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Abstract Background Ensuring that the scale and hierarchical structure of health human resources are rational, and that medical services are efficient and fair, is an important task of practical significance. On this basis, examining the impact of health human resources on the level of medical services presents a new and formidable challenge. This study aims to delve into how the scale and hierarchical structure of health human resources in China’s four major economic regions affect the fairness and efficiency of medical services, and to identify optimization strategies. Methods This study utilizes provincial panel data from China’s four major economic regions spanning the years 2009 to 2021. Initially, it provides a statistical description of the current state of health human resources and the level of medical services. Subsequently, it employs a fixed-effects model to analyze the impact of the scale and hierarchical structure of health human resources, as well as their interactive effects, on the fairness and efficiency of medical services, and discusses the interactive mechanisms between medical service fairness and medical service efficiency. Furthermore, after conducting a comprehensive evaluation of the level of medical services using the entropy weight method, it explores the regional heterogeneity and temporal dynamics in the influence of the scale and hierarchical structure of health human resources on the level of medical services. Finally, the study examines the scientific validity and rationality of the research findings through various robustness checks, including the substitution of research variables and models. Results The study found that the scale of health human resources has a promoting effect on the equity of medical services (β ≤ 0.643, p ≤ 0.01), but exhibits an inhibitory effect on the efficiency of medical services (β ≥ -0.079, p ≤ 0.1); the hierarchical structure of health human resources shows a positive impact on both the equity and efficiency of medical services (βequity ≤ 0.160, p ≤ 0.01; βefficiency ≤ 0.341, p ≤ 0.05); at the same time, the results indicate that the interactive effect of the scale and hierarchical structure of health human resources promotes equity in medical services (β = 0.067, p ≤ 0.01), but restricts the efficiency of medical services (β ≥ -0.039, p ≤ 0.01); the mechanism by which health human resources affect the level of medical services in China’s western and northeastern regions is more pronounced than in the central and eastern regions; after the implementation of the “Healthy China 2030” Planning Outline, the role of health human resources in the level of medical services has been strengthened; in the robustness tests, the model remains robust after replacing the core explanatory variables, with R2 maintained between 0.869 and 0.972, and the dynamic GMM model test shows a significant second-order lag in the level of medical services (βequity ≤ 0.149, p ≤ 0.01; βefficiency ≤ 0.461, p ≤ 0.01); the channel test results prove that managerial personnel and other technical personnel are key pathways in regulating the impact of medical staff on the level of medical services. Conclusion This study provides an in-depth analysis of the impact of health human resources on the level of medical services, revealing that both the scale and hierarchical structure of health human resources significantly affect the equity and efficiency of medical services. Furthermore, the influence of health human resources on the level of medical services exhibits regional heterogeneity and temporal characteristics. Robustness tests ensure the scientific validity and robustness of the research conclusions. This provides effective references for optimizing the allocation of health human resources and improving the level of medical services.

The covered karst collapse has the characteristics of concealment, suddenness, uncertainty, and mechanism complexity, which leads to its prevention and treatment more difficult. In the process of covered karst collapse, soil caves formed in the overlying soil, develop and expand until the surface collapse. Numerical simulation such as the finite element method is an effective method of soil cave collapse; however, the finite element method can not solve the problem of large deformation of rock mass such as particle migration and soil collapse. Based on the analysis of the geological conditions of karst collapse in Jiangshan city, Zhejiang province, this study used the particle flow code (PFC) to simulate the formation process of covered karst soil cave and then to reveal the displacement of special soil particles, the development trend of cracks, and the change of system imbalance force on a micro level. The multi-field variation characteristics of the formation of covered karst soil cave under external force conditions were reproduced. The results show that the development process of karst soil cave could be summarized into three stages including crack generation, connected surface formation, and particle peeling. As the karst soil cave began to develop, there was a good consistency among the displacement curve of soil particles, the penetration degree of cracks, and the unbalance force, and the vertical expansion speed was larger than the horizontal speed. The critical flow velocity of the initial soil cavity is 0.104 cm/s when the overburden soil is clay. This study can provide basic information for the treatment of karst collapse.

Abstract An increased risk of target organ damage (TOD) has been reported in patients with primary aldosteronism (PA). However, there is relatively little related research on the correlation between the degree of TOD and those with and without PA in newly diagnosed hypertensive patients. The aim of this study was to assess the association between PA and TOD among patients with newly diagnosed hypertension. Newly diagnosed hypertensive patients were consecutively recruited from January 2015 to June 2020 at the University of Hong Kong‐Shenzhen Hospital. Patients were stratified into those with and without PA. Data for left ventricular mass index (LVMI), carotid intima‐media thickness (CIMT) and plaque, and microalbuminuria were systematically collected. A total of 1044 patients with newly diagnosed hypertension were recruited, 57 (5.5%) of whom were diagnosed with PA. Patients with PA had lower blood pressure, serum lipids, body mass index, and plasma renin activity and a higher incidence of hypokalemia than those without PA. In contrast, the prevalence of left ventricular hypertrophy, increased CIMT, and microalbuminuria was higher in patients with PA than in those without PA. Multivariable regression analysis demonstrated that PA was independently associated with increased LVMI, CIMT and microalbuminuria. Among patients with newly diagnosed hypertension, those with PA had more severe TOD, including a higher LVMI, CIMT and microalbuminuria, than those without PA. These findings emphasize the need for screening TOD in newly diagnosed hypertension due to underlying PA.

Abstract To address the shortcomings of traditional reliability theory in characterizing the stability of deep underground structures, the advanced first order second moment of reliability was improved to obtain fuzzy random reliability, which is more consistent with the working conditions. The traditional sensitivity analysis model was optimized using fuzzy random optimization, and an analytical calculation model of the mean and standard deviation of the fuzzy random reliability sensitivity was established. A big data hidden Markov model and expectation-maximization algorithm were used to improve the digital characteristics of fuzzy random variables. The fuzzy random sensitivity optimization model was used to confirm the effect of concrete compressive strength, thick-diameter ratio, reinforcement ratio, uncertainty coefficient of calculation model, and soil depth on the overall structural reliability of a reinforced concrete double-layer wellbore in deep alluvial soil. Through numerical calculations, these characteristics were observed to be the main influencing factors. Furthermore, while the soil depth was negatively correlated, the other influencing factors were all positively correlated with the overall reliability. This study provides an effective reference for the safe construction of deep underground structures in the future.

Abstract Binding of Staphylococcus aureus protein A (SPA) to osteoblasts induces apoptosis and inhibits bone formation. Bone marrow-derived mesenchymal stem cells (BMSCs) have the ability to differentiate into bone, fat and cartilage. Therefore, it was important to analyze the molecular mechanism of SPA on osteogenic differentiation. We introduced transcript sequence data to screen out differentially expressed genes (DEGs) related to SPA-interfered BMSC. Protein–protein interaction (PPI) network of DEGs was established to screen biomarkers associated with SPA-interfered BMSC. Receiver operating characteristic (ROC) curve was plotted to evaluate the ability of biomarkers to discriminate between two groups of samples. Finally, we performed GSEA and regulatory analysis based on biomarkers. We identified 321 DEGs. Subsequently, 6 biomarkers (Cenpf, Kntc1, Nek2, Asf1b, Troap and Kif14) were identified by hubba algorithm in PPI. ROC analysis showed that six biomarkers could clearly discriminate between normal differentiated and SPA-interfered BMSC. Moreover, we found that these biomarkers were mainly enriched in the pyrimidine metabolism pathway. We also constructed '71 circRNAs-14 miRNAs-5 mRNAs' and '10 lncRNAs-5 miRNAs-2 mRNAs' networks. Kntc1 and Asf1b genes were associated with rno-miR-3571. Nek2 and Asf1b genes were associated with rno-miR-497-5p. Finally, we found significantly lower expression of six biomarkers in the SPA-interfered group compared to the normal group by RT-qPCR. Overall, we obtained 6 biomarkers (Cenpf, Kntc1, Nek2, Asf1b, Troap, and Kif14) related to SPA-interfered BMSC, which provided a theoretical basis to explore the key factors of SPA affecting osteogenic differentiation.

