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Abstract Background Tyroservatide (YSV), a bioactive tripeptide, holds potential as an anti-tumor agent. However, its specific effects on oral squamous cell carcinoma (OSCC) have not been elucidated. This study aims to investigate the inhibitory effects of YSV on OSCC and explore the underlying molecular mechanisms. Methods A series of in vitro experiments were conducted to assess the impact of YSV on OSCC cell viability, colony formation, cell cycle, and apoptosis. RNA sequencing (RNA-seq), molecular docking, and western blotting were employed to investigate the molecular mechanisms. Additionally, a subcutaneous tumor model was established to validate the in vitro findings. Furthermore, PI3K inhibitors LY294002 and PI3K-IN-1, were used to confirm the role of the PTEN/PI3K/AKT pathway in YSV-mediated OSCC inhibition. Cell cycle and apoptosis were analyzed to assess the combined effect of YSV and LY294002. Results YSV significantly inhibited OSCC proliferation by inducing cell cycle arrest and apoptosis. RNA-seq and molecular docking revealed that YSV regulated the PTEN/PI3K/AKT signaling pathway. Western blotting confirmed the modulation of this pathway both in vitro and in vivo. The use of PI3K inhibitors, LY294002 and PI3K-IN-1, further validated the involvement of the PTEN/PI3K/AKT pathway in YSV-induced anti-tumor effects. Notably, the combination of YSV and LY294002 synergistically enhanced cell cycle arrest and apoptosis, demonstrating effective anti-tumor activity. In vivo experiments also supported these findings. Conclusion YSV inhibited the progression of OSCC by promoting cell cycle arrest and apoptosis through the regulation of the PTEN/PI3K/AKT signaling pathway. The combination of YSV and PI3K inhibitors, such as LY294002, exhibited enhanced anti-tumor activity, suggesting potential therapeutic strategies for OSCC treatment. Graphical abstract

The purpose of the article. The application of multi-objective optimization in portfolio management has gained significant attention in asset management. This study aims to uncover the potential advantages of dynamic portfolio optimization using a multi-objective genetic algorithm to address the challenges of ever-changing market conditions. Methodology. By incorporating multi-objective optimization, this paper comprehensively examines three key portfolio objectives: minimizing two risk types and maximizing returns. The approach involves constructing portfolios, initializing the population using the Non-Dominated Sorting Genetic Algorithm II (NSGA-II), and employing crossover and mutation steps to achieve Pareto optimality. Additionally, this study compares the performance of two risk minimization strategies through traditional portfolio backtesting. Results of the research. The results indicate that the multi-objective risk genetic algorithm not only effectively explores the portfolio space but also handles conflicting optimization objectives, thereby enhancing the comprehensiveness and flexibility of investment decisions. However, its performance depended on the chosen risk measurement methods, and the backtesting returns were unstable.

Abstract Background Plant-based diets have been found to be associated with hypertension. Dietary intake is a dynamic and changing process that can be better characterized by trajectories of dietary indices. However, the associations between plant-based diet trajectories and hypertension over time remained unknown. Methods We used data from the China Health and Nutrition Survey 2004–2015 to analyze a cohort of Chinese adults ≥ 18 years of age who had no hypertension at baseline. Plant-based diets were measured by an overall plant-based diet index (PDI), healthful plant-based diet index (hPDI), and unhealthful plant-based diet index (uPDI) based on three 24-hour recalls. Trajectories of PDI, hPDI, and uPDI (2004 to 2011) were identified using group-based trajectory modeling. The associations between trajectories of PDIs and the risk of new-onset hypertension were estimated using Cox proportional hazard models. Results We identified three trajectories for PDI, two for hPDI, and four for uPDI among the 2853 participants with a mean follow-up of 9.6 years. Compared with the PDI “low and stable” class, the PDI “high and decreasing” class had a 23% decreased risk (HR: 0.77; 95% CI: 0.62–0.95) of hypertension. There was no significant association with PDI “low and increasing” class. Compared with the hPDI “low and stable” class, the hPDI “high and stable” class had a 24% decreased risk (HR: 0.76; 95%CI: 0.64–0.91). For uPDI trajectories, compared with the “low and decreasing” class, the “high and increasing,” “high and stable,” and “low and increasing” classes had increased risks of 43% (HR: 1.43; 95% CI: 1.06–1.94), 77% (HR: 1.77; 95% CI: 1.26–2.49), and 72% (HR: 1.72; 95% CI: 1.26–2.33), respectively. Conclusions This study underscores the importance of maintaining high intakes of healthful plant-based diets and low intakes of unhealthful plant-based diets overtime for hypertension prevention.

Abstract Background The vulnerable period to neurotoxicity of isoflurane overlaps with a developmental stage characterized by programmed neuronal death. STAT3 has been identified as a crucial molecule involved in survival pathways during this period. We aimed to investigate the role of STAT3 in cellular vulnerability to isoflurane. Methods C57/BL6 mice on postnatal day 7 or 21, primary neurons derived from mice embryos at gestational days 14–16 and cultured for 5 or 14 days, as well as human neuroglioma U251 cells were treated with isoflurane. A plasmid containing human wild-type STAT3, STAT3 anti-sense oligonucleotide, STAT3 specific inhibitor STA21, proteasome inhibitor MG-132 and calcineurin inhibitor FK506 were utilized to evaluate the influence of STAT3 levels on isoflurane-induced cytotoxicity. The levels of Western blot results, mRNA, intracellular ROS, apoptotic rate, and calcineurin activity were analyzed using unpaired Student’s t-test or one-way ANOVA followed by Bonferroni post hoc test, as appropriate. Results Elevated levels of STAT3, reduced activity of calcineurin, as well as a diminished response to isoflurane-induced calcineurin activation and neuroapoptosis were observed in more mature brain or neurons. Isoflurane accelerated the degradation of ubiquitin-conjugated proteins but did not facilitate ubiquitin conjugation to proteins. STAT3 was of particular importance in the all ubiquitin-conjugated proteins degraded by isoflurane. Knockdown or inhibition of STAT3 nuclear translocation exacerbated isoflurane-induced oxidative injury and apoptosis, while STAT3 overexpression mitigated these effects. Finally, this study demonstrated that FK506 pretreatment mitigated the apoptosis, ROS accumulation, and the impairment of neurite growth in primary neurons after exposed to isoflurane. Conclusions These findings indicate that specific regulation of STAT3 was closely related with the cellular vulnerability to isoflurane via an antioxidative pathway.

Abstract Background Identification and validation of potential biomarkers could facilitate the identification of pulmonary arterial hypertension (PAH) and thus aid to study their roles in the disease process. Methods We used the isobaric tag for relative and absolute quantitation approaches to compare the protein profiles between the serum of PAH patients and the controls. Bioinformatics analyses and enzyme-linked immunosorbent assay (ELISA) identification of PAH patients and the controls were performed to identify the potential biomarkers. The receiver operating characteristic curve (ROC) analysis was used to evaluate the diagnostic performance of these potential biomarkers. Mendelian randomization (MR) analysis further clarified the relationship between the potential biomarkers and PAH. Additionally, the expression levels of the potential biomarkers were further validated in two PAH animal models (monocrotaline-PH and Sugen5416 plus hypoxia-PH) using ELISA and reverse transcription-quantitative PCR (RT-qPCR). Results We identified significant changes in three proteins including heparanase (HPSE), gelsolin (GSN), and hepatocyte growth factor activator (HGFA) in PAH patients. The ROC analysis showed that the areas under the curve of HPSE, GSN, and HGFA in differentiating PAH patients from controls were 0.769, 0.777, and 0.964, respectively. HGFA was correlated with multiple parameters of right ventricular functions in PAH patients. Besides proteomic analysis, we also used MR method to demonstrate the causal link between genetically reduced HGFA levels and an increased risk of PAH. In subsequent validation study in PAH animal models, the mRNA expression levels of HGFA in the lung tissues were significantly lower in PAH rat models than in controls. In the rat models, serum levels of HGFA were lower compared to the control group and showed a negative correlation with right ventricular systolic pressure. Conclusion The study demonstrated that HGFA might be a promising biomarker for noninvasive detection of PAH.

