (eGFR). Finally, we used a single-point insulin sensitivity estimator to indirectly reflect the degree of insulin resistance and assess its mediating effect on the association between IMAT area and decreased renal function. Results Three-hundred thirty-nine SLE patients from institution A (internal dataset) and 114 SLE patients from institution B (external validation dataset) were included. Multivariate logistic regression revealed that IMAT area (odds ratio (OR)institution A: 1.05 (95% confidence intervals (95% CI): 1.01, 1.10), and ORinstitution B: 1.19 (95% CI: 1.03, 1.39)) was an independent risk factor for decreased renal function in SLE patients. In the adjusted linear regression model, high IMAT area was significantly associated with reduced eGFR (β institution A = −1.15, P institution A = 0.005; β institution B = −0.98, P institution B = 0.049). Additionally, insulin resistance contributed a mediating role of 22.8% to the association. Conclusion High IMAT area was associated with decreased renal function in SLE patients and insulin resistance mediated this relationship. Critical relevance statement High intermuscular adipose tissue area is associated with decreased renal function in systemic lupus erythematosus patients mediated by insulin resistance and is correlated with chronicity index in lupus nephritis patients. Key Points High intramuscular adipose tissue (IMAT) area was associated with decreased renal function in systemic lupus erythematosus (SLE) patients. Insulin resistance mediated the association between IMAT area and eGFR. IMAT area was associated with chronicity index in lupus nephritis patients. Graphical Abstract

This study examines the impact of China’s mixed-ownership reform on the innovation of non-state-owned acquirers, with a particular focus on the impact on firms with high financing constraints, low-quality accounting information or less tangible assets. We use a proprietary dataset of firms listed on the Shanghai and Shenzhen Stock Exchanges to investigate the impact of mixed ownership reform on non-state-owned enterprise (non-SOE) innovation. We employ regression analysis to examine the association between mixed ownership reform and firm innovation. The study finds that non-state-owned firms can improve innovation by acquiring equity in state-owned enterprises (SOEs) under the reform. Eased financing constraints, lowered financing costs, better access to tax incentives or government subsidies, lowered agency costs, better accounting information quality and more credit loans are underlying the impact. Additionally, cross-ownership connections amongst non-SOE executives and government intervention strengthen the impact, whilst regional marketisation weakens it. This study adds to the literature on the association between mixed ownership reform and firm innovation by focussing on the conditions under which this impact is stronger. It also sheds light on the policy implications for SOE reforms in emerging economies.

Abstract Background There are significant geographic inequities in COVID-19 case fatality rates (CFRs), and comprehensive understanding its country-level determinants in a global perspective is necessary. This study aims to quantify the country-specific risk of COVID-19 CFR and propose tailored response strategies, including vaccination strategies, in 156 countries. Methods Cross-temporal and cross-country variations in COVID-19 CFR was identified using extreme gradient boosting (XGBoost) including 35 factors from seven dimensions in 156 countries from 28 January, 2020 to 31 January, 2022. SHapley Additive exPlanations (SHAP) was used to further clarify the clustering of countries by the key factors driving CFR and the effect of concurrent risk factors for each country. Increases in vaccination rates was simulated to illustrate the reduction of CFR in different classes of countries. Findings Overall COVID-19 CFRs varied across countries from 28 Jan 2020 to 31 Jan 31 2022, ranging from 68 to 6373 per 100,000 population. During the COVID-19 pandemic, the determinants of CFRs first changed from health conditions to universal health coverage, and then to a multifactorial mixed effect dominated by vaccination. In the Omicron period, countries were divided into five classes according to risk determinants. Low vaccination-driven class (70 countries) mainly distributed in sub-Saharan Africa and Latin America, and include the majority of low-income countries (95.7%) with many concurrent risk factors. Aging-driven class (26 countries) mainly distributed in high-income European countries. High disease burden-driven class (32 countries) mainly distributed in Asia and North America. Low GDP-driven class (14 countries) are scattered across continents. Simulating a 5% increase in vaccination rate resulted in CFR reductions of 31.2% and 15.0% for the low vaccination-driven class and the high disease burden-driven class, respectively, with greater CFR reductions for countries with high overall risk (SHAP value > 0.1), but only 3.1% for the ageing-driven class. Conclusions Evidence from this study suggests that geographic inequities in COVID-19 CFR is jointly determined by key and concurrent risks, and achieving a decreasing COVID-19 CFR requires more than increasing vaccination coverage, but rather targeted intervention strategies based on country-specific risks.

The microstructures and tensile properties of the Ni–Co-based superalloys made by additive manufacturing (AM) were investigated. The results revealed that both normal and inverse Portevin-Le Châtelier (PLC) effects were observed in AM Ni–Co-based superalloys. In addition, AM significantly inhibited the PLC effect, the average stress decrements for the cast and wrought (C&W) alloys with the same nominal compositions were more than ten times as large as those for the AM alloys when tested at 400 °C with a strain rate of 3 × 10−4 s−1. In the AM Ni–Co-based superalloys, type C serrations had connections with the inverse PLC effect. Transmission electron microscope (TEM) was performed to investigate the interactions of solute atoms, dislocations, stacking faults (SFs) and the γ′ phase for a deep insight into mechanisms of the PLC effects and clarifying the changes in serration types and the conversion from normal to inverse PLC effect.

Abstract Background Stress hyperglycemia, which is associated with poor prognosis in patients with acute myocardial infarction (AMI), can be determined using the stress hyperglycemia ratio (SHR). Impaired left ventricular function and microvascular obstruction (MVO) diagnosed using cardiac magnetic resonance (CMR) have also been proven to be linked to poor prognosis in patients with AMI and aid in risk stratification. However, there have been no studies on the correlation between fasting SHR and left ventricular function and MVO in patients with acute ST-segment elevation myocardial infarction (ASTEMI). Therefore, this study aimed to investigate the additive effect of fasting SHR on left ventricular function and global deformation in patients with ASTEMI and to explore the association between fasting SHR and MVO. Methods Consecutive patients who underwent CMR at index admission (3–7 days) after primary percutaneous coronary intervention (PPCI) were enrolled in this study. Basic clinical, biochemical, and CMR data were obtained and compared among all patients grouped by fasting SHR tertiles: SHR1: SHR

Abstract Background Childhood psychological abuse (CPA) are highly correlated with depression among college students, but the underlying mechanisms between variables need further exploration. This study aims to investigate internet addiction as a mediating factor and alexithymia as a moderating factor, in order to further elucidate the potential risk factors between CPA and depression among college students. Methods A self-report survey was conducted among 1196 college students from four universities in three provinces in China. The survey included measures of CPA, internet addiction, alexithymia, and depression. Descriptive and correlational analyses were performed on these variables, and a moderated mediation model was constructed. Results CPA was positively correlated with depression among college students, as well as internet addiction with alexithymia. Internet addiction partially mediated the relationship between CPA and depression among college students, while alexithymia strengthened the relationships among the paths in the moderated mediation model. Conclusion This study provides further insights into the psychological mechanisms underlying the relationship between CPA and depression among college students. Internet addiction serves as a mediating factor in this relationship, while alexithymia may enhance the strength of the relationships among the three variables.