Abstract Floating Production Storage and Offloading (FPSO) unit being an offshore vessel, storing and producing crude oil, prior to crude oil being transported by accompanying shuttle tanker. Critical mooring/hawser strains during offloading operation have to be accurately predicted, in order to maintain operational safety and reliability. During certain types of offloading, excessive hawser tensions may occur, causing operational risks. Current study examines FPSO vessel’s dynamic reactions to hydrodynamic wave-induced loads, given realistic in situ environmental conditions, utilizing the AQWA software package. Current study advocates novel multi-dimensional spatiotemporal risks assessment approach, that is particularly well suited for large dataset analysis, based on numerical simulations (or measurements). Advocated multivariate reliability methodology may be useful for a variety of marine and offshore systems that must endure severe environmental stressors during their intended operational lifespan. Methodology, presented in this study provides advanced capability to efficiently, yet accurately evaluate dynamic system failure, hazard and damage risks, given representative dynamic record of multidimensional system’s inter-correlated critical components. Gaidai risk assessment method being novel dynamic multidimensional system’s lifetime assessment methodology. In order to validate and benchmark Gaidai risk assessment method, in this study it was applied to FPSO and potentially LNG (i.e., Liquid Natural Gas) vessels dynamics. Major advantage of the advocated approach is that there are no existing alternative risk assessment methods, able to tackle unlimited number of system’s dimensions. Accurate multi-dimensional risk assessment had been carried out, based on numerically simulated data, partially verified by available laboratory experiments. Confidence intervals had been given for predicted dynamic high-dimensional system risk levels.

Plasmon-induced hot-electron transfer from metal nanostructures is being intensely pursed in current photocatalytic research, however it remains elusive whether molecular-like metal clusters with excitonic behavior can be used as light-harvesting materials in solar energy utilization such as photocatalytic methanol steam reforming. In this work, we report an atomically precise Cu13 cluster protected by dual ligands of thiolate and phosphine that can be viewed as the assembly of one top Cu atom and three Cu4 tetrahedra. The Cu13H10(SR)3(PR’3)7 (SR = 2,4-dichlorobenzenethiol, PR’3 = P(4-FC6H4)3) cluster can give rise to highly efficient light-driven activity for methanol steam reforming toward H2 production.

The contribution of spike photosynthesis to grain yield (GY) has been overlooked in the accurate spectral prediction of yield. Thus, it’s essential to construct and estimate a yield-related phenotypic trait considering spike photosynthesis. Based on field and spectral reflectance data from 19 wheat cultivars under two nitrogen fertilization conditions in two years, our objectives were to (i) construct a yield-related phenotypic trait (spike–leaf composite indicator, SLI) accounting for the contribution of the spike to photosynthesis, (ii) develop a novel spectral index (enhanced triangle vegetation index, ETVI3) sensitive to SLI, and (iii) establish and evaluate SLI estimation models by integrating spectral indices and machine learning algorithms. The results showed that SLI was sensitive to nitrogen fertilizer and wheat cultivar variation as well as a better predictor of yield than the leaf area index. ETVI3 maintained a strong correlation with SLI throughout the growth stage, whereas the correlations of other spectral indices with SLI were poor after spike emergence. Integrating spectral indices and machine learning algorithms improved the estimation accuracy of SLI, with the most accurate estimates of SLI showing coefficient of determination, root mean square error (RMSE), and relative RMSE values of 0.71, 0.047, and 26.93%, respectively. These results provide new insights into the role of fruiting organs for the accurate spectral prediction of GY. This high-throughput SLI estimation approach can be applied for wheat yield prediction at whole growth stages and may be assisted with agronomical practices and variety selection.

Abstract Despite the growing attention on blockchain, phishing activities have surged, particularly on newly established chains. Acknowledging the challenge of limited intelligence in the early stages of new chains, we propose ADA-Spear-an automatic phishing detection model utilizing adversarial domain adaptive learning which symbolizes the method’s ability to penetrate various heterogeneous blockchains for phishing detection. The model effectively identifies phishing behavior in new chains with limited reliable labels, addressing challenges such as significant distribution drift, low attribute overlap, and limited inter-chain connections. Our approach includes a subgraph construction strategy to align heterogeneous chains, a layered deep learning encoder capturing both temporal and spatial information, and integrated adversarial domain adaptive learning in end-to-end model training. Validation in Ethereum, Bitcoin, and EOSIO environments demonstrates ADA-Spear’s effectiveness, achieving an average F1 score of 77.41 on new chains after knowledge transfer, surpassing existing detection methods.

Periodontitis is a chronic inflammatory disease caused by plaque that destroys the alveolar bone tissues, resulting in tooth loss. Poor eradication of pathogenic microorganisms, persistent malignant inflammation and impaired osteo-/angiogenesis are currently the primary challenges to control disease progression and rebuild damaged alveolar bone. However, existing treatments for periodontitis fail to comprehensively address these issues. Herein, an injectable composite hydrogel (SFD/CS/ZIF-8@QCT) encapsulating quercetin-modified zeolitic imidazolate framework-8 (ZIF-8@QCT) is developed. This hydrogel possesses thermo-sensitive and adhesive properties, which can provide excellent flowability and post-injection stability, resist oral fluid washout as well as achieve effective tissue adhesion. Inspirationally, it is observed that SFD/CS/ZIF-8@QCT exhibits a rapid localized hemostatic effect following implantation, and then by virtue of the sustained release of zinc ions and quercetin exerts excellent collective functions including antibacterial, immunomodulation, pro-osteo-/angiogenesis and pro-recruitment, ultimately facilitating excellent alveolar bone regeneration. Notably, our study also demonstrates that the inhibition of osteo-/angiogenesis of PDLSCs under the periodontitis is due to the strong inhibition of energy metabolism as well as the powerful activation of oxidative stress and autophagy, whereas the synergistic effects of quercetin and zinc ions released by SFD/CS/ZIF-8@QCT are effective in reversing these biological processes. Overall, our study presents innovative insights into the advancement of biomaterials to regenerate alveolar bone in periodontitis.