Abstract Background Chronic prostatitis (CP) is one of the general diseases in urological practice, with category III prostatitis being particularly prevalent. The trace metal abnormalities might be a primary cause of prostatitis, however, their specific roles in category III prostatitis remain largely unexplored. Method In total, 42 expressed prostatic secretion (EPS) samples from IIIa prostatitis patients, 42 from IIIb prostatitis patients, and 45 from controls were collected, along with 42 serum samples from IIIa prostatitis patients, 45 from IIIb prostatitis patients, and 50 from controls for analysis in this study. To investigate the diagnostic potential of trace metals in category III prostatitis, we analyzed the concentration of zinc (Zn), copper (Cu), calcium (Ca) and magnesium (Mg) in EPS and serum of patients with category III prostatitis and healthy controls using a flame atomic absorption spectrometer (FAAS). Results The Results showed that the concentrations of Zn, Ca and Mg in both serum and EPS samples of all subjects with category III prostatitis were significantly different compared to controls (all P

Abstract Background: Impaired cognitive function following exposure to heavy metals has emerged as a significant global health concern. Nevertheless, the impact of combined exposure to multiple heavy metals on cognitive impairment remains unclear. Objective: This study aimed to explore the association between multiple heavy metals exposure and cognitive function to provide theoretical evidence to guide prevention strategies. Methods: The blood levels of lead (Pb), cadmium (Cd), mercury (Hg), selenium (Se), copper (Cu) and zinc (Zn) and the results of the cognitive function tests were extracted from 811 elderly Americans who completed the NHANES between 2011 and 2014. Quantile regression (QR), restricted cubic splines (RCS), and Bayesian kernel machine regression (BKMR) were used to explore the individual and joint association between heavy metals exposure and performance in 4 standardized cognitive tests; Item Response Theory (IRT), Delayed Recall Test (DRT), Animal Fluency Test (AFT) and Digit Symbol Substitution Test (DSST). Results: A negative association was noted between Cd levels and IRT (p = 0.048, 95%CI: -2.7, -0.1). Se concentrations ranging between 2.197 µg/L (95%CI: 0.004, 0.15) to 2.29 µg/L (95%CI: 2.56, 7.64) (log10Se) was postively associated with DSST (p = 0.001 ). Cu was negatively associated with DSST (p = 0.049, 95%CI: -37.75, -0.09), while Zn was positively associated with IRT (p = 0.022, 95%CI: 0.55, 11.73). Exposure to the 6 heavy metals combined showed a positive linear association with IRT, DRT, and a negative linear association with DSST. An interaction between Cd and the other heavy metals (excepted for Pb). Conclusion: Exposure to Pb, Cd, Hg, Se, Cu, and Zn was associated with cognitive function. Joint exposure to the 6 heavy metals showed a positive linear association with IRT, DRT, contrarily, a negative linear association with DSST.

Abstract Background Evidence for the relationship between individual and combined volatile organic compounds (VOCs) and cardiovascular disease (CVD) is limited. Besides, the mediating role of biological aging (BA) has not been studied. Therefore, this study aimed to examine the association between VOCs and CVD risk and to explore the mediating effects of BA. Methods Logistic regression models were used to investigate the relationships of metabolites of volatile organic compounds (mVOCs) and BA with CVD. In addition, weighted quantile sum (WQS) regression, adaptive elastic networks, and Environmental Risk Score (AENET-ERS) were utilized to assess overall associations of mixed VOCs co-exposure with CVD. Mediation analyses were used to identify potential mediating effects of BA. Results In the single-pollutant model, CYMA was shown to be associated with an increased risk of CVD. Additionally, we identified significantly positive associations between the WQS index and CVD (odds ratio (OR) = 1.292, 95% confidence interval (CI): 1.006, 1.660), and DHBMA had the greatest contribution for CVD (0.246). Furthermore, the AENET-ERS results showed that 8 mVOCs were significantly associated with CVD, and ERS was related to an elevated risk of CVD (OR = 1.538, 95%CI: 1.255, 1.884). Three BA indicators mediated the association of the mVOCs mixture with CVD, with mediating effect proportions of 11.32%, 34.34%, and 7.92%, respectively. Conclusion The risk of CVD was found to increase with both individual and combined exposure to VOCs. BA mediates the positive effects of VOCs on CVD, suggesting that this pathway may be one of the mechanisms of CVD.

Abstract Background This study aims to investigate the efficacy of five analgesic strategies combined with conventional physiotherapy program (CPT) in managing chronic shoulder pain. Methods Two authors independently screened studies, extracted data using a pre-formatted chart, and assessed bias using the Cochrane Risk of Bias tool. A network meta-analysis was performed by the Stata 17.0 and R 4.3.2 software. Results A total of 14 studies with 862 subjects were identified. These analgesic strategies included extracorporeal shock wave therapy (ESWT), suprascapular nerve block (SSNB), corticosteroid injection (CSI), hyaluronic acid injection (HAI), and kinesio taping (KT). ESWT plus CPT was the most efficient intervention in alleviating pain intensity and improving physical function. SSNB plus CPT was the optimal intervention in improving shoulder mobility. Compared to CPT alone, CSI + CPT only significantly improved the SPADI total score, but showed no difference in pain intensity or shoulder mobility. HAI + CPT showed no significant difference in improving pain intensity, physical function, or shoulder mobility compared to CPT alone. Adding KT to CPT did not yield additional benefits in improving shoulder mobility. Conclusion Overall, in managing chronic shoulder pain, ESWT + CPT was the most effective intervention for reducing pain intensity and improving physical function. SSNB + CPT was optimal for enhancing shoulder mobility. Future rigorous clinical trials with larger sample sizes and higher methodological rigor are strongly required to confirm the current results.

Abstract Background Alzheimer’s disease (AD) is a neurodegenerative disorder that can result in neurotoxicity and an imbalance in gut microbiota. Probiotics have been shown to play an important role in regulating the gut microbiota, but their viability and bioactivity are often compromised as they traverse the gastrointestinal tract, thereby reducing their efficacy and limiting their clinical utility. Results In this work, layer-by-layer (LbL) encapsulation technology was used to encapsulate Lactiplantibacillus plantarum (LP) to improve the above shortcomings. Studies in APPswe/PS1dE9 (APP/PS1) transgenic mice show that LbL-encapsulated LP ((CS/SP)2-LP) protects LP from gastrointestinal damage while (CS/SP)2-LP treatment It improves brain neuroinflammation and neuronal damage in AD mice, reduces Aβ deposition, improves tau protein phosphorylation levels, and restores intestinal barrier damage in AD mice. In addition, post-synaptic density protein 95 (PSD-95) expression increased in AD mice after treatment, indicating enhanced synaptic plasticity. Fecal metabolomic and microbiological analyzes showed that the disordered intestinal microbiota composition of AD mice was restored and short-chain fatty acids (SCFAs) levels were significantly increased after (CS/SP)2-LP treatment. Conclusion Overall, the above evidence suggests that (CS/SP)2-LP can improve AD symptoms by restoring the balance of intestinal microbiota, and (CS/SP)2-LP treatment will provide a new method to improve the symptoms of AD patients.

Transfer learning aims to integrate useful information from multi-source datasets to improve the learning performance of target data. This can be effectively applied in genomics when we learn the gene associations in a target tissue, and data from other tissues can be integrated. However, heavy-tail distribution and outliers are common in genomics data, which poses challenges to the effectiveness of current transfer learning approaches. In this paper, we study the transfer learning problem under high-dimensional linear models with t-distributed error (Trans-PtLR), which aims to improve the estimation and prediction of target data by borrowing information from useful source data and offering robustness to accommodate complex data with heavy tails and outliers. In the oracle case with known transferable source datasets, a transfer learning algorithm based on penalized maximum likelihood and expectation-maximization algorithm is established. To avoid including non-informative sources, we propose to select the transferable sources based on cross-validation. Extensive simulation experiments as well as an application demonstrate that Trans-PtLR demonstrates robustness and better performance of estimation and prediction when heavy-tail and outliers exist compared to transfer learning for linear regression model with normal error distribution. Data integration, Variable selection, T distribution, Expectation maximization algorithm, Genotype-Tissue Expression, Cross validation.

The effects of rhizosphere microorganisms on plant growth and the associated mechanisms are a focus of current research, but the effects of exogenous combined inoculation with arbuscular mycorrhizal fungi (AMF) and plant growth-promoting rhizobacteria (PGPR) on seedling growth and the associated rhizosphere microecological mechanisms have been little reported. In this study, a greenhouse pot experiment was used to study the effects of single or double inoculation with AM fungi (Funneliformis mosseae) and two PGPR (Bacillus sp., Pseudomonas sp.) on the growth of tobacco seedlings, together with high-throughput sequencing technology to reveal associated rhizosphere microecological mechanisms. All inoculation treatments significantly increased the aboveground dry weight; root dry weight; seedling nitrogen, phosphorus, and potassium uptake; plant height; stem thickness; maximum leaf area; chlorophyll content; total root length, surface area, and volume; and average root diameter. The highest values for these indices were observed in the combined treatment of F. mosseae and Pseudomonas sp. SG29 (A_SG29). Furthermore, the A_SG29 treatment yielded the highest diversity indexes and largest percentages of significantly enriched bacterial taxa, and significantly promoted the colonization of AMF in tobacco roots and Pseudomonas in rhizosphere soil. Differential metabolic-pathway predictions using PICRUSt2 showed that the A_SG29 treatment significantly increased the metabolic pathway richness of tobacco rhizosphere microorganisms, and significantly up-regulated some metabolic pathways that may benefit plant growth. Co-inoculation with F. mosseae and Pseudomonas sp. SG29 promoted tobacco-seedling growth by significantly improving rhizosphere microbial communities' structure and function. In summary, the combined inoculation of AMF and SG29 promotes tobacco seedling growth, optimizes the rhizosphere microbial community's structure and function, and serves as a sustainable microbial co-cultivation method for tobacco seedling production.

