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Air spring isolator is the crucial component of ship floating raft isolation system. However, due to various factors such as manufacturing errors and installation conditions of air spring isolators, abnormal contacts cannot be avoided in the internal limiters of air spring isolator, resulting in the acoustic short circuit fault. This leads to a significant decrease in isolation effectiveness. To address this issue, experiments on the acoustic short circuit fault of air spring isolators are conducted, and the experimental results are analysed. Then the causes behind the phenomena and results of the acoustic short circuit experiments are further elucidated through finite element simulations and mathematical theory analysis. The research results indicate that the acoustic short circuit of air spring isolators affects the isolation effectiveness. The more severe the acoustic short circuit fault, the greater its impact on the isolation effectiveness, particularly in the low-frequency isolation component. This is because, during the acoustic short circuit of air spring isolators, the rubber part of the internal limiter comes into contact, causing an increase in the stiffness of the air spring support, thereby resulting in an increase in the modal frequency of the isolation device and consequently severely impacting the low-frequency isolation effectiveness.

Urban parks are a major component of urban green spaces and are reserved for recreation, aesthetics and cultural heritage. With increasing attention to carbon neutrality in China, urban parks play an important role in carbon sequestration. This new expectation requires us to examine the impacts of current design and management in urban parks on carbon density. This study took Beijing as an example and investigated a total of 9 parks within 4 functional categories, i.e., landscape parks with small, medium, and large sizes and natural forests. As parks worked for various functions, their plants species and tree sizes were distinct. Big trees were scattered in small parks; while big parks had natural-like landscape with ample medium- and small-sized trees. We analysed their aboveground and belowground carbon density, as well as associated variables, such as biodiversity, soil bulk density, nitrogen (N) content, etc. Soil types were the same for different parks, but managements leaded to different soil properties. Medium- and large-sized landscape parks had the highest aboveground carbon density (60.86 t·hm−2 and 79.18 t·hm−2, respectively), which was higher than that of natural forests (43.20 t·hm−2), while small-sized landscape parks had the highest belowground carbon density (185.22 t·hm−2), which was slightly less than that of natural forests (207.17 t·hm−2). The high aboveground carbon density in landscape parks with medium and large sizes was attributed to the well-planted trees and high biodiversity, especially for the high ratio of brush (62.12 %). High belowground carbon density in small landscape parks resulted from careful management, such as timely fertilization and frequent soil loosening, which led to high organic matter and low bulk density (1.1206 kg·cm−3), promoting soil carbon sequestration. We therefore provide specific advice in managing different parks in regard to their carbon density, expecting to increase carbon density in urban parks by an average of 224 %.

Antibiotics are widely used in the breeding production of Bamei pigs, affecting the quality and safety of pork and causing enormous harm to human health, the environment, and public health. The use of probiotic fermented feed to replace antibiotic feed is one of the solutions, which has the potential to improve the intestinal microbiota, promote animal growth, and enhance immunity. The purpose of this study was to evaluate the effect of fermented feed with Lactiplantibacillus (L.) plantarum QP28-1a or Bacillus (B.) subtilis QB8a on feed, growth performance, gut microbiota, and immunity of weaned piglets. A total of 60 freshly weaned piglets from the Tibetan Plateau were randomly divided into five groups and fed basal feed, L. plantarum fermented feed, B. subtilis fermented feed, mixed fermented feed, and antibiotic fermented feed for 60 days, respectively. The results showed fermented feed supplemented with L. plantarum QP28-1a or B. subtilis QB8a significantly lowered the pH of the feed (P < 0.05), produced lactic acid and acetic acid, inhibited the growth of harmful bacteria in the feed, and reduced the feed conversion rate in the group fed mixed fermented feed (P < 0.05). The fermented feed increased the α-diversity and prominently altered the β-diversity of the intestinal microbiota, increasing the relative abundance of beneficial bacteria such as Lactobacillus and Turicibacter and decreasing the relative abundance of conditional pathogens such as Streptococcus and Clostridium, improving the intestinal microbiota of the Bamei piglets. Notably, the mixed fermented feed improved the immunity of Bamei piglets by modulating the production of pro-inflammatory cytokines, anti-inflammatory cytokines, and inflammatory-related signaling pathways. Spearman’s correlation analysis revealed that the increased expression of immune-related cytokines may be associated with a significant enrichment of Lactobacillus, Prevotellaceae, Erysipelotrichaceae, and Ruminococcaceae in the gut. In conclusion, the probiotic fermented feed maintained an acidic environment conducive to suppressing pathogens, reduced the feed conversion ratio, optimized the intestinal microbiota, improved immunity, and alleviated intestinal inflammation that may be caused by weaning, demonstrating the excellent application prospects of L. plantarum QP28-1a and B. subtilis QB8a fermented feed in the feeding of Bamei piglets.