Purpose: Cerebral edema (CE) is the main secondary injury following traumatic brain injury (TBI) caused by road traffic accidents (RTAs). It is challenging to be predicted timely. In this study, we aimed to develop a prediction model for CE by identifying its risk factors and comparing the timing of edema occurrence in TBI patients with varying levels of injuries. Methods: This case-control study included 218 patients with TBI caused by RTAs. The cohort was divided into CE and non-CE groups, according to CT results within 7 days. Demographic data, imaging data, and clinical data were collected and analyzed. Quantitative variables that follow normal distribution were presented as mean ± standard deviation, those that do not follow normal distribution were presented as median (Q1, Q3). Categorical variables were expressed as percentages. The Chi-square test and logistic regression analysis were used to identify risk factors for CE. Logistic curve fitting was performed to predict the time to secondary CE in TBI patients with different levels of injuries. The efficacy of the model was evaluated using the receiver operator characteristic curve. Results: According to the study, almost half (47.3%) of the patients were found to have CE. The risk factors associated with CE were bilateral frontal lobe contusion, unilateral frontal lobe contusion, cerebral contusion, subarachnoid hemorrhage, and abbreviated injury scale (AIS). The odds ratio values for these factors were 7.27 (95% confidence interval (CI): 2.08 − 25.42, p = 0.002), 2.85 (95% CI: 1.11 − 7.31, p = 0.030), 2.62 (95% CI: 1.12 − 6.13, p = 0.027), 2.44 (95% CI: 1.25 − 4.76, p = 0.009), and 1.5 (95% CI: 1.10 − 2.04, p = 0.009), respectively. We also observed that patients with mild/moderate TBI (AIS ≤ 3) had a 50% probability of developing CE 19.7 h after injury (χ2 = 13.82, adjusted R2 = 0.51), while patients with severe TBI (AIS > 3) developed CE after 12.5 h (χ2 = 18.48, adjusted R2 = 0.54). Finally, we conducted a receiver operator characteristic curve analysis of CE time, which showed an area under the curve of 0.744 and 0.672 for severe and mild/moderate TBI, respectively. Conclusion: Our study found that the onset of CE in individuals with TBI resulting from RTAs was correlated with the severity of the injury. Specifically, those with more severe injuries experienced an earlier onset of CE. These findings suggest that there is a critical time window for clinical intervention in cases of CE secondary to TBI.

Low-density lipoprotein receptor-related protein 2 (LRP2) is a multifunctional endocytic receptor expressed in epithelial cells. In mammals, it acts as an endocytic receptor that mediates the cellular uptake of cholesterol-containing apolipoproteins to maintain lipid homeostasis. However, little is known about the role of LRP2 in lipid homeostasis in insects. In the present study, we investigated the function of LRP2 in the migratory locust Locusta migratoria (LmLRP2). The mRNA of LmLRP2 is widely distributed in various tissues, including integument, wing pads, foregut, midgut, hindgut, Malpighian tubules and fat body, and the amounts of LmLRP2 transcripts decreased gradually in the early stages and then increased in the late stages before ecdysis during the nymphal developmental stage. Fluorescence immunohistochemistry revealed that the LmLRP2 protein is mainly located in cellular membranes of the midgut and hindgut. Using RNAi to silence LmLRP2 caused molting defects in nymphs (more than 60%), and the neutral lipid was found to accumulate in the midgut and surface of the integument, but not in the fat body, of dsLmLRP2-treated nymphs. The results of a lipidomics analysis showed that the main components of lipids (diglyceride and triglyceride) were significantly increased in the midgut, but decreased in the fat body and hemolymph. Furthermore, the content of total triglyceride was significantly increased in the midgut, but markedly decreased in the fat body and hemolymph in dsLmLRP2-injected nymphs. Our results indicate that LmLRP2 is located in the cellular membranes of midgut cells, and is required for lipid export from the midgut to the hemolymph and fat body in locusts.

Developing antibacterial and biocompatible coatings remains a challenge. A promising new thought is addressed to control the ion release behaviors through the design of the phases, structures, and morphologies of the products. In this study, TiO2-CuxO/Ag coatings were prepared via co-sputtering combined with annealing, the changes brought by different annealing temperatures were characterized, the physical, electrochemical, and antibacterial properties were concerned, and the relationship between biological performance and ions-releasing behavior was investigated. Results showed that the TiO2-CuxO/Ag coatings performed the morphologies of larger Ag particles seeded like islands on the dense CuO, such features improved the hydrophilicity and corrosion resistance of the Ti substrate. Rising the annealing temperature further enhanced the surface roughness, hydrophilicity, Young's modulus, hardness, and dynamic coefficient of friction of the coatings. Within the initial 3 h of soaking, both metal ions contributed to playing the antibacterial roles and produced a synergistic enhancement effect to satisfy the reduction of Staphylococcus aureus to 99.9%. In the next 3–120 h soaking, Ag releasing was suppressed and Cu releasing maintained its slow and stable trend, which made sure that the MC3T3-E1 cells could proliferate and adhere on the negatively charged coating surface, and copper oxide nanoparticles were phagocytized by cells. Among all TiO2-CuxO/Ag coatings, the M500 sample displayed superior performances on the surface roughness, contact angle, mechanical Young's modulus, and surface hardness, also realized the aim of killing pathogenic bacteria first and then activating cell survival, which enabled it to be potentially applied in clinical treatment.

A two-year field experiment was conducted to measure the effects of densification methods on photosynthesis and yield of densely planted wheat. Inter-plant and inter-row distances were used to define rate-fixed pattern (RR) and row-fixed pattern (RS) density treatments. Meanwhile, four nitrogen (N) rates (0, 144, 192, and 240 kg N ha−1, termed N0, N144, N192, and N240) were applied with three densities (225, 292.5, and 360 × 104 plants ha−1, termed D225, D292.5, and D360). The wheat canopy was clipped into three equal vertical layers (top, middle, and bottom layers), and their chlorophyll density (ChD) and photosynthetically active radiation interception (FIPAR) were measured. Results showed that the response of ChD and FIPAR to N rate, density, and pattern varied with different layers. N rate, density, and pattern had significant interaction effects on ChD. The maximum values of whole-canopy ChD in the two seasons appeared in N240 combined with D292.5 and D360 under RR, respectively. Across two growing seasons, FIPAR values of RR were higher than those of RS by 29.37% for the top layer and 5.68% for the middle layer, while lower than those of RS by 20.62% for the bottom layer on average. With a low N supply (N0), grain yield was not significantly affected by density for both patterns. At N240, increasing density significantly increased yield under RR, but D360 of RS significantly decreased yield by 3.72% and 9.00% versus D225 in two seasons, respectively. With an appropriate and sufficient N application, RR increased the yield of densely planted wheat more than RS. Additionally, the maximum yield in two seasons appeared in the combination of D360 with N144 or N192 rather than of D225 with N240 under both patterns, suggesting that dense planting combined with an appropriate N-reduction application is feasible to increase photosynthesis capacity and yield.

Abstract Head and neck squamous cell carcinoma (HNSCC) is characterized by high recurrence or distant metastases rate and the prognosis is challenging. There is mounting evidence that tumor-infiltrating B cells (TIL-Bs) have a crucial, synergistic role in tumor control. However, little is known about the role TIL-Bs play in immune microenvironment and the way TIL-Bs affect the outcome of immune checkpoint blockade. Using single-cell RNA sequencing (scRNA-seq) data from the Gene Expression Omnibus (GEO) database, the study identified distinct gene expression patterns in TIL-Bs. HNSCC samples were categorized into TIL-Bs inhibition and TIL-Bs activation groups using unsupervised clustering. This classification was further validated with TCGA HNSCC data, correlating with patient prognosis, immune cell infiltration, and response to immunotherapy. We found that the B cells activation group exhibited a better prognosis, higher immune cell infiltration, and distinct immune checkpoint levels, including elevated PD-L1. A prognostic model was also developed and validated, highlighting four genes as potential biomarkers for predicting survival outcomes in HNSCC patients. Overall, this study provides a foundational approach for B cells-based tumor classification in HNSCC, offering insights into targeted treatment and immunotherapy strategies.