Summary: Background: Pulmonary embolism (PE) as a preventable and potentially fatal noncommunicable disease was believed to have a lower incidence in Asian populations compared to Western populations. However, the incidence and mortality rates of PE in China and the impact of venous thromboembolism (VTE) prevention system constructions on PE still lack nationwide evidence. Methods: For this nationwide hospital-based observational study, we used data from the National Hospital Quality Monitoring System (HQMS) and public database in China. We estimated the incidence and in-hospital mortality rates of PE by age group, sex, and regions of geographical and socioeconomic level. VTE prevention and management system constructions were quantified by geographical density. We then calculated the incidence and mortality rates in different conditions of VTE prevention and management system construction. Findings: During the 12 months period between January and December 2021, a total number of 200,112 PE patients and 14,123 deaths were recorded from 5101 hospitals in the HQMS database. The incidence of PE was 14.19 (200,112, 95% CI 14.13–14.26) per 100,000 population and the mortality rate was 1.00 (95% CI 0.99–1.02) per 100,000 population. The incidence of PE was higher in male patients (14.43 per 100,000 population) than in female patients (13.95 per 100,000 population). Disparities of incidence and mortality rates were shown within age groups and geographical regions. The incidence and mortality rates of PE showed decreasing trend with increasing geographical density of VTE-related facilities and VTE prevention system developments. Interpretation: China had a substantially large number of PE patients. The incidence and mortality rates of PE showed disparities in terms of sex, age, and geography. The incidence and mortality rates of PE decrease across regions with increasing levels of socioeconomic development, potentially influenced by the existing VTE prevention and management systems. Optimizing the health policies and healthcare investment in VTE prevention may help reduce the disease burden of PE. Funding: CAMS Innovation Fund for Medical Sciences (CIFMS) (2023-I2M-A-014); National High Level Hospital Clinical Research Funding (2022-NHLHCRF-LX-01-0108); National Key Research and Development Program of China (2023YFC2507200); Discipline-Innovation and Talent-Introduction Program for Colleges and Universities (111 Plan, B23038).

Internal migrants are a challenge for TB control in large Chinese cities and understanding this epidemiology is crucial for designing effective control and prevention strategies. We conducted a prospective genomic epidemiological study of culture-positive TB patients diagnosed between June 1, 2018 and May 31, 2021 in the Longhua District of Shenzhen. Treatment status was obtained from local and national TB registries and all isolates were sequenced. Genomic clusters were defined as strains differing by ≤12 SNPs. Risk factors for clustering were identified with multivariable analysis and then Bayesian models and TransPhylo were used to infer the timing of transmission within clusters. Of the 2277 culture-positive patients, 70.1% (1596/2277) were migrants: 72.1% (1043/1446) of the migrants patients developed TB within two years of arriving in Longhua; 38.8% within 6 months of arriving; and 12.3% (104/843) had TB symptoms when they arrived. Only 15.4% of Longhua strains were in genomic clusters. More than one third (33.6%) of patients were not treated in Shenzhen but were involved in nearly one third of the recent transmission events. Clustering was associated with migrants not treated in Shenzhen, males, and teachers/trainers. TB in Longhua is prinicipally due to reactivation of infections in migrants, but a proportion may have had clinical or incipient TB upon arrival in the district. Patients diagnosed but not treated in Longhua were involved in recent local TB transmission. Controlling TB in Shenzhen will require strategies to comprehensively diagnose and treat active TB in the internal migrant population.

Trans-acting small interfering RNAs (tasiRNAs) are 21-nt phased (phased siRNAs) resulting from successive DCL-catalyzed processing from the end of a double-stranded RNA substrate originating from the RDR of an AGO-catalyzed cleaved RNA at a micro RNA target site. Plant tasiRNAs have been synthesized to produce synthetic tasiRNAs (syn-tasiRNAs) targeting viral RNAs that confer viral resistance. In this study, we engineered syn-tasiRNAs to target potato virus Y (PVY) infection by replacing five native siRNAs of TAS1c with 210-bp fragments from the coat protein (CP) region of the PVY genome. The results showed that the transient expression of syn-tasiR-CPpvy2 in Nicotiana benthamiana (N. benthamiana) plants conferred antiviral resistance, supported by the absence of PVY infection symptoms and viral accumulation. This indicated that syn-tasiR-CPpvy2 successfully targeted and silenced the PVY CP gene, effectively inhibiting viral infection. syn-tasiR-CPpvy1 displayed attenuated symptoms and decreased viral accumulation in these plants However, severe symptoms of PVY infection and a similar amount of viral accumulation as the control were observed in plants expressing syn-tasiR-CPpvy3. syn-tasiR-CPpvy/pvx, which targets both PVY and potato virus X (PVX), was engineered using a single precursor. After the transient expression of syn-tasiR-CPpvy/pvx3 and syn-tasiR-CPpvy/pvx5 in N. benthamiana, the plants were resistant to both PVY and PVX. These results suggested that engineered syn-tasiRNAs could not only specifically induce antiviral resistance against one target virus but could also be designed for multi-targeted silencing of different viruses, thereby preventing complex virus infection in plants.

Potassium (K+) plays a role in enzyme activation, membrane transport, and osmotic regulation processes. An increase in potassium content can significantly improve the elasticity and combustibility of tobacco and reduce the content of harmful substances. Here, we report that the expression analysis of Nt GF14e, a 14-3-3 gene, increased markedly after low-potassium treatment (LK). Then, chlorophyll content, POD activity and potassium content, were significantly increased in overexpression of Nt GF14e transgenic tobacco lines compared with those in the wild type plants. The net K+ efflux rates were severely lower in the transgenic plants than in the wild type under LK stress. Furthermore, transcriptome analysis identified 5708 upregulated genes and 2787 downregulated genes between Nt GF14e overexpressing transgenic tobacco plants. The expression levels of some potassium-related genes were increased, such as CBL-interacting protein kinase 2 (CIPK2), Nt CIPK23, Nt CIPK25, H+-ATPase isoform 2 a (AHA2a), Nt AHA4a, Stelar K+ outward rectifier 1(SKOR1), and high affinity K+ transporter 5 (HAK5). The result of yeast two-hybrid and luciferase complementation imaging experiments suggested Nt GF14e could interact with CIPK2. Overall, these findings indicate that NtGF14e plays a vital roles in improving tobacco LK tolerance and enhancing potassium nutrition signaling pathways in tobacco plants.

It was common to see that older adults were reluctant to be vaccinated for coronavirus disease 2019 (COVID-19) in China. There is a lack of practical prediction models to guide COVID-19 vaccination program. A nationwide, self-reported, cross-sectional survey was conducted from September 2022 to November 2022, including people aged 60 years or older. Stratified random sampling was used to divide the dataset into derivation, validation, and test datasets at a ratio of 6:2:2. Least absolute shrinkage and selection operator and multivariable logistic regression were used for variable screening and model construction. Discrimination and calibration were assessed primarily by area under the receiver operating characteristic curve (AUC) and calibration curve. A total of 35057 samples (53.65% males and mean age of 69.64 ± 7.24 years) were finally selected, which constitutes 93.73% of the valid samples. From 33 potential predictors, 19 variables were screened and included in the multivariable logistic regression model. The mean AUC in the validation dataset was 0.802, with sensitivity, specificity, and accuracy of 0.732, 0.718 and 0.729 respectively, which were similar to the parameters in the test dataset of 0.755, 0.715 and 0.720, respectively, and the mean AUC in the test dataset was 0.815. There were no significant differences between the model predicted values and the actual observed values for calibration in these groups. The prediction model based on self-reported characteristics of older adults was developed that could be useful for predicting the willingness for COVID-19 vaccines, as well as providing recommendations in improving vaccine acceptance.

Post-reperfusion syndrome (PRS) is a severe and highly lethal syndrome that occurs after declamping the portal vein forceps during liver transplantation. It is marked by severe hemodynamic disturbances manifested by decreased mean arterial pressure, increased heart rate and elevated pulmonary artery pressure. The complex pathogenesis of PRS remains understudied. It is generally believed to be related to the large amount of acidic, cold blood that enters the circulation after release of the portal clamp. This blood is rich in oxygen-free radicals and metabolic toxins, which not only aggravate the ischemia-reperfusion injury of the liver but also further attack the systemic organs indiscriminately. Considering the range of possible adverse prognoses including acute kidney injury, delirium and graft nonfunction, it is imperative that clinicians increase their awareness and prevention of PRS. The aim of this article is to review the current risk factors, pathophysiological mechanisms and prevention strategies for PRS.