Abstract Background Acute ischemic stroke (AIS) is one of the most common cerebrovascular diseases which accompanied by a disruption of aminothiols homeostasis. To explore the relationship of aminothiols with neurologic impairment severity, we investigated four aminothiols, homocysteine (Hcy), cysteine (Cys), cysteinylglycine (CG) and glutathione (GSH) in plasma and its influence on ischemic stroke severity in AIS patients. Methods A total of 150 clinical samples from AIS patients were selected for our study. The concentrations of free reduced Hcy (Hcy), own oxidized Hcy (HHcy), free reduced Cys (Cys), own oxidized Cys (cysteine, Cyss), free reduced CG (CG) and free reduced GSH (GSH) were measured by our previously developed hollow fiber centrifugal ultrafiltration (HFCF-UF) method coupled with high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). The concentration ratio of Hcy to HHcy (Hcy/HHcy), Cys to Cyss (Cys/Cyss) were also calculated. The neurologic impairment severity of AIS was evaluated using National Institutes of Health Stroke Scale (NIHSS). The Spearman correlation coefficient and logistic regression analysis was used to estimate and perform the correlation between Hcy, HHcy, Cys, Cyss, CG, GSH, Hcy/HHcy, Cys/Cyss and total Hcy with NIHSS score. Results The reduced Hcy and Hcy/HHcy was both negatively correlated with NIHSS score in AIS patients with P = 0.008, r=-0.215 and P = 0.002, r=-0.249, respectively. There was no significant correlation of Cys, CG, GSH, HHcy, Cyss, Cys/Cyss and total Hcy with NIHSS score in AIS patients with P value > 0.05. Conclusions The reduced Hcy and Hcy/HHcy, not total Hcy concentration should be used to evaluate neurologic impairment severity of AIS patient.

Abstract Background Interleukin-17 (IL-17) has been hypothesized to be involved in ischemic cardiovascular disease (ICVD). However, the association of IL-17 with ICVD remained unclear. The aim of this study was to systematically analyze the available evidence regarding the association between IL-17 and ICVD. Methods We searched the PubMed, Web of Science, Cochrane Library, and Embase databases up to October 2023 to identify publications on the association between IL-17 and ICVD. The merged results were analyzed using a random effects model for meta-analysis and subgroup analysis. Results A total of 955 publications were initially identified in our search and screened; six studies were eventually included in the analysis. The average age of study participants was 60.3 ± 12.6 years and 65.5% were men. There was a high degree of heterogeneity among studies. The results showed that IL-17 level were higher in the case group than those in the control group (standardized mean difference, SMD = 1.60, 95% confidence interval (95% CI): 0.53–2.66, P = 0.003). In sensitivity analysis, the merged results showed good robustness. Additionally, subgroup analysis showed that race and ethnicity, sample size, and detection methods were significant factors influencing heterogeneity in the published studies. Conclusion Our finding revealed that increased IL-17 level contributed to the development of ICVD, suggesting IL-17 as a potential risk marker. Further research is needed to establish IL-17 as a therapeutic biomarker of ICVD.

Excavation-induced disturbances in deep tunnels will lead to deterioration of rock properties and formation of excavation damaged zone (EDZ). This excavation damage effect may affect the potential rockburst pit depth. Taking two diversion tunnels of Jinping II hydropower station for example, the relationship between rockburst pit depth and excavation damage effect is first surveyed. The results indicate that the rockburst pit depth in tunnels with severe damage to rock masses is relatively large. Subsequently, the excavation-induced damage effect is characterized by disturbance factor D based on the Hoek–Brown criterion and wave velocity method. It is found that the EDZ could be further divided into a high-damage zone (HDZ) with D = 1 and weak-damage zone (WDZ), and D decays from one to zero linearly. For this, a quantitative evaluation method for potential rockburst pit depth is established by presenting a three-element rockburst criterion considering rock strength, geostress and disturbance factor. The evaluation results obtained by this method match well with actual observations. In addition, the weakening of rock mass strength promotes the formation and expansion of potential rockburst pits. The potential rockburst pit depth is positively correlated with HDZ and WDZ depths, and the HDZ depth has a significant contribution to the potential rockburst pit depth.

Abstract The wide applications of liquid chromatography - mass spectrometry (LC-MS) in untargeted metabolomics demand an easy-to-use, comprehensive computational workflow to support efficient and reproducible data analysis. However, current tools were primarily developed to perform specific tasks in LC-MS based metabolomics data analysis. Here we introduce MetaboAnalystR 4.0 as a streamlined pipeline covering raw spectra processing, compound identification, statistical analysis, and functional interpretation. The key features of MetaboAnalystR 4.0 includes an auto-optimized feature detection and quantification algorithm for LC-MS1 spectra processing, efficient MS2 spectra deconvolution and compound identification for data-dependent or data-independent acquisition, and more accurate functional interpretation through integrated spectral annotation. Comprehensive validation studies using LC-MS1 and MS2 spectra obtained from standards mixtures, dilution series and clinical metabolomics samples have shown its excellent performance across a wide range of common tasks such as peak picking, spectral deconvolution, and compound identification with good computing efficiency. Together with its existing statistical analysis utilities, MetaboAnalystR 4.0 represents a significant step toward a unified, end-to-end workflow for LC-MS based global metabolomics in the open-source R environment.

Abstract There is a certain relationship between alexithymia and depression, but further investigation is needed to explore their underlying mechanisms. The aims of this study was to explore the mediating role of internet addiction between alexithymia and depression and the moderating role of physical activity. A total of 594 valid responses were included in the analysis, with a mean age of 18.72 years (SD = 1.09). The sample comprised 250 males (42.09%) and 344 females (57.91%). These responses were utilized for descriptive analysis, correlation analysis, regression analysis, and the development of mediation and moderation models. Alexithymia showed positive correlations with depression and internet addiction, and physical activity was negatively correlated with internet addiction and depression. Internet addiction partially mediated the relationship between alexithymia and depression, while physical activity weakened the association between internet addiction and depression, acting as a moderator. Our findings suggest that excessive Internet engagement may mediate the relationship between alexithymia and depression as an emotional regulatory coping strategy, and that physical activity attenuates the predictive effect of Internet addiction on depression.