Abstract Objective To evaluate the surface electromyography (sEMG) of pelvic floor muscles (PFMs), compare between vaginal birth and cesarean section and correlate with maternity and obstetrics characteristics in primiparous 6–8 weeks postpartum. Methods PFMs surface electromyography screening data of primiparous postpartum women in our hospital at 6–8 weeks postpartum from 2018 to 2021 were selected and analyzed. The study collected data on delivery activities of 543 postpartum women totally. Results In general, the abnormal incidence of pelvic floor electromyography in postpartum women mainly occurred in slow muscle (type I fiber) stage and endurance testing stage. Compared to vaginal birth postpartum women, the incidence of abnormal pelvic floor electromyography in cesarean section postpartum women is lower. There were statistical differences in measurement values of pelvic floor electromyography in several different stages between cesarean section and vaginal birth (P

Objective To explore the predictive value of monocyte-to-high-density lipoprotein (HDL) ratio (MHR) for all-cause mortality in maintenance hemodialysis (MHD) patients. Methods From November 2014 to November 2020, 100 MHD patients admitted into Blood Purification Center were recruited. At the end of the study, 24 patients died and 76 survived. The inter-group differences of general profiles, laboratory parameters, MHR, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR) and C-reactive protein (CRP)-to-albumin ratio (CAR) were compared. The influencing factors of death were analyzed by Logistics regression. Based upon the level of median MHR, they were divided into two groups of high MHR (n=50) and low MHR (n=50). Survival analysis was conducted by the Kaplan-Meier method. Receiver operating characteristic (ROC) curve was plotted for assessing the predictive values of the relevant parameters for all-cause death. Results Patients were older in death group than those in survival group [77.00(71.25, 85.75) years vs 64.00(52.25, 73.75) years, P

Abstract Background Zoonotic viruses cause substantial public health and socioeconomic problems worldwide. Understanding how viruses evolve and spread within and among wildlife species is a critical step when aiming for proactive identification of viral threats to prevent future pandemics. Despite the many proposed factors influencing viral diversity, the genomic diversity and structure of viral communities in East Africa are largely unknown. Results Using 38.3 Tb of metatranscriptomic data obtained via ultradeep sequencing, we screened vertebrate-associated viromes from 844 bats and 250 rodents from Kenya and Uganda collected from the wild. The 251 vertebrate-associated viral genomes of bats (212) and rodents (39) revealed the vast diversity, host-related variability, and high geographic specificity of viruses in East Africa. Among the surveyed viral families, Coronaviridae and Circoviridae showed low host specificity, high conservation of replication-associated proteins, high divergence among viral entry proteins, and frequent recombination. Despite major dispersal limitations, recurrent mutations, cocirculation, and occasional gene flow contribute to the high local diversity of viral genomes. Conclusions The present study not only shows the landscape of bat and rodent viromes in this zoonotic hotspot but also reveals genomic signatures driven by the evolution and dispersal of the viral community, laying solid groundwork for future proactive surveillance of emerging zoonotic pathogens in wildlife. Video Abstract

Abstract Interplay between innate and adaptive immune cells is important for the antitumor immune response. However, the tumor microenvironment may turn immune suppressive, and tumor associated macrophages are playing a role in this transition. Here, we show that CD276, expressed on tumor-associated macrophages (TAM), play a role in diminishing the immune response against tumors. Using a model of tumors induced by N-butyl-N-(4-hydroxybutyl) nitrosamine in BLCA male mice we show that genetic ablation of CD276 in TAMs blocks efferocytosis and enhances the expression of the major histocompatibility complex class II (MHCII) of TAMs. This in turn increases CD4 + and cytotoxic CD8 + T cell infiltration of the tumor. Combined single cell RNA sequencing and functional experiments reveal that CD276 activates the lysosomal signaling pathway and the transcription factor JUN to regulate the expression of AXL and MerTK, resulting in enhanced efferocytosis in TAMs. Proving the principle, we show that simultaneous blockade of CD276 and PD-1 restrain tumor growth better than any of the components as a single intervention. Taken together, our study supports a role for CD276 in efferocytosis by TAMs, which is potentially targetable for combination immune therapy.

As a burgeoning energy storage technology, Zn microbatteries (ZMBs) exhibit expansive potential for applications. This article initially presents a method for fabricating ZMBs utilizing interdigitated electrodes, employing advanced techniques such as 3D printing, screen printing, laser etching, and electrodeposition. These methodologies play a crucial role in mitigating anode-related issues, consequently enhancing battery performance. Subsequently, the challenges encountered by ZMBs anodes, including dendrite formation, corrosion passivation, hydrogen evolution, and Zn cycle exfoliation, are thoroughly examined. Lastly, a comprehensive strategy for stabilizing the anode is delineated, encompassing anode material selection, anode structure construction, interface engineering, and electrolyte optimization. In essence, the preparation and fine-tuning of ZMBs present ongoing challenges. With continued research and development efforts, it is anticipated that ZMBs will attain efficient, stable, and secure performance on the microscale, offering enduring and dependable energy solutions for applications in miniature electronic devices and wearable technology.

Purpose: Acute kidney injury (AKI) is one of the most common functional injuries observed in trauma patients. However, certain trauma medications may exacerbate renal injury. Therefore, the early detection of trauma-related AKI holds paramount importance in improving trauma prognosis. Methods: Qualified datasets were selected from public databases, and common differentially expressed genes related to trauma-induced AKI and hub genes were identified through enrichment analysis and the establishment of protein-protein interaction (PPI) networks. Additionally, the specificity of these hub genes was investigated using the sepsis dataset and conducted a comprehensive literature review to assess their plausibility. The raw data from both datasets were downloaded using R software (version 4.2.1) and processed with the ''affy'' package19 for correction and normalization. Results: Our analysis revealed 585 upregulated and 629 downregulated differentially expressed genes in the AKI dataset, along with 586 upregulated and 948 downregulated differentially expressed genes in the trauma dataset. Concurrently, the establishment of the PPI network and subsequent topological analysis highlighted key hub genes, including CD44, CD163, TIMP metallopeptidase inhibitor 1, cytochrome b-245 beta chain, versican, membrane spanning 4-domains A4A, mitogen-activated protein kinase 14, and early growth response 1. Notably, their receiver operating characteristic curves displayed areas exceeding 75%, indicating good diagnostic performance. Moreover, our findings postulated a unique molecular mechanism underlying trauma-related AKI. Conclusion: This study presents an alternative strategy for the early diagnosis and treatment of trauma-related AKI, based on the identification of potential biomarkers and therapeutic targets. Additionally, this study provides theoretical references for elucidating the mechanisms of trauma-related AKI.