The incidence of tuberculosis (TB) has declined more slowly in rural than urban areas in China, and data on the patterns of transmission and the high-risk populations in rural areas remains scarce. We conducted a population-based study of culture-positive pulmonary TB patients diagnosed in rural Linzhou City, Henan Province from July 2018 to February 2023. Genomic clusters were defined based on whole-genome sequencing and risk factors for clustering were identified by logistic regression. Transmission events were inferred with phybreak and transmission links were sought through epidemiological investigation of clustered patients. Logistic regression was used to explore the relationship between genomic differences of patient isolates and geographical distances of patient residences. Spatial hotspots were defined using kernel density estimation. Of 455 culture-positive patients, 430 were included in the final analysis. Overall, 192 (44.7%,192/430) patients were grouped into 49 clusters. Clusters containing ≥5 patients accounted for 18.4% (9/49) of the clusters and clustering was highest in student patients. No super-spreaders were detected. Confirmed epidemiologic links were identified for only 18.2% of clustered patients. The clustering risk decreased rapidly with increasing distances between patient residences, but 77.6% of clustered patient pairs lived ≥5.0 km apart. Both the Central Subdistrict and Rencun Township were identified as hotspots for TB transmission. Recent transmission appears to be an important driver of the TB burden in Linzhou. The formulation of effective strategies to reduce TB incidence in rural areas will require further studies to identify high-risk populations and venues where local inhabitants congregate and transmit the infection.

Summary: Plant virus vectors have emerged as promising tools for CRISPR-Cas reagent delivery. Here, we present a protocol for DNA-free plant genome editing using an engineered RNA virus vector for the transient delivery of CRISPR-Cas components. We describe steps for viral vector construction, viral vector recovery through agroinoculation of Nicotiana benthamiana, mechanical inoculation of target plant hosts, analysis of somatic mutagenesis frequency, and regeneration of mutant plants. The method achieves high editing efficiency and eliminates the need for stable plant transformation.For complete details on the use and execution of this protocol, please refer to Liu et al.1 : Publisher’s note: Undertaking any experimental protocol requires adherence to local institutional guidelines for laboratory safety and ethics.

Abstract The migratory insertion of metal-hydride into alkene has allowed regioselective access to organometallics, readily participating in subsequent functionalization as one conventional pathway of hydroalkylation, whereas analogous process with feedstock alkyne is drastically less explored. Among few examples, the regioselectivity of metal-hydride insertion is mostly governed by electronic bias of alkynes. To alter the regioselectivity and drastically expand the intermediate pools that we can access, one aspirational design is through alternative nickel-alkyl insertion, providing opposite regioselectivity induced by steric demand. Leveraging in situ formed nickel-alkyl species, we herein report the regio- and enantioselective hydroalkylation of alkynes with broad functional group tolerance, excellent regio- and enantioselectivity, enabling efficient route to diverse valuable chiral allylic amines motifs. Preliminary mechanistic studies indicate the aminoalkyl radical species can participate in metal-capture and lead to formation of nickel-alkyl, of which the migratory insertion is key to reverse regioselectivity observed in metal-hydride insertion.

Abstract Background The risk stratification of pulmonary arterial hypertension proposed by the European Society of Cardiology /European Respiratory Society guidelines in 2015 and 2022 included two to three echocardiographic indicators. However, the specific value of echocardiography in risk stratification of pre-capillary pulmonary hypertension (pcPH) has not been efficiently demonstrated. Given the complex geometry of the right ventricular (RV) and influencing factors of echocardiographic parameter, there is no single echocardiographic parameter that reliably informs about PH status. We hypothesize that a multi-parameter comprehensive index can more accurately evaluate the severity of the pcPH. The purpose of this study was to develop and validate an echocardiographic risk score model to better assist clinical identifying high risk of pcPH during initial diagnosis and follow-up. Methods We studied 197 consecutive patients with pcPH. A multivariable echocardiographic model was constructed to predict the high risk of pcPH in the training set. Points were assigned to significant risk factors in the final model based on β-coefficients. We validated the model internally and externally. Results The echocardiographic score was constructed by multivariable logistic regression, which showed that pericardial effusion, right atrial (RA) area, RV outflow tract proximal diameter (RVOT-Prox), the velocity time integral of the right ventricular outflow tract (TVIRVOT) and S’ were predictors of high risk of pcPH. The area under curve (AUC) of the training set of the scoring model was 0.882 (95%CI: 0.809–0.956, p

Abstract Background Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary vascular disorder with substantial morbidity and mortality, also a disease underdiagnosed and undertreated. It is potentially curable by pulmonary endarterectomy (PEA) in patients with surgically accessible thrombi. Balloon pulmonary angioplasty (BPA) and targeted medical therapy are options for patients with distal lesions or persistent/recurrent pulmonary hypertension after PEA. There is an urgent need to increase the awareness of CTEPH. Qualified CTEPH centers are still quite limited. Baseline characteristics, management pattern and clinical outcome of CTEPH in China needs to be reported. Methods and design The CHinese reAl-world study to iNvestigate the manaGEment pattern and outcomes of chronic thromboembolic pulmonary hypertension (CHANGE) study is designed to provide the multimodality treatment pattern and clinical outcomes of CTEPH in China. Consecutive patients who are ≥ 14 year-old and diagnosed with CTEPH are enrolled. The diagnosis of CTEPH is confirmed in right heart catheterization and imaging examinations. The multimodality therapeutic strategy, which consists of PEA, BPA and targeted medical therapy, is made by a multidisciplinary team. The blood sample and tissue from PEA are stored in the central biobank for further research. The patients receive regular follow-up every 3 or 6 months for at least 3 years. The primary outcomes include all-cause mortality and changes in functional and hemodynamic parameters from baseline. The secondary outcomes include the proportion of patients experiencing lung transplantation, the proportion of patients experiencing heart and lung transplantation, and changes in health-related quality of life. Up to 31 December 2023, the study has enrolled 1500 eligible patients from 18 expert centers. Conclusions As a real-world study, the CHANGE study is expected to increase our understanding of CTEPH, and to fill the gap between guidelines and the clinical practice in the diagnosis, assessment and treatment of patients with CTEPH. Registration Number in ClinicalTrials.gov NCT05311072.

Abstract Background Migraine, a neurological disorder with a significant female predilection, is the leading cause of disability-adjusted life years (DALYs) in women of childbearing age (WCBA). There is currently a lack of comprehensive literature analysis on the overall global burden and changing trends of migraines in WCBA. Methods This study extracted three main indicators, including prevalence, incidence, and DALYs, related to migraine in WCBA from the Global Burden of Disease(GBD) database from 1990 to 2021. Our study presented point estimates with 95% uncertainty intervals (UIs). It evaluated the changing trends in the burden of migraine in WCBA using the estimated annual percentage change (EAPC) and percentage change. Results In 2021, the global prevalence, incidence, and DALYs cases of migraine among WCBA were 493.94 million, 33.33 million, and 18.25 million, respectively, with percentage changes of 48%, 43%, and 47% compared to 1990. Over the past 32 years, global prevalence rates and DALYs rates globally have increased, with an EAPC of 0.03 (95% UI: 0.02 to 0.05) and 0.04 (95% UI: 0.03 to 0.05), while incidence rates have decreased with an EAPC of -0.07 (95% UI: -0.08 to -0.05). Among the 5 Socio-Demographic Index (SDI) regions, in 2021, the middle SDI region recorded the highest cases of prevalence, incidence, and DALYs of migraine among WCBA, estimated at 157.1 million, 10.56 million, and 5.81 million, respectively, approximately one-third of the global total. In terms of age, in 2021, the global incidence cases for the age group 15–19 years were 5942.5 thousand, with an incidence rate per 100,000 population of 1957.02, the highest among all age groups. The total number of migraine cases and incidence rate among WCBA show an increasing trend with age, particularly in the 45–49 age group. Conclusions Overall, the burden of migraine among WCBA has significantly increased globally over the past 32 years, particularly within the middle SDI and the 45–49 age group. Research findings emphasize the importance of customized interventions aimed at addressing the issue of migraines in WCBA, thus contributing to the attainment of Sustainable Development Goal 3 set by the World Health Organization.