Objective Common peroneal nerve (CPN) injury is a frequently encountered lower extremity injury. Furthermore, several previous studies have demonstrated that patients who underwent direct suturing of the CPN following rupture experienced unfavorable postoperative prognoses. Therefore, we aimed to present a novel modified surgical approach for CPN rupture and assess the effectiveness of this technique in restoring lower limb functionality. Methods In this retrospective observational study, we included patients with CPN rupture who underwent one‐stage neurorrhaphy and posterior transposition combined with nerve wrapping using a gastrocnemius fascial flap for CPN rupture between January 2016 and December 2020. Lower limb function was evaluated using the lower extremity functional scale (LEFS) and British Medical Research Council (BMRC) grading system. We also assessed the influence of age, sex, duration of symptoms, mechanism of injury, and surgical modality on the postoperative recovery of lower extremity function using subgroup and regression analyses. Results Thirty‐seven patients (mean age = 35.76 ± 13.01 years) with at least 2 years of follow‐up were included in the final analysis. The LEFS scores significantly improved after surgery at the last follow‐up (p

Abstract Aims/Introduction To explore the association between estimated small dense low‐density lipoprotein cholesterol (sdLDL‐C) and the risk of incident nonalcoholic fatty liver disease (NAFLD) in nonobese populations. Materials and Methods This study included participants who underwent health checkups in 2014 and were followed up until 2019. We carried out Cox proportional hazards regression analyses to evaluate the association of estimated sdLDL‐C with NAFLD. Discordance analyses were carried out to estimate the relative NAFLD risk in estimated sdLDL‐C versus low‐density lipoprotein cholesterol (LDL‐C) discordant/concordant groups. Estimated sdLDL‐C was calculated by equations based on LDL‐C and triglycerides. The diagnosis of NAFLD was based on the presence of abdominal ultrasonography after excluding other causes of chronic liver disease. Results Over a mean follow‐up period of 26,694 person‐years, 844 incident NAFLD cases were recorded. Compared with the first quartile of estimated sdLDL‐C, the fourth quartile was associated with a 2.933‐fold increased risk of NAFLD (95% confidence interval 2.095–4.107). With the increase in estimated sdLDL‐C, the risk of NAFLD gradually increased both in participants within the normal range of LDL‐C (hazard ratio 2.854, 95% confidence interval 1.650–5.617) and beyond the normal range of LDL‐C (hazard ratio 2.636, 95% confidence interval 1.263–5.502). In addition, the inconsistent high estimated sdLDL‐C/low LDL‐C group was associated with an increased risk of NAFLD, but not the low estimated sdLDL‐C/high LDL‐C group. Conclusions Estimated sdLDL‐C was positively associated with the risk of incident NAFLD in a nonobese population, independent of LDL‐C.

Abstract Autistic individuals generally demonstrate impaired emotion recognition but it is unclear whether effects are emotion-specific or influenced by oxytocin receptor (OXTR) genotype. Here we implemented a dimensional approach using an implicit emotion recognition task together with functional MRI in a large cohort of neurotypical adult participants (N = 255, male = 131, aged 17–29 years) to establish associations between autistic traits and neural and behavioral responses to specific face emotions, together with modulatory effects of OXTR genotype. A searchlight-based multivariate pattern analysis (MVPA) revealed an extensive network of frontal, basal ganglia, cingulate and limbic regions exhibiting significant predictability for autistic traits from patterns of responses to angry relative to neutral expression faces. Functional connectivity analyses revealed a genotype interaction (OXTR SNPs rs2254298, rs2268491) for coupling between the orbitofrontal cortex and mid-cingulate during angry expression processing, with a negative association between coupling and autistic traits in the risk-allele group and a positive one in the non-risk allele group. Overall, results indicate extensive emotion-specific associations primarily between patterns of neural responses to angry faces and autistic traits in regions processing motivation, reward and salience but not in early visual processing. Functional connections between these identified regions were not only associated with autistic traits but also influenced by OXTR genotype. Thus, altered patterns of neural responses to threatening faces may be a potential biomarker for autistic symptoms although modulatory influences of OXTR genotype need to be taken into account.

Abstract Retrosynthetic planning, which aims to identify synthetic pathways for target molecules from starting materials, is a fundamental problem in synthetic chemistry. Computer-aided retrosynthesis has made significant progress, in which heuristic search algorithms, including Monte Carlo Tree Search (MCTS) and A* search, have played a crucial role. However, unreliable guiding heuristics often cause search failure due to insufficient exploration. Conversely, excessive exploration also prevents the search from reaching the optimal solution. In this paper, MCTS exploration enhanced A* (MEEA*) search is proposed to incorporate the exploratory behavior of MCTS into A* by providing a look-ahead search. Path consistency is adopted as a regularization to improve the generalization performance of heuristics. Extensive experimental results on 10 molecule datasets demonstrate the effectiveness of MEEA*. Especially, on the widely used United States Patent and Trademark Office (USPTO) benchmark, MEEA* achieves a 100.0% success rate. Moreover, for natural products, MEEA* successfully identifies bio-retrosynthetic pathways for 97.68% test compounds.

Abstract Taking the return-airway 4204 with roof cutting in Longquan Coal Mine as the engineering background, roof structure, key parameters, and deviatoric stress evolution were studied. Conclusion: The Key Stratum within a 4–8 times mining height is considered as Near Key Stratum. Cutting the roof makes it possible to form a cantilever structure of the Key Stratum on the solid coal side, which is more conducive to the stability of gob-side roadway. During cutting angle of 90–55°, the deviatoric stress increases linearly, and the increase rate is coal pillar > solid coal > roof > floor. While cutting length from 0 to 35 m, the deviatoric stress decreases linearly, and the decreasing range: coal pillar > solid coal > roof > floor. When coal pillar width is from 30 to 4 m, the deviatoric stress of left side and floor presents a “single peak” distribution. The deviatoric stress of coal pillar changes from an asymmetric “double peak” to a bell-shaped distribution, and the deviatoric stress of roof changes from a “single peak” to an asymmetric “double peak” distribution. Under same coal pillar width, the deviatoric stress of left, coal pillar and roof after roof cutting decreases most obviously, followed by the floor. Finally, the coal pillar width is 8 m, the cutting angle is 75°, the cutting length is 20 m, and the hole spacing is 1.0 m. The support scheme is bolt + metal mesh + steel belt + anchor cable combined support. The stable period of roadway is about 10 days.