Abstract Background Pyroptosis of the renal tubular epithelial cells (RTECs) and interstitial inflammation are central pathological characteristics of acute kidney injury (AKI). Pyroptosis acts as a pro-inflammatory form of programmed cell death and is mainly dependent on activation of the NLRP3 inflammasome. Previous studies revealed that acetyl-CoA synthetase 2 (ACSS2) promotes inflammation during metabolic stress suggesting that ACSS2 might regulate pyroptosis and inflammatory responses of RTECs in AKI. Methods and results The expression of ACSS2 was found to be significantly increased in the renal epithelial cells of mice with lipopolysaccharide (LPS)-induced AKI. Pharmacological and genetic strategies demonstrated that ACSS2 regulated NLRP3-mediated caspase-1 activation and pyroptosis through the stimulation of the KLF5/NF-κB pathway in RTECs. The deletion of ACSS2 attenuated renal tubular pathological injury and inflammatory cell infiltration in an LPS-induced mouse model, and ACSS2-deficient mice displayed impaired NLRP3 activation-mediated pyroptosis and decreased IL-1β production in response to the LPS challenge. In HK-2 cells, ACSS2 deficiency suppressed NLRP3-mediated caspase-1 activation and pyroptosis through the downregulation of the KLF5/NF-κB pathway. The KLF5 inhibitor ML264 suppressed NF-κB activity and NLRP3-mediated caspase-1 activation, thus protecting HK-2 cells from LPS-induced pyroptosis. Conclusion Our results suggested that ACSS2 regulates activation of the NLRP3 inflammasome and pyroptosis by inducing the KLF5/NF-κB pathway in RTECs. These results identified ACSS2 as a potential therapeutic target in AKI. Graphical Abstract We found that the expression of ACSS2 was significantly increased in RTECs in septic AKI. ACSS2-deficient mice displayed resistance to renal damage in this model. ACSS2 regulated NLRP3-mediated caspase-1 activation and pyroptosis through the KLF5/NF-κB pathway in RTECs. Pharmacological inhibition of KLF5 suppressed NLRP3 activation and caspase-1 cleavage by downregulating of NF-κB. Our results suggest that ACSS2 is a pro-pathogenic mediator of cell pyroptosis of RTECs and renal inflammation in sepsis-induced AKI.

Abstract Respiratory disease caused by coronavirus infection remains a global health crisis. Although several SARS-CoV-2-specific vaccines and direct-acting antivirals are available, their efficacy on emerging coronaviruses in the future, including SARS-CoV-2 variants, might be compromised. Host-targeting antivirals provide preventive and therapeutic strategies to overcome resistance and manage future outbreak of emerging coronaviruses. Cathepsin L (CTSL) and calpain-1 (CAPN1) are host cysteine proteases which play crucial roles in coronaviral entrance into cells and infection-related immune response. Here, two peptidomimetic α-ketoamide compounds, 14a and 14b, were identified as potent dual target inhibitors against CTSL and CAPN1. The X-ray crystal structures of human CTSL and CAPN1 in complex with 14a and 14b revealed the covalent binding of α-ketoamide groups of 14a and 14b to C25 of CTSL and C115 of CAPN1. Both showed potent and broad-spectrum anticoronaviral activities in vitro, and it is worth noting that they exhibited low nanomolar potency against SARS-CoV-2 and its variants of concern (VOCs) with EC50 values ranging from 0.80 to 161.7 nM in various cells. Preliminary mechanistic exploration indicated that they exhibited anticoronaviral activity through blocking viral entrance. Moreover, 14a and 14b exhibited good oral pharmacokinetic properties in mice, rats and dogs, and favorable safety in mice. In addition, both 14a and 14b treatments demonstrated potent antiviral potency against SARS-CoV-2 XBB 1.16 variant infection in a K18-hACE2 transgenic mouse model. And 14b also showed effective antiviral activity against HCoV-OC43 infection in a mouse model with a final survival rate of 60%. Further evaluation showed that 14a and 14b exhibited excellent anti-inflammatory effects in Raw 264.7 mouse macrophages and in mice with acute pneumonia. Taken together, these results suggested that 14a and 14b are promising drug candidates, providing novel insight into developing pan-coronavirus inhibitors with antiviral and anti-inflammatory properties.

Abstract Background Impaired osteo-/angiogenesis, excessive inflammation, and imbalance of the osteoimmune homeostasis are involved in the pathogenesis of the alveolar bone defect caused by periodontitis. Unfortunately, there is still a lack of ideal therapeutic strategies for periodontitis that can regenerate the alveolar bone while remodeling the osteoimmune microenvironment. Quercetin, as a monomeric flavonoid, has multiple pharmacological activities, such as pro-regenerative, anti-inflammatory, and immunomodulatory effects. Despite its vast spectrum of pharmacological activities, quercetin’s clinical application is limited due to its poor water solubility and low bioavailability. Results In this study, we fabricated a quercetin-loaded mesoporous bioactive glass (Quercetin/MBG) nano-delivery system with the function of continuously releasing quercetin, which could better promote the bone regeneration and regulate the immune microenvironment in the alveolar bone defect with periodontitis compared to pure MBG treatment. In particular, this nano-delivery system effectively decreased injection frequency of quercetin while yielding favorable therapeutic results. In view of the above excellent therapeutic effects achieved by the sustained release of quercetin, we further investigated its therapeutic mechanisms. Our findings indicated that under the periodontitis microenvironment, the intervention of quercetin could restore the osteo-/angiogenic capacity of periodontal ligament stem cells (PDLSCs), induce immune regulation of macrophages and exert an osteoimmunomodulatory effect. Furthermore, we also found that the above osteoimmunomodulatory effects of quercetin via macrophages could be partially blocked by the overexpression of a key microRNA——miR-21a-5p, which worked through inhibiting the expression of PDCD4 and activating the NF-κB signaling pathway. Conclusion In summary, our study shows that quercetin-loaded mesoporous nano-delivery system has the potential to be a therapeutic approach for reconstructing alveolar bone defects in periodontitis. Furthermore, it also offers a new perspective for treating alveolar bone defects in periodontitis by inhibiting the expression of miR-21a-5p in macrophages and thereby creating a favorable osteoimmune microenvironment. Graphical Abstract

Over the past decades, there has been ongoing effort to develop complex biomimetic tissue engineering strategies for in vitro cultivation and maintenance of organoids. The defined hydrogels can create organoid models for various organs by changing their properties and various active molecules. An increasing number of researches has been done on the application of hydrogels in organoids, and a large number of articles have been published on the topic. Although there have been existing reviews describing the application of hydrogels in the field of organoids, there is still a lack of comprehensive studies summarizing and analyzing the overall research trends in this field. The citation can be used as an indicator of the scientific influence of an article in its field. This study aims to evaluate the application of hydrogels in organoids through bibliometric analysis, and to predict the hotspots and developing trends in this field.

The timely and accurate acquisition of crop-growth information is a prerequisite for implementing intelligent crop-growth management, and portable multispectral imaging devices offer reliable tools for monitoring field-scale crop growth. To meet the demand for obtaining crop spectra information over a wide band range and to achieve the real-time interpretation of multiple growth characteristics, we developed a novel portable snapshot multispectral imaging crop-growth sensor (PSMICGS) based on the spectral sensing of crop growth. A wide-band co-optical path imaging system utilizing mosaic filter spectroscopy combined with dichroic mirror beam separation is designed to acquire crop spectra information over a wide band range and enhance the device’s portability and integration. Additionally, a sensor information and crop growth monitoring model, coupled with a processor system based on an embedded control module, is developed to enable the real-time interpretation of the aboveground biomass (AGB) and leaf area index (LAI) of rice and wheat. Field experiments showed that the prediction models for rice AGB and LAI, constructed using the PSMICGS, had determination coefficients (R²) of 0.7 and root mean square error (RMSE) values of 1.611 t/ha and 1.051, respectively. For wheat, the AGB and LAI prediction models had R² values of 0.72 and 0.76, respectively, and RMSE values of 1.711 t/ha and 0.773, respectively. In summary, this research provides a foundational tool for monitoring field-scale crop growth, which is important for promoting high-quality and high-yield crops.