Abstract Background Bitter taste receptors (Tas2rs) are generally considered to sense various bitter compounds to escape the intake of toxic substances. Bitter taste receptors have been found to widely express in extraoral tissues and have important physiological functions outside the gustatory system in vivo. Methods To investigate the physiological functions of the bitter taste receptor cluster Tas2r106/Tas2r104/Tas2r105/Tas2r114 in lingual and extraoral tissues, multiple Tas2rs mutant mice and Gnat3 were produced using CRISPR/Cas9 gene‐editing technique. A mixture containing Cas9 and sgRNA mRNAs for Tas2rs and Gnat3 gene was microinjected into the cytoplasm of the zygotes. Then, T7EN1 assays and sequencing were used to screen genetic mutation at the target sites in founder mice. Quantitative real‐time polymerase chain reaction (qRT‐PCR) and immunostaining were used to study the expression level of taste signaling cascade and bitter taste receptor in taste buds. Perception to taste substance was also studied using two‐bottle preference tests. Results We successfully produced several Tas2rs and Gnat3 mutant mice using the CRISPR/Cas9 technique. Immunostaining results showed that the expression of GNAT3 and PLCB2 was not altered in Tas2rs mutant mice. But qRT‐PCR results revealed the changed expression profile of mTas2rs gene in taste buds of these mutant mice. With two‐bottle preference tests, these mutant mice eliminate responses to cycloheximide due to genetic mutation of Tas2r105. In addition, these mutant mice showed a loss of taste perception to quinine dihydrochloride, denatonium benzoate, and cucurbitacin B (CuB). Gnat3‐mediated taste receptor and its signal pathway contribute to CuB perception. Conclusions These findings implied that these mutant mice would be a valuable means to understand the biological functions of TAS2Rs in extraoral tissues and investigate bitter compound–induced responses mediated by these TAS2Rs in many extraoral tissues.

Sodium metabisulfite (SMB) is commonly utilized in food to preserve freshness by acting as an antioxidant and antimicrobial agent. However, when SMB interacts with water in biological systems, it produces harmful byproducts such as sulfite and sulfur dioxide. These byproducts induce cellular stress and programmed cell death, known as apoptosis, by triggering excessive production of reactive oxygen species. Our study demonstrates that supplementation with nicotinamide mononucleotide (NMN) effectively mitigates the damage caused by SMB to porcine oocytes during their cultivation in laboratory conditions. NMN supplementation not only preserves the oocytes' ability to undergo meiosis with intact spindle and chromosome structures but also enhances their capacity for fertilization by promoting the activity of cortical granule component protease. The protective effects of NMN on porcine oocytes exposed to SMB involve the restoration of mitochondrial function and the reduction of accumulated reactive oxygen species, leading to inhibition of apoptosis. These findings suggest that excessive SMB will impair mitochondrial function in porcine oocytes, which in turn causes oxidative stress and apoptosis, and impedes maturation of porcine oocytes and development of post-fertilised embryos, and that supplementation with NMN is a promising strategy to protect oocytes from the deleterious effects of SMB exposure.

Abstract The appearance of van Hove singularities near the Fermi level leads to prominent phenomena, including superconductivity, charge density wave, and ferromagnetism. Here a bilayer Kagome lattice with multiple van Hove singularities is designed and a novel borophene with such lattice (BK‐borophene) is proposed by the first‐principles calculations. BK‐borophene, which is formed via three‐center two‐electron (3c–2e) σ‐type bonds, is predicted to be energetically, dynamically, thermodynamically, and mechanically stable. The electronic structure hosts both conventional and high‐order van Hove singularities in one band. The conventional van Hove singularity resulting from the horse saddle is 0.065 eV lower than the Fermi level, while the high‐order one resulting from the monkey saddle is 0.385 eV below the Fermi level. Both the singularities lead to the divergence of electronic density of states. Besides, the high‐order singularity is just intersected to a Dirac‐like cone, where the Fermi velocity can reach 1.34 × 106 m s−1. The interaction between the two Kagome lattices is critical for the appearance of high‐order van Hove singularities. The novel bilayer Kagome borophene with rich and intriguing electronic structure offers an unprecedented platform for studying correlation phenomena in quantum material systems and beyond.

Worldwide grasslands are experiencing degradation due to overgrazing and the effects of climate change, and warming-induced changes in degraded grasslands could accelerate degradation. As one of the direct manipulating factors of grassland degradation, soil water is governed by climatological and anthropogenic processes. Evapotranspiration (ET) plays a key role in regulating soil water content in these processes, but the underlying mechanisms remain unclear. In this study, a two-year field experiment was conducted in different degraded grasslands. The calibrated Hydrus-1D model was applied to identified the dynamic of ET and soil water in 2022 and 2023 under normal condition and warming (+1.5 °C) scenarios. ET decreased slightly with grassland degradation, mainly due to the reduction of transpiration (T). T/ET decreased as well, 57.87 %∼69.06 %, 51.71 %∼65.60 %, 31.76 %∼49.44 % and 15.54 %∼22.61 % in undegraded control (CK), light degraded (LD), moderately degraded (MD) and heavy degraded (HD) grasslands, respectively, during growing seasons. With the aggravation of grassland degradation, the influence of warming on ET was gradually enhanced. Soil water content (SWC) responded differently to degraded degrees. Additionally, warming showed more significant effects on SWC in LD and MD grasslands than in HD grassland. Furthermore, ET contribution to regulating SWC response to degradation and warming in LD and MD grasslands at 30–100 cm soil depth. Compared to other meteorological factors, vapor pressure deficit (VPD) exhibited significantly stronger correlation with T, and this correlation weakened gradually with grassland degradation, indicating a diminished regulatory role of vegetation in response to environmental moisture changes. Grassland T/ET during the growing season could serve as a potential parameter for predicting vegetation productivity. In dry conditions, irrigation at critical growth stages in the field can be implemented to achieve optimal results in enhancing water use efficiency and degraded grassland restoration. These findings not only can improve our understanding of the hydrological processes and water budget during grassland degradation, but also provide valuable guidelines for the management of water resources and the restoration of ecological environment.

Background: Toxicological and epidemiological studies have shown that environmental endocrine disruptors interfere with hormonal homeostasis. However, there is limited research on the effects of mixed exposure to nonpersistent endocrine disruptors on thyroid hormones and the factors (e.g., presence status of thyroid autoantibodies or nutritional status of organismal iodine) that may influence this association. Methods: Data were collected from the National Health and Nutrition Examination Survey (NHANES) 2007–2008 and 2011–2012. Relationships between single pollutants and thyroid hormone and thyroid autoantibody levels were assessed using generalized linear (GLM) and restricted cubic spline (RCS) regression models. Weighted quantile sum regression (WQS), group-weighted quantile sum regression (GWQS), quantile-based g-computation (qgcomp), and adaptive elasticity network (AENET) were applied to assess the mixed exposure effect. Next, subgroup analyses were performed on the basis of the urinary iodine concentration or thyroid autoantibody status to assess the modifying role of urinary iodine and thyroid autoantibodies. Results: A total of 2385 study participants were included in this study. Both the single-pollutant model and the multipollutant mixed model revealed that parabens and bis(2-ethylhexyl) phthalate (DEHP) metabolites were significantly and negatively associated with serum thyroxine (T4) levels. However, no associations were found between the target pollutants and thyroid autoantibodies (thyroglobulin antibodies (TgAb) and thyroid peroxidase antibodies (TPOAb)). In addition, this study revealed that urinary iodine or thyroid autoantibody status altered the associations of some of the target pollutants with thyroid hormones. WQS and qgcomp analyses, revealed that the associations of mixed pollutants with hormones differed depending on the urinary iodine or antibody status, especially T4 and thyroid-stimulating hormone (TSH). Conclusion: Significant associations were found between phenols, parabens, and phthalates and serum thyroid hormone levels, with parabens and DEHP metabolites playing major roles. Urinary iodine and thyroid autoantibody status act as modifiers between environmental endocrine-disrupting pollutants and thyroid hormones.