The emergence and spread of Acinetobacter baumannii pose a severe threat to public health, highlighting the urgent need for the next generation of therapeutics due to its increasing resistance to existing antibiotics. BfmR, a response regulator modulating virulence and antimicrobial resistance, shows a promising potential as a novel antimicrobial target. Developing BfmR inhibitors may propel a new therapeutic direction for intractable infection of resistant strains. In this study, we conducted a structure-based hierarchical virtual screening pipeline combining molecular docking, molecular dynamics simulation and MM/GBSA calculation to sift Specs chemical library and finally discover three novel potential BfmR inhibitors. The three hits can reduce the MIC of meropenem for the carbapenem-resistant Acinetobacter baumannii (CRAB) strain ZJ06. Similar to the BfmR knockout strain, Cmp-98 was demonstrated to downregulate the expression of K locus genes, indicating it as a BfmR inhibitor. Bacteria underwent harmful morphological changes after treatment with these inhibitors. Molecular dynamics simulations found that all the hits tend to dynamically bind to different positions of the phosphorylation site of BfmR. Wherein we identified a potential inhibitory binding cleft, beside a possible activated binding cleft at the edge of the phosphorylation site. Restraining the ligand binding poses may help exerting inhibitory effects. This study reports a group of new-scaffold BfmR inhibitors, offering new insights for novel antibiotic therapeutics against CRAB.

The successful evolution of KPC-2 in bacteria has limited the clinical practice of carbapenems. This dilemma deteriorated the prognosis of associated infections and hence attracted increasing attention from researchers to explore alternative therapeutic options. Here, the enzyme inhibition assay was first performed to screen for a potent KPC-2 inhibitor. The synergistic effect of the candidate with carbapenems was further confirmed by checkboard minimum inhibitory concentration (MIC) assay, time-killing assay, disk diffusion method, and live/dead bacteria staining analysis. The mechanisms by which the candidate acts were subsequently explored through molecular dynamics (MD) simulations, etc. Our study found that Ginkgolic Acid (C13:0) (GA) exhibited effective KPC-2 inhibitory activity in both laboratory strain and clinical strain containing KPC-2. It could potentiate the killing effect of carbapenems on KPC-2-positive Klebsiella pnenmoniae(K. pnenmoniae). Further explorations revealed that GA could competitively bind to the active pocket of KPC-2 with meropenem (MEM) via residues Trp104, Gly235, and Leu166. The secondary structure and functional groups of KPC-2 were subsequently altered, which may be the main mechanism by which GA exerted its KPC-2 inhibitory effect. In addition, GA was also found to synergize with MEM to disrupt membrane integrity and increase membrane permeability, which may be another mechanism by which GA reinforced the bactericidal ability of carbapenems. Our study indicated that GA was a significant KPC-2 inhibitor that could prolong the lifespan of carbapenems and improve the prognosis of patients.

Abstract Efficient topical drug delivery remains a significant challenge in glaucoma management. Although nanoparticle formulations offer considerable promise, their complex preparation processes, co‐delivery issues, and batch consistency have hindered their potential. A scalable fabrication strategy is developed here for preparing solid drug nanoparticles (SDNs) with enhanced drug delivery efficiency. Utilizing hydrophobic antiglaucoma drugs brimonidine (BM) and betaxolol (BX), uniform fixed combination BM/BX SDNs are fabricated through a continuous process, improving batch‐to‐batch consistency for combined glaucoma treatment. With trehalose being used as a lyoprotectant, BM/BX SDNs can be stored as dry powder and easily reconstituted in phosphate buffered saline. Importantly, reconstituted BM/BX SDNs form clear, homogenous solutions, and exhibit negligible cytotoxicity and irritation, making them well‐suited for topical administration as eyedrops. Ex vivo and in vivo studies demonstrated that topically applied BM/BX SDNs permeate through the cornea significantly (about two fold to three fold) compared to their hydrophilic counterparts, i.e., brimonidine tartrate, and betaxolol hydrogen chloride. Notably, BM/BX SDNs displayed consistent intraocular pressure lowering effects in vivo in both normotensive rats and glaucoma mice. Collectively, this study demonstrates the potential of the scalable fabrication strategy and the resultant BM/BX SDNs for improving glaucoma management through eyedrops.

BackgroundNumerous studies have investigated the relationship between gut microbiota (GM) and multiple sclerosis(MS), highlighting the significant role of GM in MS. However, there is a lack of systematic Scientometric analyses published in this specific research area to provide an overall understanding of the current research status.MethodsPerform a scientometric analysis on research conducted between 2010 and 2023 concerning the link between GM and MS using quantitative and visual analysis software (CiteSpace and VOSviewer.)ResultsFrom January 1, 2010, and December 31, 2023, a total of 1019 records about GM and MS were retrieved. The number of publications exhibited a consistent upward trend annually. The United States led in publications, showed the strongest level of collaboration among countries. The University of California, San Francisco stands as the top institution in terms of output, and the most prolific and cited authors were Lloyd H. Kasper and Javier Ochoa-Reparaz from the USA. The research in this field primarily centers on investigating the alterations and associations of GM in MS or EAE, the molecular immunological mechanisms, and the potential of GM-based interventions to provide beneficial effects in MS or EAE. The Keywords co-occurrence network reveals five primary research directions in this field. The most frequently occurring keywords are inflammation, probiotics, diet, dysbiosis, and tryptophan. In recent years, neurodegeneration and neuropsychiatric disorders have been prominent, indicating that the investigation of the mechanisms and practical applications of GM in MS has emerged as a current research focus. Moreover, GM research is progressively extending into the realm of neurodegenerative and psychiatric diseases, potentially becoming future research hotspots.ConclusionsThis study revealed a data-driven systematic comprehension of research in the field of GM in MS over the past 13 years, highlighted noteworthy research within the field, provided us with a clear understanding of the current research status and future trends, providing a valuable reference for researchers venturing into this domain.