Aiming at the problems of traditional image super-resolution reconstruction algorithms in the image reconstruction process, such as small receptive field, insufficient multi-scale feature extraction, and easy loss of image feature information, a super-resolution reconstruction algorithm of multi-scale dilated convolution network based on dilated convolution is proposed in this paper. First, the algorithm extracts features from the same input image through the dilated convolution kernels of different receptive fields to obtain feature maps with different scales; then, through the residual attention dense block, further obtain the features of the original low resolution images, local residual connections are added to fuse multi-scale feature information between multiple channels, and residual nested networks and jump connections are used at the same time to speed up deep network convergence and avoid network degradation problems. Finally, deep network extraction features, and it is fused with input features to increase the nonlinear expression ability of the network to enhance the super-resolution reconstruction effect. Experimental results show that compared with Bicubic, SRCNN, ESPCN, VDSR, DRCN, LapSRN, MemNet, and DSRNet algorithms on the Set5, Set14, BSDS100, and Urban100 test sets, the proposed algorithm has improved peak signal-to-noise ratio and structural similarity, and reconstructed images. The visual effect is better.

ObjectiveThis study aimed to explore the correlation between microbiota dysbiosis and hypothyroidism in early pregnancy by 16S rRNA amplicon sequencing combined with metagenomic sequencing.MethodsSixty pregnant women (30 with hypothyroidism and 30 normal controls) were recruited for 16S rRNA amplicon sequencing, and 6 patients from each group were randomly selected for metagenomic sequencing to assess the gut microbiome profile.ResultsThe 16S rRNA results showed that beta-diversity in the hypothyroidism group was decreased. The relative abundances of the Prevotella and Paraprevotella genera increased in the hypothyroidism group, and Blautia predominated in the controls. The metagenomics results revealed that Prevotella_stercorea_CAG_629, Prevotella_hominis, Prevotella_sp_AM34_19LB, etc. were enriched in the hypothyroidism group at the species level. Functional analysis revealed that the pyridoxal 5’-phosphate synthase pdxT subunit module was decreased, and the short-chain fatty acid (SCFA) transporter and phospholipase/carboxylesterase modules were strongly enriched in the hypothyroidism group. Hypothyroidism patients had increased C-reactive protein (CRP), interleukin-2 (IL-2), IL-4, IL-10, and tumor necrosis factor (TNF)-α levels. The pyridoxal 5’-phosphate synthase pdxT subunit, the SCFA transporter, and the phospholipase/carboxylesterase module were associated with different Prevotella species.ConclusionIn early pregnancy, women with hypothyroidism exhibit microbiota dysbiosis, and Prevotella may affect the metabolism of glutamate, SCFA, and phospholipases, which could be involved in the development of hypothyroidism during pregnancy.