IntroductionSeveral clinical studies have demonstrated that brain-computer interfaces (BCIs) controlled functional electrical stimulation (FES) facilitate neurological recovery in patients with stroke. This review aims to evaluate the effectiveness of BCI-FES training on upper limb functional recovery in stroke patients.MethodsPubMed, Embase, Cochrane Library, Science Direct and Web of Science were systematically searched from inception to October 2023. Randomized controlled trials (RCTs) employing BCI-FES training were included. The methodological quality of the RCTs was assessed using the PEDro scale. Meta-analysis was conducted using RevMan 5.4.1 and STATA 18.ResultsThe meta-analysis comprised 290 patients from 10 RCTs. Results showed a moderate effect size in upper limb function recovery through BCI-FES training (SMD = 0.50, 95% CI: 0.26–0.73, I2 = 0%, p

Abstract Rationale and objectives Bleeding is a major complication of transbronchial lung cryobiopsy (TBLC), and pre-placing a bronchial balloon is one of the clinical practices used to prevent it, but with very weak evidence, which should be confirmed. This study aimed to conduct whether pre-placing a bronchial balloon in TBLC for diagnosing interstitial lung disease (ILD) is more safety. Materials and methods In this prospective, single-center, randomized controlled trial, patients with suspected ILD were enrolled and randomly assigned to pre-placed balloon and none-pre-placed balloon groups. The primary outcome was incidence of moderate bleeding in each group. The secondary endpoints were the incidence of severe bleeding, pneumothorax, and other procedural complications. Results Exactly 250 patients were enrolled between August 2019 and March 2022, with 125 in each group. There were no significant differences in severe bleeding between the none-pre-placed balloon group and pre-placed balloon group (1.6% vs. 0.8%; adjusted p = 0.520), while more moderate bleeding occurred in the none-pre-placed balloon group (26.4% vs. 6.4%, adjusted p = 0.001), as well as more use of hemostatic drug (28.0% vs. 6.4%, adjusted p = 0.001). Three patients in the none-pre-placed balloon group used the bronchial balloon. More samples could be acquired in the pre-placed balloon group than in the none-pre-placed balloon group (3.8 ± 0.9 vs. 3.1 ± 0.9, p

Abstract In this study, dynamic formation tracking and interception are performed by controlling multi-agent using a Euler-like Lagrangian model. The purpose is to use the distance-based rigid graph method to control multi-agent, and ultimately achieve dynamic formation tracking and target interception of multi-agent. Initially, distance-based graph stiffness and back-stepping techniques were considered to address the formation control challenge. This method helps achieve the initial expected formation and effectively complete the formation mission. Leaders continue to chase the moving target, while followers stick to the expected arrangement. The leader then precisely tracks the moving target and surrounds it within the formation. By using Lyapunov stability theory with adaptive control, it is ensured that the total distance meets finite and consistent error limits. Finally, the numerical simulation of the interception plan was carried out by 6 multi-agents and 1 target at different times to verify the effectiveness of the control method.

Abstract Background and aims To investigate the impact of intrahepatic cholestasis of pregnancy (ICP) with hepatitis B virus (HBV) infection on pregnancy outcomes. Methods We selected 512 pregnant women, collected the data including maternal demographics, main adverse pregnancy outcomes and maternal HBV infected markers HBeAg and HBV-DNA loads status, then have a comparative analysis. Results There were 319 solitary ICP patients without HBV infection (Group I) and 193 ICP patients with HBV infection. Of the latter, there were 118 cases with abnormal liver function(Group II) and 80 cases with normal liver function(Group III). All HBV-infected pregnant women with ICP were divided into hepatitis Be antigen (HBeAg)-positive group (102 cases) and HBeAg-negative group (91 cases), according to the level of the serum HBeAg status; and into high viral load group (92 cases), moderate viral load group (46 cases) and low viral load group (55 cases) according to the maternal HBV-DNA level. Group II had a higher level of serum total bile acids, transaminase, bilirubin as well as a higher percentage of premature delivery, neonatal intensive care unit (NICU) admission and meconium-stained amniotic fluid (MSAF) compared with the other two groups(P 106 IU/ml) had a higher level of transaminase, bilirubin, and bile acid as well as shorter gestational weeks of delivery, lower birth weight of new-borns and a higher rate of NICU admission compared with those with a low or moderate viral load (P

Abstract Transcriptional regulation is a critical adaptive mechanism that allows bacteria to respond to changing environments, yet the concept of transcriptional plasticity (TP) – the variability of gene expression in response to environmental changes – remains largely unexplored. In this study, we investigate the genome-wide TP profiles of Mycobacterium tuberculosis (Mtb) genes by analyzing 894 RNA sequencing samples derived from 73 different environmental conditions. Our data reveal that Mtb genes exhibit significant TP variation that correlates with gene function and gene essentiality. We also find that critical genetic features, such as gene length, GC content, and operon size independently impose constraints on TP, beyond trans-regulation. By extending our analysis to include two other Mycobacterium species -- M. smegmatis and M. abscessus -- we demonstrate a striking conservation of the TP landscape. This study provides a comprehensive understanding of the TP exhibited by mycobacteria genes, shedding light on this significant, yet understudied, genetic feature encoded in bacterial genomes.

Abstract The rise in sea levels, driven by global climate change, poses a significant threat to cultural heritage in coastal regions. Traditional risk assessment methods, focusing on direct inundation, often fail to consider the crucial impact of socio-economic factors, which are significantly vulnerable to sea level rise. To bridge this gap, this study introduces an innovative Sea Level Rise Cultural Heritage Impact Assessment Model (SLR-CHIA Model), a novel approach that integrates both land inundation and socio-economic aspects. This comprehensive model evaluates potential risks to various types of cultural heritage in coastal China, including intangible cultural heritage, relics, and traditional villages. The study’s findings are striking: (1) About 7.79% of coastal villages, 53.94% of relics, and 2.53% of intangible cultural heritage are potentially at high risk in a 100-year sea level rise event; (2) Relics in the Eastern coast and villages in the Southern coast are most vulnerable; (3) Different types of cultural heritage rely on diverse principal factors for protection, resulting in varied risk levels under sea level rise conditions. The SLR-CHIA Model provides a vital methodological framework for evaluating cultural heritage risks in other global regions.

Abstract Background To investigate serum irisin levels in girls at different developmental status and explore the significance of irisin for the diagnosis of central precocious puberty (CPP) in girls. Methods In this cross-sectional study 111 girls were enrolled, including 43 cases of CPP, 44 cases of peripheral precocious puberty (PPP) and 24 cases of girls with normal sexual development as controls. The data on age, weight and height, measured blood levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol, and irisin were collected. Pelvic Doppler ultrasound was performed to evaluate uterine length, transverse diameter, anteroposterior diameter. The girls were divided into non-CPP group and CPP group according to gonadotropin-releasing hormone (GnRH) stimulation test. Results Serum irisin levels were significantly higher in CPP group than in PPP group and normal control group. Serum irisin level was positively correlated with basal LH level, basal FSH level, peak LH level, peak LH /FSH ratio, uterine volume, bone age, and bone age index. The area under the curve, cut-off value, sensitivity and specificity of serum irisin were 0.958, 219.255 pg/ml, 100% and 80.6%. The combined diagnosis of CPP in girls by serum irisin and serum basal LH combined with uterine volume had an AUC, sensitivity, and specificity of 0.994, 97.6%, and 100%, superior to that of the single index. Conclusions Serum irisin level in girls with CPP is significantly increased. An irisin combined index could help the diagnosis of CPP in girls.

Abstract Six compounds were isolated from Penicillium sp. SG-W3, a marine-derived fungus, and their inhibitory activities against target enzymes relating to neurological diseases were evaluated. Compound 1 (pannorin) was a potent and selective monoamine oxidase (MAO)-A inhibitor with a 50% inhibitory concentration (IC50) of 1.734 μM and a selectivity index (SI) of > 23.07 versus MAO-B, and it showed an efficient antioxidant activity. All compounds showed weak inhibitory activities against acetylcholinesterase, butyrylcholinesterase, and β-secretase. The inhibition constant (Ki) of 1 for MAO-A was 1.049 ± 0.030 μM with competitive inhibition. Molecular docking simulation predicted that compound 1 forms hydrogen bonds with MAO-A, and binds more tightly to MAO-A than to MAO-B (− 25.02 and − 24.06 kcal/mol, respectively). These results suggest that compound 1 is a selective, reversible, and competitive MAO-A inhibitor that can be a therapeutic candidate for treating neurological diseases.