BackgroundHepatocellular carcinoma (HCC) poses a significant health burden globally, with high mortality rates despite various treatment options. Immunotherapy, particularly immune-checkpoint inhibitors (ICIs), has shown promise, but resistance and metastasis remain major challenges. Understanding the intricacies of the tumor microenvironment (TME) is imperative for optimizing HCC management strategies and enhancing patient prognosis.MethodsThis study employed a comprehensive approach integrating multi-omics approaches, including single-cell RNA sequencing (scRNA-seq), bulk RNA sequencing (Bulk RNA-seq), and validation in clinical samples using spatial transcriptomics (ST) and multiplex immunohistochemistry (mIHC). The analysis aimed to identify key factors influencing the immunosuppressive microenvironment associated with HCC metastasis and immunotherapy resistance.ResultsHMGB2 is significantly upregulated in HCCTrans, a transitional subgroup associated with aggressive metastasis. Furthermore, HMGB2 expression positively correlates with an immunosuppressive microenvironment, particularly evident in exhausted T cells. Notably, HMGB2 expression correlated positively with immunosuppressive markers and poor prognosis in HCC patients across multiple cohorts. ST combined with mIHC validated the spatial expression patterns of HMGB2 within the TME, providing additional evidence of its role in HCC progression and immune evasion.ConclusionHMGB2 emerges as a critical player of HCC progression, metastasis, and immunosuppression. Its elevated expression correlates with aggressive tumor behavior and poor patient outcomes, suggesting its potential as both a therapeutic target and a prognostic indicator in HCC management.

The association between serum pentraxin-3 (PTX-3) levels and chronic obstructive pulmonary disease (COPD) has been explored in several studies. However, the results remain inconsistent. This meta-analysis aims to evaluate the differences in serum PTX-3 levels between COPD patients and healthy controls, as well as between patients with acute exacerbations of COPD (AECOPD) and stable COPD. Databases including PubMed, Embase, Web of Science, Wanfang, and CNKI were systematically searched. A random-effects model was used to pool the results, accounting for the potential impact of heterogeneity. Subgroup and meta-regression analyses were performed to evaluate the influence of study characteristics on the outcome. The initial search identified 274 articles, with 17 studies meeting the inclusion criteria. These studies included a total of 996 AECOPD patients, 1414 stable COPD patients, and 1016 healthy controls. The meta-analysis showed significantly higher serum PTX-3 levels in COPD patients compared to healthy controls (standardized mean difference [SMD]: 0.51, 95% confidence interval [CI]: 0.30 to 0.73, P < 0.001; I² = 85%). Subgroup and meta-regression analyses suggested that the results were not significantly affected by the age, sex, or smoking status of the patients. Additionally, serum PTX-3 levels were higher in AECOPD patients compared to stable COPD patients (SMD: 0.58, 95% CI: 0.41 to 0.74, P < 0.001; I² = 59%). In conclusion, serum PTX-3 levels are elevated in COPD patients, particularly during acute exacerbations, compared to stable COPD patients and healthy controls. PTX-3 may serve as a potential biomarker for COPD severity and exacerbation status.

Rheumatoid arthritis (RA) is a chronic autoimmune disease with a complex etiology. Neutrophil extracellular traps (NETs are NETwork protein structures activated by neutrophils to induce the cleavage and release of DNA-protein complexes). Current studies have shown the critical involvement of NETs in the progression of autoimmune diseases, Neutrophils mostly gather in the inflammatory sites of patients and participate in the pathogenesis of autoimmune diseases in various ways. NETs, as the activated state of neutrophils, have attracted much attention in immune diseases. Many molecules released in NETs are targeted autoantigens in autoimmune diseases, such as histones, citrulline peptides, and myeloperoxidase. All of these suggest that NETs have a direct causal relationship between the production of autoantigens and autoimmune diseases. For RA in particular, as a disorder of the innate and adaptive immune response, the pathogenesis of RA is inseparable from the generation of RA. In this article, we investigate the emerging role of NETs in the pathogenesis of RA and suggest that NETs may be an important target for the treatment of inflammatory autoimmune diseases.

ObjectivesThe purpose of this paper is to explore the relationship between blood levels of cadmium, lead, and mercury and anxiety in American adults.MethodsBlood metals and self-reported anxiety days were extracted from laboratory data and questionnaire data, respectively, using NHANES data from 2007–2012. Weighted logistic regression was used to assess the relationship between cadmium, lead and mercury with anxiety. Restricted cubic spline was used to visualize the non-linear relationship between metal concentrations and anxiety. Weighted quantile sum (WQS) regression was used to investigate the effect of combined exposure to the three metals on anxiety.ResultsThe prevalence of anxiety in adults was 26.0%. After adjusting for potential confounding variables, cadmium levels in the highest quartile (Q4) were associated with a higher risk of anxiety compared to the lowest quartile (Q1) (OR = 1.279, 95% CI: 1.113–1.471, p < 0.01). Restricted cubic spline analysis indicated a positive association between blood cadmium levels and anxiety. Furthermore, co-exposure to multiple heavy metals was positively associated with anxiety risk (WQS positive: OR = 1.068, 95% CI: 1.016–1.160, p < 0.05), with cadmium contributing the most to the overall mixture effect. Compared to the Light RPA, the Vigorous/Moderate RPA group had a relatively low risk of anxiety after cadmium exposure.ConclusionHigh levels of blood cadmium are positively associated with the development of anxiety disorders, which needs to be further verified in future studies.

Inflammation is a biological response of multicellular organisms caused by injuries, pathogens or irritants. An excessive inflammatory response can lead to tissue damage and various chronic diseases. Chronic inflammation is a common feature of many diseases, making the search for drugs to treat inflammation-related diseases urgent. Scutellarin, a natural flavonoid metabolite, is widely used in the treatment of various inflammation-related diseases for its anti-inflammatory, anti-oxidant and anti-cancer activities. Scutellarin can inhibit key inflammatory pathways (PI3K/Akt, MAPK, and NF-κB, etc.) and activate the anti-oxidant related pathways (Nrf2, ARE, ect.), thereby protecting tissues from inflammation and oxidative stress. Modern extraction technologies, such as microwave-assisted, ultrasound assisted, and supercritical fluid extraction, have been utilized to extract scutellarin from Scutellaria and Erigeron genera. These technologies improve efficiency and retain biological activity, making scutellarin suitable for large-scale production. Scutellarin has significant therapeutic effects in treating osteoarthritis, pulmonary fibrosis, kidney injury, and cardiovascular diseases. However, due to its low bioavailability and short half-life, its clinical application is limited. Researchers are exploring innovative formulations (β-cyclodextrin polymers, triglyceride mimetic active ingredients, and liposome precursors, etc.) to improve stability and absorption rates. Despite these challenges, the potential of scutellarin in anti-inflammatory, anti-oxidant, and anti-cancer applications remains enormous. By optimizing formulations, exploring combination therapies, and conducting in-depth mechanistic research, scutellarin can play an important role in treating various inflammatory diseases, providing patients with more and effective treatment options.