IntroductionThe prognosis of relapsed/refractory acute myeloid leukemia (r/rAML) is dismal, and allogeneic hematopoietic stem cell transplant (allo-HSCT) is a potential cure. Combining anti-PD-1, hypomethylating agent (HMA), and CAG (cytarabine, aclarubicin/idarubicin, granulocyte colony-stimulating factor) regimen has showed primary efficacy in r/rAML. However, pre-transplant exposure to anti-PD-1 may lead to severe graft-versus-host disease (GVHD). This preliminary study aimed to evaluate the safety and efficacy of allo-HSCT in r/rAML patients receiving the anti-PD-1+HMA+CAG regimen.MethodsFifteen r/rAML patients (12 related haploidentical donors [HIDs], 2 matched siblings, 1 unrelated donor) received this regimen and subsequent peripheral blood HSCT.ResultsFour patients with HIDs received a GVHD prophylaxis regimen consisted of Anti-thymocyte globulin and a reduced-dose of post-transplant cyclophosphamide. The median follow-up was 20.9 months (range, 1.2-34.2). The cumulative incidences of acute GVHD grade 2-4 and grade 3-4 were 40% and 13.3%, respectively. The 2-year incidence of moderate-to-severe chronic GVHD, non-relapse mortality, and relapse were 10%, 22.3%, and 22.5%, respectively. The 2-year overall survival and GVHD-free/relapse-free survival rates were 54% and 48.6%, respectively. No death or relapse was observed in the PTCy group.ConclusionThe anti-PD-1+HMA+CAG regimen bridging to allo-HSCT for r/r AML was tolerable with promising efficacy. GVHD prophylaxis with PTCy for HID-HSCT showed preliminary survival advantage.

PurposeThe aim of this study was to develop an integrated model that combines clinical-radiologic and radiomics features based on gadoxetic acid-enhanced MRI for preoperative evaluating of vessels encapsulating tumour clusters (VETC) patterns in hepatocellular carcinoma (HCC).MethodsThis retrospective study encompassed 234 patients who underwent surgical resection. Among them, 101 patients exhibited VETC-positive HCC, while 133 patients displayed VETC-negative HCC. Volumes of interest were manually delineated for entire tumour regions in the arterial phase (AP), portal phase (PP), and hepatobiliary phase (HBP) images. Independent predictors for VETC were identified through least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic regression analysis, utilising radiomics-AP, PP, HBP, along with 24 imaging features and 19 clinical characteristics. Subsequently, the clinico-radiologic model, radiomics model, and integrated model were established, with a nomogram visualising the integrated model. The performance for VETC prediction was evaluated using a receiver operating characteristic curve.ResultsThe integrated model, composed of 3 selected traditional imaging features (necrosis or severe ischemia [OR=2.457], peripheral washout [OR=1.678], LLR_AP (Lesion to liver ratio_AP) [OR=0.433] and radiomics-AP [OR=2.870], radiomics-HBP [OR=2.023], radiomics-PP [OR=1.546]), showcased good accuracy in predicting VETC patterns in both the training (AUC=0.873, 95% confidence interval [CI]: 0.821-0.925)) and validation (AUC=0.869, 95% CI:0.789-0.950) cohorts.ConclusionThis study established an integrated model that combines traditional imaging features and radiomic features from gadoxetic acid-enhanced MRI, demonstrating good performance in predicting VETC patterns.

Abstract Mammalian cochlear hair cells (HCs) are essential for hearing, and damage to HCs results in severe hearing impairment. Damaged HCs can be regenerated by neighboring supporting cells (SCs), thus the functional regeneration of HCs is the main goal for the restoration of auditory function in vivo. Here, cochlear SC trans‐differentiation into outer and inner HC by the induced expression of the key transcription factors Atoh1 and its co‐regulators Gfi1, Pou4f3, and Six1 (GPAS), which are necessary for SCs that are destined for HC development and maturation via the AAV‐ie targeting the inner ear stem cells are successfully achieved. Single‐cell nuclear sequencing and lineaging tracing results showed that the majority of new Atoh1‐derived HCs are in a state of initiating differentiation, while GP (Gfi1, Pou4f3) and GPS (Gfi1, Pou4f3, and Six1) enhanced the Atoh1‐induced new HCs into inner and outer HCs. Moreover, the patch‐clamp analysis indicated that newborn inner HCs induced by GPAS forced expression have similar electrophysiological characteristics to those of native inner HCs. Also, GPAS can induce HC regeneration in the HC‐damaged mice model. In summary, the study demonstrates that AAV‐mediated co‐regulation of multiple genes, such as GPAS, is an effective means to achieve functional HC regeneration in the mouse cochlea.

Pseudorabies virus is a major pathogen in the pig industry, causing substantial economic losses. The emergence of pseudorabies virus variant strains in China has led to extensive spread, raising concerns about their potential impact. However, the differences in pathogenicity between the classical strains and the variant strains of genotype II are not well understood. In this study, we isolated three pseudorabies virus strains to evaluate their replication characteristics and to examine the differences in virulence genes among various subgenotypes strains. Additionally, a piglet infection model was utilized to investigate the clinical features of infection, tissue tropism, and the inflammatory responses induced by these strains. Our results showed that the genotype II variant strains (MS, XJ, LS, and CZ) had significantly larger plaque sizes and higher replication capacities than the genotype II classical strain Fa. The animal experiments revealed significant differences in pathogenicity among the pseudorabies virus subgenotype strains, with the variant strains showing higher mortality rates, more severe clinical symptoms, increased nasal virus shedding, and a more robust inflammatory response compared to the genotype II classical strain. There were also notable differences in tissue tropism among the strains. In terms of tissue viral loads, the genotype II variant strains did not exhibit a significant advantage over the genotype I classical strain. Furthermore, our findings indicate that antibodies against the genotype II classical strains have a reduced neutralizing capacity against the genotype II variant strains. On the other hand, antibodies against the genotype II variant strains displayed similar neutralizing abilities against both classical and variant strains. Overall, these findings offer important insights into the distinctions among pseudorabies virus subgenotypes and their implications for the clinical control of pseudorabies virus infections in pig farming.