Abstract Chemodynamic therapy (CDT) based on intracellular Fenton reaction to produce highly cytotoxic reactive oxygen species (ROS) has played an essential role in tumor therapy. However, this therapy still needs to be improved by weakly acidic pH and over-expression of glutathione (GSH) in tumor microenvironment (TEM), which hinders its future application. Herein, we reported a multifunctional bimetallic composite nanoparticle MnO2@GA-Fe@CAI based on a metal polyphenol network (MPN) structure, which could reduce intracellular pH and endogenous GSH by remodeling tumor microenvironment to improve Fenton activity. MnO2 nanoparticles were prepared first and MnO2@GA-Fe nanoparticles with Fe3+ as central ion and gallic acid (GA) as surface ligands were prepared by the chelation reaction. Then, carbonic anhydrase inhibitor (CAI) was coupled with GA to form MnO2@GA-Fe@CAI. The properties of the bimetallic composite nanoparticles were studied, and the results showed that CAI could reduce intracellular pH. At the same time, MnO2 could deplete intracellular GSH and produce Mn2+ via redox reactions, which re-established the TME with low pH and GSH. In addition, GA reduced Fe3+ to Fe2+. Mn2+ and Fe2+ catalyzed the endogenous H2O2 to produce high-lever ROS to kill tumor cells. Compared with MnO2, MnO2@GA-Fe@CAI could reduce the tumor weight and volume for the xenograft MDA-MB-231 tumor-bearing mice and the final tumor inhibition rate of 58.09 ± 5.77%, showing the improved therapeutic effect as well as the biological safety. Therefore, this study achieved the high-efficiency CDT effect catalyzed by bimetallic through reshaping the tumor microenvironment. Graphical Abstract

Abstract Background The evaluation of inter-rater reliability (IRR) is integral to research designs involving the assessment of observational ratings by two raters. However, existing literature is often heterogeneous in reporting statistical procedures and the evaluation of IRR, although such information can impact subsequent hypothesis testing analyses. Methods This paper evaluates a recent publication by Chen et al., featured in BMC Nephrology, aiming to introduce an alternative statistical approach to assessing IRR and discuss its statistical properties. The study underscores the crucial need for selecting appropriate Kappa statistics, emphasizing the accurate computation, interpretation, and reporting of commonly used IRR statistics between two raters. Results The Cohen’s Kappa statistic is typically used for two raters dealing with two categories or for unordered categorical variables having three or more categories. On the other hand, when assessing the concordance between two raters for ordered categorical variables with three or more categories, the commonly employed measure is the weighted Kappa. Conclusion Chen and colleagues might have underestimated the agreement between AU5800 and UN2000. Although the statistical approach adopted in Chen et al.’s research did not alter their findings, it is important to underscore the importance of researchers being discerning in their choice of statistical techniques to address their specific research inquiries.

Abstract. Background:. Acute pulmonary embolism (APE) is a fatal cardiovascular disease, yet missed diagnosis and misdiagnosis often occur due to non-specific symptoms and signs. A simple, objective technique will help clinicians make a quick and precise diagnosis. In population studies, machine learning (ML) plays a critical role in characterizing cardiovascular risks, predicting outcomes, and identifying biomarkers. This work sought to develop an ML model for helping APE diagnosis and compare it against current clinical probability assessment models. Methods:. This is a single-center retrospective study. Patients with suspected APE were continuously enrolled and randomly divided into two groups including training and testing sets. A total of 8 ML models, including random forest (RF), Naïve Bayes, decision tree, K-nearest neighbors, logistic regression, multi-layer perceptron, support vector machine, and gradient boosting decision tree were developed based on the training set to diagnose APE. Thereafter, the model with the best diagnostic performance was selected and evaluated against the current clinical assessment strategies, including the Wells score, revised Geneva score, and Years algorithm. Eventually, the ML model was internally validated to assess the diagnostic performance using receiver operating characteristic (ROC) analysis. Results:. The ML models were constructed using eight clinical features, including D-dimer, cardiac troponin T (cTNT), arterial oxygen saturation, heart rate, chest pain, lower limb pain, hemoptysis, and chronic heart failure. Among eight ML models, the RF model achieved the best performance with the highest area under the curve (AUC) (AUC = 0.774). Compared to the current clinical assessment strategies, the RF model outperformed the Wells score (P = 0.030) and was not inferior to any other clinical probability assessment strategy. The AUC of the RF model for diagnosing APE onset in internal validation set was 0.726. Conclusions:. Based on RF algorithm, a novel prediction model was finally constructed for APE diagnosis. When compared to the current clinical assessment strategies, the RF model achieved better diagnostic efficacy and accuracy. Therefore, the ML algorithm can be a useful tool in assisting with the diagnosis of APE.

Prominent interfacial bonding can significantly improve the stress transfer efficiency between carbon fibers and matrix, which is the basis of efficient and long-term application of composites. In this paper, a bicomponent collaborative strategy was proposed to fully utilize the advantages of silicon nitride nanowires (SNs) and carbon nanotubes (CNTs) to optimize the interfacial strength of carbon fiber modified double matrix composites (CD), in which the double matrix was represented by polymers-hydroxyapatite and pyrocarbon-hydroxyapatite. The microstructure displayed that SNs were randomly distributed inside CD and completely wrapped by CNTs, which combined to form an interlocking structure. The mechanical and friction behavior of modified and unmodified composites was investigated. The compression strength and shear strength of CNTs-SNs modified carbon fiber/polymers-hydroxyapatite composites were 110 ± 2.39 MPa and 56 ± 1.13 MPa, displaying an increment of 69% and 87%. The wear rate was 0.4 × 10−14 ± 0.008 m3 N−1 m−1, exhibiting a 61% decline. The fracture morphologies were observed to analyze the strengthening mechanism. Interlocked CNTs-SNs could strengthen the effective bonding of fiber/matrix interface and SNs/matrix interface, provide lots of nucleation sites for the matrix, and enhance the matrix cohesion. The enhancement was further verified by a 56% increase in the compression strength (237 ± 4.67 MPa), a 235% increase in the shear strength (77 ± 1.53 MPa), a 78% decrease in wear rate (0.38 × 10−13 ± 0.011 m3 N−1 m−1) of CNTs-SNs modified carbon fiber/pyrocarbon-hydroxyapatite composites, indicating that CNTs-SNs played an indispensable role in making CD possess brilliant mechanical and biological friction properties.

Interleukin-21 (IL-21) is produced mainly by activated CD4+ T cells and promotes the proliferation, survival and differentiation of immune cells. This study characterised a high affinity binding receptor of IL-21 (IL-21 Rα) from grass carp (Ctenopharyngodon idella, Ci) and analyzed the expression of CiIL-21 and CiIL-21 Rα. It has been shown that they were modulated by PAMPs and during infection with bacterial and viral pathogens. Recombinant CiIL-21 protein produced in bacteria was active in inducing the expression of genes involved in Th responses. A monoclonal CiIL-21 antibody was generated against the rCiIL-21 and showed good reactive specificity with the rCiIL-21 proteins expressed in E. coli cells, and HEK293 T cells and the native protein from PHA-stimulated kidney leukocytes. In addition, the IL-21-producing cells detected by the CiIL-21 monoclonal antibody were found to be increased to in the kidney, spleen and hindgut after infection with Flavobacterium columnare. Our data indicate that IL-21 is involved in the regulation of immune response to bacterial and viral infection.

The Chang 2 bottom water reservoir area in the western part of northern Shaanxi constitutes one of the key oil-producing regions within the Ordos Basin. A principal reservoir here is the Triassic Yanchang Formation’s Chang 2 reservoir, which is characterized by favorable physical properties, dynamic edge and bottom water activity, and a high geothermal gradient. This study employs the STARS module of the CMG reservoir numerical simulation software to model water intake and heat recovery processes in the target region. It analyzes the heat recovery rate and efficiency of three water production methods—direct water extraction, four-injection–one-production, and one-injection–four-production—under varying injection pressures. The results indicate that direct water extraction from the bottom water reservoir is challenging. However, the annual heat recovery per well for the four-injection–one-production and one-injection–four-production methods equates to a standard coal production ranging between 190 and 420 tons, suggesting that there is significant potential for water injection and heat recovery in the Chang 2 reservoir in the western part of northern Shaanxi.

Tuberculosis (TB) remains the major cause of mortality and morbidity, causing approximately 1.3 million deaths annually. As a highly successful pathogen, Mycobacterium tuberculosis (Mtb) has evolved numerous strategies to evade host immune responses, making it essential to understand the interactions between Mtb and host cells. G-protein-coupled receptor 84 (GPR84), a member of the G-protein-coupled receptor family, contributes to the regulation of pro-inflammatory reactions and the migration of innate immune cells, such as macrophages. Its role in mycobacterial infection, however, has not yet been explored. We found that GPR84 is induced in whole blood samples from tuberculosis patients and Mycobacterium marinum (Mm)-infected macrophage models. Using a Mm-wasabi infection model in mouse tails, we found that GPR84 is an important determinant of the extent of tissue damage. Furthermore, from our studies in an in vitro macrophage Mm infection model, it appears that GPR84 inhibits pro-inflammatory cytokines expression and increases intracellular lipid droplet (LD) accumulation, thereby promoting intracellular bacterial survival. Our findings suggest that GPR84 could be a potential therapeutic target for host-directed anti-TB therapeutics.