Abstract Commencing with the breakdown of the diabetic osteoimmune microenvironment, multiple pathogenic factors, including hyperglycemia, inflammation, hypoxia, and deleterious cytokines, are conjointly involved in the progression of diabetic periodontal bone regeneration. Based on the challenge of periodontal bone regeneration treatment and the absence of real‐time feedback of blood oxygen fluctuation in diabetes mellitus, a novel self‐adaptive hyperthermia supramolecular cascade nano‐reactor ACFDG is constructed via one‐step supramolecular self‐assembly strategy to address multiple factors in diabetic periodontal bone regeneration. Hyperthermia supramolecular ACFDG possesses high photothermal conversion efficiency (32.1%), and it can effectively inhibit the vicious cycle of ROS‐inflammatory cascade through catalytic cascade reactions, up‐regulate the expression of heat shock proteins (HSPs) under near‐infrared (NIR) irradiation, which promotes periodontal bone regeneration. Remarkably, ACFDG can provide real‐time non‐invasive diagnosis of blood oxygen changes during periodontal bone regeneration through photoacoustic (PA) imaging, thus can timely monitor periodontal hypoxia status. In conclusion, this multifunctional supramolecular nano‐reactor combined with PA imaging for real‐time efficacy monitoring provides important insights into the biological mechanisms of diabetic periodontal bone regeneration and potential clinical theranostics.

Abstract A graphene field‐effect transistor (GFET) based on chemical vapour deposited (CVD) Ge‐based graphene was reported and the low‐temperature electrical characteristics primarily investigated. The self‐alignment technique was used to fabricate a GFET to reduce parasitic effects and improve transconductance and cut‐off frequency. To further explore the electrical properties, the direct current and radio frequency characteristics of the GFET were studied over a temperature range from 4.2 to 300 K, considering the temperature‐dependent resistivity of intrinsic Ge. The direct current characteristic of the GFET for 110‐nm gate length, particularly the transconductance performance, exhibits a tiny variation of only ∼5% across this temperature range. However, the cut‐off frequency experiences a considerable increase, improving several tens of times when the temperature decreases to 4.2 K, with a maximum value of 3.49 GHz. This work illustrates a meaningful advancement in applying GFETs in the low‐temperature, high‐frequency domain.

BackgroundThe sudden emergence of the COVID-19 pandemic in early 2020 posed an enormous threat to public health. Vaccination is currently recognized as the most cost-effective preventive and control measure against the COVID-19 pandemic worldwide and is the key to constructing a line of defense against the virus, while the epidemic prevention policies adopted by governments have an important impact on the protective behavior of the public. The purpose of this study is to analyze the mechanism by which the stringency of epidemic prevention policies affects public vaccination willingness and to explore the mediating effect of public risk perception.MethodsA cross-sectional survey was conducted among 387 adults from December 2022 to June 2023 in China. A multiple linear regression model was used to explore the impact of epidemic prevention policy stringency on public vaccination willingness, and a hierarchical regression model was used to test the mediating effect of public risk perception.ResultsOur results showed that public vaccination willingness increased by approximately 45.5% for every one-unit increase in the stringency of the epidemic prevention policies, which shows that the stringency of epidemic prevention policies has a significant positive influence on public vaccination willingness. In addition, public risk perception increased by approximately 38.9% during the period of stringent government policies on epidemic prevention. For every one-unit increase in risk perception, public vaccination willingness increased by approximately 40.9%, and the relationship between the stringency of epidemic prevention policies and public vaccination willingness was partially mediated by risk perception.ConclusionThe stricter the epidemic prevention policies, the stronger the public vaccination willingness; risk perception plays a mediating effect between the stringency of epidemic prevention policies and public vaccination willingness. This finding is particularly important for exploring and analyzing the factors influencing public vaccination willingness and for improving public health.

Recycled demolition waste (RDW) and ground granulated blast furnace slag-fly ash-based geopolymer (GFG) are promising materials for treating high-plasticity clay (CH) in highway subgrades. However, the underlying synergistic stabilization mechanisms remain unclear. To elucidate the fundamental mechanisms governing post-treatment soil stabilization, a multi-scale laboratory investigation was undertaken. This investigation encompassed the evaluation of mechanical properties (compaction, California bearing ratio (CBR), and unconfined compressive strength (UCS)) to quantify the enhanced performance of the treated soil. Additionally, microstructural and mineralogical characterization was performed using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), and atomic force microscopy (AFM) to elucidate the microscopic mechanisms responsible for this improvement. The results indicated that the addition of RDW led to a reduction in the optimum moisture content (OMC) while increasing the maximum dry density (MDD) of CH. Moreover, upon incorporating RDW-GFG, the mechanical properties of the cured soil exhibited significant improvement. Specifically, the addition of 25% RDW to CH resulted in a 184% increase in CBR and effective improvement in water stability (immersion swelling percentage is reduced). Furthermore, when 25% RDW and 15% GFG were added to CH, the UCS has increased significantly by 8 times. The addition of RDW effectively enhanced the particle size distribution, compacted the soil, thus increased the shear strength. The results from XRD and SEM analyses revealed that the inclusion of GFG could generate geopolymer cementitious bonding network in the soil matrix. These materials facilitated bonding between CH particles and RDW, filling the pores and densifying the overall structure, thus increasing its strength. The synergy of RDW-GFG substantially improved the highly plastic soil through physicochemical actions, markedly elevating both its strength and water stability. Consequently, the outcomes of this experimental study offer valuable insights for road engineering applications.