Background and purposeThis study explores the relationship between serum 25-hydroxyvitamin D [25(OH)D] levels and mortality among Parkinson’s disease (PD) patients, providing evidence for the potential benefits of vitamin D (VD) supplementation.MethodsPD patients were collected from the National Health and Nutrition Examination Survey (NHANES) database from 1999 to 2020. These patients were categorized based on their serum 25(OH)D levels: deficiency, insufficiency, and sufficiency. We compared demographic information and analyzed mortality data from the National Death Index. A restricted cubic spline model assessed the nonlinear association between 25(OH)D levels and mortality, complemented by multivariable Cox regression analysis. Consistency of results was checked through subgroup analysis.ResultsThe study included 364 PD patients: 87 (23.9%) with VD deficiency, 121 (33.2%) with insufficiency, and 156 (42.9%) with sufficiency. Demographically, 46.4% were male, and 56% were over 65 years. The deficiency group predominantly consisted of Mexican Americans (53.1%), had lower income levels, a higher unmarried rate, and increased liver disease incidence. The analysis showed a U-shaped curve between 25(OH)D levels and mortality risk, with the lowest risk at 78.68 nmol/L (p-non-linear = 0.007, p-overall = 0.008). Kaplan–Meier analysis found the highest survival rates in patients with 25(OH)D levels between 75–100 nmol/L (p = 0.039). Compared to this group, patients with levels below 50 nmol/L had a 3.52-fold increased mortality risk (95% CI = 1.58–7.86, p = 0.002), and those above 100 nmol/L had a 2.92-fold increase (95% CI = 1.06–8.05, p = 0.038). Age-specific subgroup analysis (p = 0.009) revealed that both very low (100 nmol/L) levels increased mortality risk in patients under 65, while levels below 75 nmol/L raised mortality risk in older patients.ConclusionSerum 25(OH)D levels are nonlinearly linked to mortality in PD patients, with optimal survival rates occurring at 75–100 nmol/L. Deviations from this range increase the risk of death.

Abstract Periodontal disease ranks third among noncommunicable illnesses, behind cancer and cardiovascular disease, and is closely related to the occurrence and progression of various systemic diseases. However, elucidating the processes of periodontal disease and promoting periodontal bone regeneration remains a challenge. Here, quercetin is demonstrated to reduce the oxidative stress state of orofacial mesenchymal stem cells (OMSCs) in vitro and to affect the osteogenic growth of OMSCs through molecular mechanisms that mediate the m6A change in Per1. Nevertheless, the limited therapeutic efficacy of systemic medication and the limitations of local medication resulting from the small, moist, and highly dynamic periodontal environment make it challenging to treat periodontal tissues with medication. Herein, a biosafe injectable hydrogel drug‐controlled delivery system is constructed as a bone‐enhancing factory and loaded with quercetin to treat oxidative stress injury in periodontal tissues. This drug‐carrying system made up of nanoscale bioglass microspheres and a light‐cured injectable hydrogel, allows effective drug particle loading and cementation in the dynamic and moist periodontal environment. Furthermore, the system demonstrates the ability to stimulate OMSCs osteogenic differentiation in a Per1‐dependent manner, which ultimately promotes periodontal bone repair, suggesting that this system has potential for clinical periodontal therapy.

High-throughput phenotypic analysis plays an increasingly important role in crop breeding. In such research, the breeder usually establishes hundreds to thousands of plots, with each plot having its independent genetic breeding sources. The breeding plot extraction of genetic sources is usually outlined manually on RGB UAV imagery, which is time-consuming and subject to human bias. Therefore, a rapid method to extract the breeding plot for each genetic source in high-throughput phenotypic analysis would be very significant. In this paper, we propose a transferable method for extracting breeding plots from UAV RGB imagery. We utilized the fully convolutional neural network model A-UNet with an attention gate. After obtaining binary raster data from deep learning, we introduced post-processing. Subsequently, the raster data after post-processing were converted to vector data to obtain geographical coordinates. Finally, the UAV imagery was masked by the vector data to obtain the extraction results for each plot. The results showed that A-UNet achieved accuracies of over 90 % in precision, recall, and F1 score. Post-processing resulted in a 93 % average IoU in breeding plot extraction in the main study area. The average IOU achieved over 86 % in different spatial resolutions (1.6 cm and 0.4 cm), plot sizes (1 m × 1.5 and 2 m × 5 m), and crop types (rice). In summary, this study developed a method for extracting breeding plots in high-throughput phenotype analysis, which would help to be used as a high-throughput screening technique for accelerating crop breeding.

As a chronic autoimmune disease with complex aetiology, rheumatoid arthritis (RA) has been demonstrated to be associated with mitochondrial dysfunction since mitochondrial dysfunction can affect the survival, activation, and differentiation of immune and non-immune cells involved in the pathogenesis of RA. Nevertheless, the mechanism behind mitochondrial dysfunction in RA remains uncertain. Accordingly, this review addresses the possible role and mechanisms of mitochondrial dysfunction in RA and discusses the potential and challenges of mitochondria as a potential therapeutic strategy for RA, thereby providing a breakthrough point in the prevention and treatment of RA.

Background With the increasing survival rate of smaller newborns and twins, previous growth curves may not accurately assess the growth of extremely preterm infants (EPIs). Our study aimed to establish birth weight percentile curves for singletons and twins in EPIs from China and the USA and compare the differences between them.Methods In China, EPIs were from 31 provinces, from 2010 to 2021. The collected information was sex, gestational age, birth weight, singletons and twins. We used the generalised additive models for location scale and shape method to construct the birth weight percentile curves by gestational age and sex for EPIs. The National Vital Statistics System database from 2016 to 2021 was also analysed. We compared the differences between the 50th birth weight percentile curves of the two databases.Results We identified 8768 neonates in China (5536 singletons and 3232 twins) and 121 933 neonates in the USA (97 329 singletons and 24 604 twins). We established the 3rd, 10th, 25th, 50th, 75th, 90th and 97th birth weight reference curves for China and the USA. The results showed that males had higher birth weights than females. In China, for the same gestational age and sex, birth weights in singletons and twins were found to be similar, though singleton males born in China had slightly higher birth weights than male twins. In the USA, birth weights were also similar for females and males, with the same gestational age in singletons and twins.Conclusion We established birth weight reference percentile curves by gestational age and sex for singletons and twins among EPIs in China and the USA.

FPSO (Floating Production, Storage and Offloading) or FLNG (Floating Liquefied Natural Gas) vessels produce and store crude oil or liquified natural gas before being transported by ST (Shuttle Tanker). Robust prediction of excessive mooring and hawser stresses being crucial for structural design and operational safety. Offloading activities may result in excessive hawser or mooring line tensions, impacting environmental and operational safety. Current study employed ANSYS-AQWA software to simulate vessels dynamics, subjected to wind-wave hydrodynamic loads, given realistic in-situ environmental conditions.State-of-the-art multi-dimensional risk assessment methodology, presented in this work being based on direct MC (Monte Carlo) simulations, however, it is equally applicable to measured data. Advocated methodology effectively utilizes underlying dataset, offering accurate failure/damage risk assessment. Current study aims to benchmark recently developed multivariate Gaidai risk assessment approach, allowing for the straightforward yet efficient prediction of failure and damage risks for nonlinear multi-dimensional dynamic offshore/naval system as a whole. Primary benefit of the proposed methodology lies in its multi-dimensionality, as it can encompass virtually infinite number of system’s dimensions/components, each having its distinct physical dimension. In contrast, traditional reliability methods are usually limited to a maximum of two-dimensional systems. Novel deconvolution extrapolation scheme offers additional advantage, being non-parametrical by its nature, as opposed to existing parametric extrapolation techniques.