Nowadays, dielectric materials are playing an increasingly important role in various fields. A high dielectric constant (D) can store more charge per unit volume, improving performance, reducing device size, lowering D limit cross communication, and enabling better packaging of devices. Differentiating high D and low D has been recognized as a significant concern in electronics. However, calculating the dielectric constant from first principles is notoriously difficult. Therefore, it is essential to find important descriptors for predicting the dielectric constant (D) of different dielectric materials. In this work, a novel intelligence optimization approach was proposed based on data-driven methods to predict the dielectric constant (D) of ABO3-type perovskites. By applying the machine learning (ML) algorithm, key features strongly correlated with D were identified. To reduce feature dimension, Random Forest Regression-Gradient Boosting Regressor (RFR-GBR) feature screening, sure independence screening, and the sparsifying operator approach were employed to compress the feature set for creating valid descriptors. Furthermore, the Shapley additive explanation technique was used to reveal the scaling relation between the dielectric constant and the identified descriptors for predicting the D of ABO3-type perovskites. In addition, a hybrid artificial rabbits optimization algorithm and random forest regression were developed for predicting D, achieving remarkable predictive performance with an R2 score of 0.95, MAE of 0.23, and RMSE of 0.108 using five-fold cross-validation. Ultimately, from a pool of 300 candidate materials, we screened and identified two potential dielectric perovskites with different D values. The proposed framework will facilitate D prediction technology for the discovery of dielectric perovskite materials with favorable performance.

BackgroundEpididymal cysts (ECs) are uncommon in the pediatric population. The objective of this study was to evaluate the frequency, clinical characteristics, and management strategies of ECs in children.MethodsWe performed a retrospective review of pediatric scrotal ultrasounds between January 2014 and August 2022 to identify children with ECs.ResultsOne hundred and forty-three children boys were found to have ECs, with 95 being pre-pubertal and 48 post-pubertal. The age of the patients ranged from 1 day to 18 years, with a mean age of 10.64 ± 4.55 years. The size of the cysts varied from 2 mm to 35 mm. The most common comorbidities observed were hydrocele, testicular microlithiasis and varicocele. The majority of ECs were detected through routine physical examination. Conservative management was employed for all patients, except for one who required surgical excision. Resolution of ECs occurred in 12 patients, while a reduction in cyst size was observed in 6 cases. Conversely, 2 patients experienced an increase in cyst size, and 6 patients exhibited an increase in cyst number during the follow-up period.ConclusionConservative management is the preferred approach for the majority of cases, with surgical intervention reserved for specific instances.

ObjectiveThis study aims to analyze the awareness of influenza prevention and control and the behavioral attitudes toward the work among parents and staff in schools in Taicang City and the impact of the vaccination rate among students on influenza outbreaks in schools. The findings can provide references for the development of effective control strategies for the spread of influenza.MethodsAn anonymous questionnaire survey was conducted on 10,962 students from 20 schools in Taicang City, with class as the unit of analysis. The survey investigated their awareness of influenza prevention and control, their attitudes, and the vaccination coverage.ResultsFrom January to June 2023, a total of 388 influenza outbreaks were reported in schools in Taicang City, involving 77 schools. There were 3,475 confirmed cases, with an average infection rate of 18.53%. In schools where influenza outbreaks had occurred, the incidence rate of those who received influenza vaccine was significantly lower than those who did not, and the vaccine protection rate was 28.22%. The knowledge awareness rates of “the main transmission routes of influenza” and “influenza vaccination can prevent influenza” among parents of students were 95.49 and 93.16%, respectively. The differences between schools involved in the epidemic and non-epidemic were statistically significant (p

BackgroundThis study aims to use six nutrition-related indicators to assess the relationship between nutritional status and the risk of COPD as well as the all-cause mortality rate, and to determine the most reliable predictive indicators.MethodsData from the National Health and Nutrition Examination Survey (NHANES) spanning the years 2013 to 2018 were extracted. Nutritional status was evaluated using Controlling nutritional status (CONUT) score, Geriatric Nutritional Risk Index (GNRI), Advanced Lung Cancer Inflammation Index (ALI), Prognostic Nutritional Index (PNI), Triglycerides (TG) × Total Cholesterol (TC) × Body Weight (BW) Index (TCBI), and Albumin-to-Globulin Ratio (AGR) nutritional-related indicators. Multivariate weighted logistic and Cox regression models were employed to assess the correlation between the six nutritional-related indicators and the risk of COPD and as all-cause mortality. The restricted cubic spline tests were applied to explore potential nonlinear relationships, and ROC curves and C-index analyses were conducted to compare the predictive capabilities of different indicators. Stratified analysis and propensity score matching (PSM) to assess the robustness of the results.ResultsIn this study, Lower ALI, lower GNRI, and higher CONUT scores were positively correlated with an increased risk of COPD (OR: 1.77, 95% CI: 1.10–2.84) (OR: 8.66, 95% CI: 2.95–25.5), and (OR: 5.11, 95% CI: 1.72–15.2), respectively. It was found that ALI and GNRI had a non-linear relationship with the risk of COPD. After propensity score matching (PSM), the associations between ALI, GNRI, CONUT scores, and COPD remained consistent. Lower ALI, PNI, and GNRI scores were positively associated with all-cause mortality in COPD patients (HR: 2.41, 95% CI: 1.10–5.27), (HR: 3.76, 95% CI: 1.89–7.48), and (HR: 4.55, 95% CI: 1.30–15.9), respectively, with GNRI displaying a non-linear relationship with all-cause mortality. ROC curve and C-index analyses indicated that ALI had the best predictive ability for both COPD risk and all-cause mortality.ConclusionALI, GNRI, and CONUT scores are correlated with the risk of COPD, while ALI, PNI, and GNRI scores are associated with all-cause mortality in COPD patients. Compared to other nutritional scores, ALI may provide more effective predictive value for both risk and all-cause mortality.

Continuous wetland restoration initiatives in China are increasing, due to the global degradation of wetland ecosystems. However, monitoring of the restoration situation remains incomplete. In this study, we investigated the effects of wetland restoration on the macroinvertebrate taxonomic structure and feeding functional groups (FFGs) in the Naolihe National Nature Reserve (NNNR). Macroinvertebrate taxonomic diversity can be used to monitor wetlands, and we hypothesized that FFGs serve the same function. We calculated the diversity index, performed a non-metric multidimensional analysis based on macroinvertebrate taxonomics and FFGs, and subsequently, performed a t-test on the results. The results showed that macroinvertebrate diversity and FFGs analyses were in general agreement with taxonomic diversity, indicating that the macroinvertebrate community in the wetland with five years of fallow land was resembled that of the natural wetland. In contrast, the macroinvertebrate community in the wetland with two years of fallow differed significantly from that in the natural wetland. Additionally, the results of the ecosystem attributes based on biomass and FFGs showed that restored wetlands exhibited lower habitat stability than natural wetlands. Nutrients (NH4+-N, NO3−-N, and total phosphorus) explained the changes in macroinvertebrate FFGs in the restored wetlands to a greater extent than in the natural wetlands. The results of this study highlight the importance of macroinvertebrate FFGs in wetland monitoring, which supports the use of macroinvertebrate FFGs in the NNNR to monitor wetland restoration.