Intercropping has the potential to improve phosphorus (P) uptake and crop growth, but the potential benefits and relative contributions of root morphology and arbuscular mycorrhizal fungi (AMF) colonization are largely unknown for the intercropping of rice and soybean under dry cultivation. Both field and pot experiments were conducted with dry-cultivated rice (Oryza sativa L.) and soybean (Glycine max L. Merr.) grown alone or intercropped under two P levels. Two root separation modes between rice and soybean were employed to explore the contribution of AMF association and root plasticity on P uptake in intercrops. The results showed that rice/soybean intercropping resulted in a notable increase in the total biomass and yield compared to monoculture in the field. In the potted experiment, compared to the plastic root separation treatment (PS), the no root separation treatment (NS) increased the total biomass and P uptake by 9.4% and 19.9%, irrespective of the P levels. This was primarily attributable to a considerable enhancement in biomass and phosphorus uptake in soybean by 40.4% and 49.7%, which offset a slight decline in the rice of NS compared to PS by 26.8% and 18.0%, respectively. The results of random forest analysis indicate that the P uptake by the dominant species, soybean, was mainly contributed by root morphology, while rice was more dependent on AMF colonization in the intercropping system. Therefore, dry-cultivated rice/soybean intercropping enhances P uptake and productivity by leveraging complementary belowground strategies, with soybean benefiting primarily from root morphological adjustments and rice relying more on arbuscular mycorrhizal fungi colonization.

Abstract Neurological diseases are expected to become the leading cause of death in the next decade. Although little is known about it, the interaction between oxidative stress and inflammation is harmful to the nervous system. To find an advanced tool for neural genetics, mouse haploid neural stem cells (haNSCs) from the somite of chimeric mouse embryos at E8.5 is established. The haNSCs present a haploid neural progenitor identity for long‐term culture, promising to robustly differentiate into neural subtypes and being able to form cerebral organoids efficiently. Thereafter, haNSC mutants via a high‐throughput approach and screened targets of oxidative stress is generated using the specific mutant library. Deletion of Nfkbia (the top hit among the insertion mutants) reduces damage from reactive oxygen species (ROS) in NSCs exposed to H2O2. Transcriptome analysis revealed that Atp2b4 is upregulated significantly in Nfkbia‐null NSCs and is probably responsible for the observed resistance. Additionally, overexpression of Atp2b4 itself can increase the survival of NSCs in the presence of H2O2, suggesting that Atp2b4 is closely involved in this resistance. Herein, a powerful haploid system is presented to study functional genetics in neural lineages, shedding light on the screening of critical genes and drugs for neurological diseases.

The preparation of mechanical robust organic room‐temperature phosphorescence (RTP) materials especially with white afterglow is attractive but rarely reported. Herein, a method to produce mechanical robust colorful RTP transparent wood (PTW) by infiltrating delignified wood with poly (vinyl alcohol) solutions containing arylboronic acids with various π conjugations is reported. The doubly rigid environment provided by the B─O covalent bonds and hydrogen bonds can stabilize the triplet excitons, leading to a ultralong lifetime of up to 2.13 s and excellent RTP emission stability (without obviously quenching over a month) of the target PTW. Besides, as a promising structural material for optical applications, the PTW shows combined advantages of multicolored persistent luminescence (from blue to green and then to red), good optical transmittance (≈90%), and striking mechanical strength (≈154 MPa). More importantly, by introducing appropriate amount of fluorescent dye rhodamine 6 G to the PTW with blue afterglow, white afterglow with a lifetime of 1.85 s is successfully achieve through triplet‐to‐singlet Förster resonance energy transfer. The PTW can function as afterglow window, anticounterfeiting label, and time delay lighting. This success paves the way for the development of mechanical robust, ecofriendly, and practical RTP materials.

ABSTRACT Bacterial ribonuclease E (RNase E) is vital for posttranscriptional regulation by degrading and processing RNA. The RraA protein inhibits RNase E activity through protein-protein interactions, exerting a global regulatory effect on gene expression. However, the specific role of RraA remains unclear. In this study, we investigated rraA expression in Vibrio alginolyticus ZJ-T and identified three promoters responsible for its expression, resulting in transcripts with varying 5′-UTR lengths. During the stationary phase, rraA was significantly posttranscriptionally inhibited. Deletion of rraA had no impact on bacterial growth in rich medium Luria-Bertani broth with salt (LBS) but resulted in decreased biofilm formation and increased resistance to polymyxin B. Transcriptome analysis revealed 350 differentially expressed genes (DEGs) between the wild type and the rraA mutant, while proteome analysis identified 267 differentially expressed proteins (DEPs). Integrative analysis identified 55 genes common to both DEGs and DEPs, suggesting that RraA primarily affects gene expression at the posttranscriptional level. KEGG (Kyoto Encyclopedia of Genes and Genomes) analysis demonstrated that RraA facilitates the conversion of fatty acids, propionic acid, and branched-chain amino acids to acetyl-CoA while enhancing amino acid and peptide uptake. Notably, RraA positively regulates the expression of virulence-associated genes, including those involved in biofilm formation and the type VI secretion system. This study expands the understanding of the regulatory network of RraA through transcriptome analysis, emphasizing the importance of proteomic analysis in investigating posttranscriptional regulation.IMPORTANCERraA is an inhibitor protein of ribonuclease E that interacts with and suppresses its endonucleolytic activity, thereby playing a widespread regulatory role in the degradation and maturation of diverse mRNAs and noncoding small RNAs. However, the physiological functions and associated regulon of RraA in Vibrio alginolyticus have not been fully elucidated. Here, we report that RraA impacts virulence-associated physiological processes, namely, antibiotic resistance and biofilm formation, in V. alginolyticus. By conducting an integrative analysis of both the transcriptome and proteome, we revealed the involvement of RraA in carbon metabolism, amino acid catabolism, and transport, as well as in the type VI secretion system. Collectively, these findings elucidate the regulatory influence of RraA on multiple pathways associated with metabolism and pathogenesis in V. alginolyticus.

ObjectiveWhile bone metastases (BMs) are present in a minority of thyroid cancer (TC) patients at the time of initial diagnosis, there has been growing concern regarding their impact on life expectancy and quality of life. The aim of this study was to identify prognostic factors associated with overall survival (OS) and cancer-specific survival (CSS) in these patients and provide therapeutic recommendations based on the findings.MethodsIn this retrospective cohort study, we included 82 patients diagnosed as TC with BM received treatment in our department from 2011.03 to 2023.03 (average follow-up duration was 3.02 years). The retrospective study was performed according to the inclusion and exclusion criteria. Kaplan-Meier analysis was used to estimate the OS and CSS, while the univariate and multivariate Cox proportional hazard models were employed to determine prognostic factors associated with OS and CSS. Also, 287 patients’ data were collected from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2015 to confirm the prognostic factors identified in the retrospective study.ResultsThe average survival time of the 82 patients was estimated to be 5.818 years (with a 95% confidence interval (CI) of 4.767 to 6.868 years). The cox regression analysis showed that older age (hazard ratio (HR) = 1.045, 95% CI: 1.001-1.092, P = 0.047), larger tumor size (>5cm, HR = 11.087, 95% CI: 3.728 - 32.976, P = 0.000), and the presence of extraosseous metastasis (HR = 3.247, 95% CI: 1.376 - 7.665, P = 0.007) were statistically significant factors associated with worse CSS. The results were furtherly confirmed in 287 SEER-sourced patients (age (HR = 1.020, 95% CI: 1.006 - 1.034, P = 0.006), tumor size (HR = 2.917, 95% CI: 2.044 - 4.161, P = 0.000), and extraosseous metastasis (HR = 3.726, 95% CI: 2.571 - 5.398, P = 0.000)).ConclusionsThese results offer a population-based assessment of prognostic factors for patients with TC and BMs, revealing that age, primary tumor size (>5cm), and presence of extraosseous metastases are independent prognostic factors that correlate with worse survival. Accordingly, treatment for such patients ought to concentrate on systemic integrative therapy instead of surgical intervention.

The Density Peak Clustering (DPC) algorithm encounters challenges such as difficulty in choosing cluster centers and the chain reaction caused by incorrect assignment of data points when clustering spatial datasets containing clusters with significant density differences or multi-peak clusters. To address these problems, in this paper, starting from enhancing the local density definition, optimizing the selection of cluster centers, and improving the assignment strategy of non-cluster center data points, an Adaptive DPC (NRA-DPC) algorithm is proposed based on the neighbor relationship. The NRA-DPC algorithm utilizes the reverse K-nearest neighbors of data points as the basis for defining the local density of data points and divides the spatial dataset into a core point set and a boundary point set based on the number of elements in the reverse K-nearest neighbor set of data points. The idea of iteration is adopted to select cluster centers from the core point set and assign non-cluster center data points, forming the initial clusters. For each initial cluster formed by the core point set, the corresponding minimum spanning tree (MST) is generated, and based on the average edge length of the MST, the assignment threshold of this cluster is set. The boundary point set completes the corresponding data point assignment task based on this assignment threshold and the mutual K-nearest neighbor relationship. Experimental results indicate that, compared with other typical clustering algorithms, the NRA-DPC algorithm can automatically select cluster centers, reduce the probability of incorrect assignment of non-cluster center data points, and effectively suppress the chain reaction triggered by incorrect assignment of non-cluster center data points, demonstrating more stable clustering performance when dealing with different datasets.