Abstract In early June 2023, New York City (NYC) and other cities in the northeastern US experienced a severe air pollution event. Although reports associated this hazardous pollution event with the smoke from Canadian wildfires, the factors triggering the southward waft of the smoke remain unclear. We found the northerly anomaly that transported the smoke was linked to the Rossby wave train excited by the Madden–Julian Oscillation (MJO) over the Philippine Sea, which led to the formation of an enhanced northerly at the western edge of the cyclonic anomaly over the East Coast–North Atlantic. When the MJO convection left the western Pacific, the disorganized teleconnection caused the pollution to dissipate. Observational findings were further supported by model simulations and predictions. These results suggest that monitoring and predictions of MJO activity may help mitigate air pollution events over the northeastern US during Canadian wildfire seasons.

Abstract Background Research has shown that visual perceptual learning (VPL) is related to modifying neural activity in higher level decision‐making regions. However, the causal roles of the prefrontal and visual cortexes in VPL are still unclear. Here, we investigated how anodal transcranial direct current stimulation (tDCS) of the prefrontal and visual cortices modulates VPL in the early and later phases and the role of multiple brain regions. Methods Perceptual learning on the coherent motion direction identification task included early and later stages. After early training, participants needed to continuously train to reach a plateau; once the plateau was reached, participants entered a later stage. Sixty participants were randomly divided into five groups. Regardless of the training at the early and later stages, four groups received multitarget tDCS over the right dorsolateral prefrontal cortex (rDLPFC) and right middle temporal area (rMT), single‐target tDCS over the rDLPFC, and single‐target tDCS over the rMT or sham stimulation, and one group was stimulated at the ipsilateral brain region (i.e., left MT). Results Compared with sham stimulation, multitarget and two single‐target tDCS over the rDLPFC or rMT improved posttest performance and accelerated learning during the early period. However, multitarget tDCS and two single‐target tDCS led to equivalent benefits for VPL. Additionally, these beneficial effects were absent when anodal tDCS was applied to the ipsilateral brain region. For the later period, the above facilitating effects on VPL induced by multitarget or single‐target tDCS disappeared. Conclusions This study suggested the causal role of the prefrontal and visual cortices in visual motion perceptual learning by anodal tDCS but failed to find greater beneficial effects by simultaneously stimulating the prefrontal and visual cortices. Future research should investigate the functional associations between multiple brain regions to further promote VPL.

Abstract Autism spectrum disorder (ASD) is a neurodevelopmental disorder, characterized by social communication disability and stereotypic behavior. This study aims to investigate the impact of prenatal exposure to 1‐nitropyrene (1‐NP), a key component of motor vehicle exhaust, on autism‐like behaviors in a mouse model. Three‐chamber test finds that prenatal 1‐NP exposure causes autism‐like behaviors during the weaning period. Patch clamp shows that inhibitory synaptic transmission is reduced in medial prefrontal cortex of 1‐NP‐exposed weaning pups. Immunofluorescence finds that prenatal 1‐NP exposure reduces the number of prefrontal glutamate decarboxylase 67 (GAD67) positive interneurons in fetuses and weaning pups. Moreover, prenatal 1‐NP exposure retards tangential migration of GAD67‐positive interneurons and downregulates interneuron migration‐related genes, such as Nrg1, Erbb4, and Sema3F, in fetal forebrain. Mechanistically, prenatal 1‐NP exposure reduces hydroxymethylation of interneuron migration‐related genes through inhibiting ten‐eleven translocation (TET) activity in fetal forebrain. Supplement with alpha‐ketoglutarate (α‐KG), a cofactor of TET enzyme, reverses 1‐NP‐induced hypohydroxymethylation at specific sites of interneuron migration‐related genes. Moreover, α‐KG supplement alleviates 1‐NP‐induced migration retardation of interneurons in fetal forebrain. Finally, maternal α‐KG supplement improves 1‐NP‐induced autism‐like behaviors in weaning offspring. In conclusion, prenatal 1‐NP exposure causes autism‐like behavior partially by altering DNA hydroxymethylation of interneuron migration‐related genes in developing brain.

Summary: Polymyxins are often the only effective antibiotics against the “Critical” pathogen Acinetobacter baumannii. Worryingly, highly polymyxin-resistant A. baumannii displaying dependence on polymyxins has emerged in the clinic, leading to diagnosis and treatment failures. Here, we report that arginine metabolism is essential for polymyxin-dependent A. baumannii. Specifically, the arginine degradation pathway was significantly altered in polymyxin-dependent strains compared to wild-type strains, with critical metabolites (e.g., L-arginine and L-glutamate) severely depleted and expression of the astABCDE operon significantly increased. Supplementation of arginine increased bacterial metabolic activity and suppressed polymyxin dependence. Deletion of astA, the first gene in the arginine degradation pathway, decreased phosphatidylglycerol and increased phosphatidylethanolamine levels in the outer membrane, thereby reducing the interaction with polymyxins. This study elucidates the molecular mechanism by which arginine metabolism impacts polymyxin dependence in A. baumannii, underscoring its critical role in improving diagnosis and treatment of life-threatening infections caused by “undetectable” polymyxin-dependent A. baumannii.

ABSTRACT Polymyxin is used as a last resort antibiotics for infections caused by multi-drug resistant (MDR) Gram-negative bacteria and is often combined with other antibiotics to improve clinical effectiveness. However, the synergism of colistin and other antibiotics remains obscure. Here, we revealed a notable synergy between colistin and flavomycin, which was traditionally used as an animal growth promoter and has limited activity against Gram-negative bacteria, using checkerboard assay and time–kill curve analyses. The importance of membrane penetration induced by colistin was assessed by examining the intracellular accumulation of flavomycin and its antimicrobial impact on Escherichia coli (E. coli) strains with truncated lipopolysaccharides. Besides, a mutation in the flavomycin binding site was created to confirm its role in the observed synergy. This synergy is manifested as an augmented penetration of the E. coli outer membrane by colistin, leading to increased intracellular accumulation of flavomycin and enhanced cell killing thereafter. The observed synergy was dependent on the antimicrobial activity of flavomycin, as mutation of its binding site abolished the synergy. In vivo studies confirmed the efficacy of colistin combined with flavomycin against MDR E. coli infections. This study is the first to demonstrate the synergistic effect between colistin and flavomycin, shedding light on their respective roles in this synergism. Therefore, we propose flavomycin as an adjuvant to enhance the potency of colistin against MDR Gram-negative bacteria.IMPORTANCEColistin is a critical antibiotic in combating multi-drug resistant Gram-negative bacteria, but the emergence of mobilized colistin resistance (mcr) undermines its effectiveness. Previous studies have found that colistin can synergy with various drugs; however, its exact mechanisms with hydrophobic drugs are still unrevealed. Generally, the membrane destruction of colistin is thought to be the essential trigger for its interactions with its partner drugs. Here, we use clustered regularly interspaced palindromic repeats (CRISPR)–CRISPR-associated protein 9 (Cas9) for specifically mutating the binding site of one hydrophobic drug (flavomycin) and show that antimicrobial activity of flavomycin is critical for the synergy. Our results first give the evidence that the synergy is set off by colistin's membrane destruction and operated the final antimicrobial function by its partner drugs.