The use of wide-ranging dairy herd improvement (DHI) measurements has resulted in the investigation of somatic cell count (SCC) and the identification of many genes associated with mastitis resistance. In this study, blood samples of Xinjiang brown cattle with different SCCs were collected, and genome-wide DNA methylation was analyzed by MeDIP-seq. The results showed that peaks were mostly in intergenic regions, followed by introns, exons, and promoters. A total of 1,934 differentially expressed genes (DEGs) associated with mastitis resistance in Xinjiang brown cattle were identified. The enrichment of differentially methylated CpG islands of the TRAPPC9 and CD4 genes was analyzed by bisulfate genome sequencing. The methylation rate of differentially methylated CpGs was higher in the TRAPPC9 gene of cattle with clinical mastitis (mastitis group) compared with healthy cattle (control group), while methylation of differentially methylated CpGs was significantly lower in CD4 of the mastitis group compared with the control group. RT-qRCR analysis showed that the mastitis group had significantly reduced expression of CD4 and TRAPPC9 genes compared to the control group (p < 0.05). Furthermore, Mac-T cells treated with lipopolysaccharide and lipoteichoic acid showed significant downregulation of the TRAPPC9 gene in the mastitis group compared with the control group. The identified epigenetic biomarkers provide theoretical reference for treating cow mastitis, breeding management, and the genetic improvement of mastitis resistance in Xinjiang brown cattle.

ABSTRACT African swine fever (ASF) is a highly fatal viral disease that poses a significant threat to domestic pigs and wild boars globally. In our study, we aimed to explore the potential of a multiplexed CRISPR-Cas system in suppressing ASFV replication and infection. By engineering CRISPR-Cas systems to target nine specific loci within the ASFV genome, we observed a substantial reduction in viral replication in vitro. This reduction was achieved through the concerted action of both Type II and Type III RNA polymerase-guided gRNA expression. To further evaluate its anti-viral function in vivo, we developed a pig strain expressing the multiplexable CRISPR-Cas-gRNA via germline genome editing. These transgenic pigs exhibited normal health with continuous expression of the CRISPR-Cas-gRNA system, and a subset displayed latent viral replication and delayed infection. However, the CRISPR-Cas9-engineered pigs did not exhibit a survival advantage upon exposure to ASFV. To our knowledge, this study represents the first instance of a living organism engineered via germline editing to assess resistance to ASFV infection using a CRISPR-Cas system. Our findings contribute valuable insights to guide the future design of enhanced viral immunity strategies.IMPORTANCEASFV is currently a devastating disease with no effective vaccine or treatment available. Our study introduces a multiplexed CRISPR-Cas system targeting nine specific loci in the ASFV genome. This innovative approach successfully inhibits ASFV replication in vitro, and we have successfully engineered pig strains to express this anti-ASFV CRISPR-Cas system constitutively. Despite not observing survival advantages in these transgenic pigs upon ASFV challenges, we did note a delay in infection in some cases. To the best of our knowledge, this study constitutes the first example of a germline-edited animal with an anti-virus CRISPR-Cas system. These findings contribute to the advancement of future anti-viral strategies and the optimization of viral immunity technologies.

Temozolomide (TMZ) is a widely utilized chemotherapy treatment for patients with glioblastoma (GBM), although drug resistance constitutes a major therapeutic hurdle. Emerging evidence suggests that ferroptosis-mediated therapy could offer an appropriate alternative treatment option against cancer cells that are resistant to certain drugs. However, recurrent gliomas display robust ferroptosis resistance, although the precise mechanism of resistance remains elusive. In the present work, we report that proline rich protein 11 (PRR11) depletion significantly sensitizes GBM cells to TMZ by inducing ferroptosis. Mechanistically, PRR11 directly binds to and stabilizes dihydroorotate dehydrogenase (DHODH), which leads to glioma ferroptosis-resistant in a DHODH-dependent manner in vivo and in vitro. Furthermore, PRR11 inhibits HERC4 and DHODH binding, by suppressing the recruitment of E3 ubiquitin ligase HERC4 and polyubiquitination degradation of DHODH at the K306 site, which maintains DHODH protein stability. Importantly, downregulated PRR11 increases lipid peroxidation and alters DHODH-mediated mitochondrial morphology, thereby promoting ferroptosis and increasing TMZ chemotherapy sensitivity. In conclusion, our results reveal a mechanism via which PRR11 drives ferroptosis resistance and identifies ferroptosis induction and TMZ as an attractive combined therapeutic strategy for GBM.

Co-firing NH3 with conventional hydrocarbon fuels is an important approach for reducing CO2 emissions in existing combustion systems. Besides CO2, the blending of NH3 would also notably affect soot formation and its oxidation behaviors. In the present study, we focus on the effects of NH3 on the nanostructure and oxidation characteristics of soot produced in diffusion flames of n-heptane/toluene mixtures. Two configurations of laminar co-flow diffusion flame, including both normal and inverse diffusion flames (NDF and IDFs), were used for investigation. High-resolution transmission electron microscopy (HRTEM), Raman spectroscopy (Raman), and Thermogravimetric analysis (TGA) were employed for soot characterization. The HRTEM and Raman spectra showed that with the increase of NH3 blending ratio, the fringe length (La) and the degree of graphitization decreased while the microcrystal tortuosity (Tf) increased. The results are in consistent with TGA analysis which suggests the promoting effects of NH3 on the soot oxidation reactivity. Difference between NDF and IDF with respect to the soot nanostructure and oxidation activity were discussed. It is our hope that the present results could deepen our understanding on the effects of NH3 on soot nanostructure and oxidation behavior and benefit the design of particulate filters for combustion devices fueled with hydrocarbon/NH3 mixtures.

Biliary atresia (BA) is a severe and progressive biliary obstructive disease in infants that requires early diagnosis and new therapeutic targets. This study employed bioinformatics methods to identify diagnostic biomarkers and potential therapeutic targets for BA. Our analysis of mRNA expression from Gene Expression Omnibus datasets revealed 3,273 differentially expressed genes between patients with BA and those without BA (nBA). Weighted gene coexpression network analysis determined that the turquoise gene coexpression module, consisting of 298 genes, is predominantly associated with BA. The machine learning method then filtered out the top 2 important genes, CXCL8 and TMSB10, from the turquoise module. The area under receiver operating characteristic curves for TMSB10 and CXCL8 were 0.961 and 0.927 in the training group and 0.819 and 0.791 in the testing group, which indicated a high diagnostic value. Besides, combining TMSB10 and CXCL8, a nomogram with better diagnostic performance was built for clinical translation. Several studies have highlighted the potential of CXCL8 as a therapeutic target for BA, while TMSB10 has been shown to regulate cell polarity, which was related to BA progression. Our analysis with qRT PCR and immunohistochemistry also confirmed the upregulation of TMSB10 at mRNA and protein levels in BA liver samples. These findings highlight the sensitivity of CXCL8 and TMSB10 as diagnostic biomarkers and their potential as therapeutic targets for BA.

Abstract Background Patients with pulmonary hypertension (PH) and chronic obstructive pulmonary disease (COPD) have an increased risk of disease exacerbation and decreased survival. We aimed to develop and validate a non‐invasive nomogram for predicting COPD associated with severe PH and a prognostic nomogram for patients with COPD and concurrent PH (COPD–PH). Methods This study included 535 patients with COPD–PH from six hospitals. A multivariate logistic regression analysis was used to analyse the risk factors for severe PH in patients with COPD and a multivariate Cox regression was used for the prognostic factors of COPD–PH. Performance was assessed using calibration, the area under the receiver operating characteristic curve and decision analysis curves. Kaplan–Meier curves were used for a survival analysis. The nomograms were developed as online network software. Results Tricuspid regurgitation velocity, right ventricular diameter, N‐terminal pro‐brain natriuretic peptide (NT‐proBNP), the red blood cell count, New York Heart Association functional class and sex were non‐invasive independent variables of severe PH in patients with COPD. These variables were used to construct a risk assessment nomogram with good discrimination. NT‐proBNP, mean pulmonary arterial pressure, partial pressure of arterial oxygen, the platelet count and albumin were independent prognostic factors for COPD–PH and were used to create a predictive nomogram of overall survival rates. Conclusions The proposed nomograms based on a large sample size of patients with COPD–PH could be used as non‐invasive clinical tools to enhance the risk assessment of severe PH in patients with COPD and for the prognosis of COPD–PH. Additionally, the online network has the potential to provide artificial intelligence‐assisted diagnosis and treatment. Highlights A multicentre study with a large sample of chronic obstructive pulmonary disease (COPD) patients diagnosed with PH through right heart catheterisation. A non‐invasive online clinical tool for assessing severe pulmonary hypertension (PH) in COPD. The first risk assessment tool was established for Chinese patients with COPD–PH.

AimMagnesium levels may influence the effect of vitamin D levels on the body. This study aimed to assess the combined effect of magnesium status as reflected by magnesium depletion score (MDS) and vitamin D status on the risk of retinopathy.MethodsThis cross-sectional study included participants aged 40 years and older with complete information on vitamin D, MDS, and retinopathy assessment from the 2005–2008 National Health and Nutrition Examination Survey (NHANES). Logistic regression analysis was utilized to analyze the relationship of MDS and vitamin D with retinopathy and expressed as odds ratio (OR) and 95% confidence interval (CI).ResultsOf these 4,953 participants included, 602 (9.53%) participants had retinopathy. Serum vitamin D levels ≤30 nmol/L (vs. >30 nmol/L) (OR = 1.38, 95%CI: 1.05–1.81) and MDS >2 points (vs. ≤2 points) (OR = 1.47, 95%CI: 1.01–2.16) were associated with higher odds of retinopathy. There was an interaction between MDS and vitamin D on the increased odds of retinopathy (OR = 2.29, 95%CI: 1.12–4.68, Pinteraction = 0.025). In different MDS groups, serum vitamin D levels ≤30 nmol/L increased the odds of retinopathy only in the MDS >2 group (OR = 2.90, 95%CI: 1.16–7.24), but not in the MDS ≤2 group (p = 0.293). Subgroups analyses demonstrated that the interaction between MDS and serum vitamin D on retinopathy was observed in males (OR = 6.88, 95%CI: 1.41–33.66, Pinteraction = 0.019), people with diabetes (OR = 3.43, 95%CI: 1.78–6.63, Pinteraction

The fabrication of devices that integrate two or more topological states simultaneously and achieve precise control over their edge state and interface states holds paramount importance. We report the quantized edge-channel transport and spin-polarized interface states in folded graphene ribbons under a magnetic field and predict that fully spin-polarized states can be generated at the interface. Our results also suggest that the system has the potential to exhibit the quantum spin Hall phase, the quantum Hall phase, and a coexistence of both phases. These phases can be manipulated by applying a bias potential and Zeeman splitting. Furthermore, the quantized conductance demonstrates a plateau at 3e2/h, which can be attributed to the presence of fully spin-polarized states. These outcomes provide a foundation for future explorations and manipulations of this novel form of edge-channel transport.

ABSTRACT: We aimed to determine the onset time of hypophosphatemic rickets and investigate the mechanism of motility impairment through adenosine triphosphate (ATP) production in goslings. Two hundred and sixteen 1-day-old male Jiangnan white geese were randomly divided into 3 groups, with 6 replicates and 12 geese per replicate. Birds were fed on 3 diets: a control diet (nonphytic phosphorus, NPP, 0.38%), a P-deficient diet (PD; NPP, 0.08%), and a high P diet (HP; NPP, 0.80%) for 14 d. Subsequently, all birds were shifted to the control diet for an additional 14 d. The cumulative incidence of lameness increased significantly (P < 0.01) starting on d 4, reaching over 80% on d 7 and 100% on d 12 in the PD group. Drinking and eating frequency decreased from d 4 and d 5, respectively, in the PD group compared to the other groups (most P < 0.01). The PD group exhibited shorter and narrower beaks, higher (worse) curvature scores of the beak and costochondral junctions, swelling caput costae, and dirtier feathers since d 4, in contrast to the control and HP groups (most P < 0.01). The HP had bigger (P < 0.05) beak and sternum sizes than the control groups on d 4 to 11. Leg muscle ATP levels were lower (P < 0.01 or 0.05) on d 4 to 11; in contrast, adenosine diphosphate (d 7–11) was higher in PD compared to the control (P < 0.05). Leg muscle ATP level had positive linear (R2 > 0.40) correlations (r > 0.60) with eating and drinking frequencies on d 7 and 11 (P < 0.01). Bone stiffness, feather cleanliness, and ATP levels recovered (P > 0.05) to the control level, whereas bone size did not recover (P < 0.05) in PD and HP after eating the control diet for 2 wk. The onset time of hypophosphatemic rickets was around 4 d in goslings, and insufficient leg muscle ATP was related to the impaired motility observed in early P-deficient geese.