To ensure the operation safety and efficiency of an autonomous rice transplanter, a path planning method of obstacle avoidance based on the improved artificial potential field is proposed. Firstly, the obstacles are divided into circular or elliptic obstacles according to the difference between the length and width of an obstacle as well as the angle between the vehicle’s forward direction and the length direction of the obstacle. Secondly, improved repulsive fields for circular and elliptic models are developed. To escape the local minimum and goal inaccessibility of the traditional artificial potential field as well as meet the requirements of agronomy and vehicle kinematics constraints, the adaptive setting and adjusting strategy for virtual goal points is proposed according to relative azimuth between obstacle and vehicle. The path smoothing method based on the B-spline interpolation method is presented. Finally, the intelligent obstacle avoidance algorithm is designed, and the path evaluation rule is given to obtain the low-cost, non-collision, smooth and shortest obstacle avoidance path. To verify the effectiveness of the proposed obstacle avoidance algorithm, simulation and field experiments are conducted. Simulation and experimental results demonstrate that the proposed improved collision avoidance algorithm is highly effective and realizable.

Abstract Background Fusobacterium necrophorum (F. necrophorum)-induced necrotizing pneumonia is a rare but severe pulmonary infection. Insufficient microbiological detection methods can lead to diagnostic difficulties. Methods We report a case of F. necrophorum lung abscess diagnosed by next-generation sequencing (NGS) of bronchoalveolar lavage fluid (BALF). Results BALF-NGS detected F. necrophorum, guiding subsequent targeted antibiotic therapy. With active drainage and metronidazole treatment, the patient’s condition was effectively treated. Conclusion BALF-NGS is a valuable tool for the rapid diagnosis of infections caused by difficult-to-culture bacteria. It played a decisive role in the early identification of F. necrophorum, enabling timely and targeted antibiotic intervention. Early diagnosis and appropriate treatment are crucial for the management of F. necrophorum pneumonia.

Multimodal Language Models (MMLMs), such as LLaVA and GPT-4V, have shown zero-shot generalization capabilities for understanding images and text across various domains. However, their effectiveness in open-world visual tasks, particularly anomaly detection under challenging conditions, such as low light or poor image quality, has yet to be thoroughly investigated. Assessing the robustness and limitations of MMLMs in these scenarios is essential to ensuring their reliability and safety in real-world applications, where the input image quality can vary significantly. To address this gap, we propose a benchmark comprising 460 images captured under challenging conditions, including low light and blurring. This benchmark is specifically designed to evaluate the anomaly detection capabilities of MMLMs. We assess the performance of state-of-the-art MMLMs, such as Qwen-VL-Max-0809, GPT-4V, Gemini-1.5, Claude3-opus, ERNIE-Bot-4, and SparkDesk-v3.5, across six diverse scenes. Our evaluations indicate that these MMLMs struggle with error detection in adverse scenarios, thereby highlighting the need for further investigation into the underlying causes and potential improvement strategies. To tackle these limitations, we introduce a novel anomaly detection agent (ADAGENT) framework, which is an AI agent framework that combines the “Chain of Critical Self-Reflection (CCS)”, specialized toolsets, and “Heuristic Retrieval-Augmented Generation (RAG)” to enhance anomaly detection performance with MMLMs. ADAGENT sequentially evaluates abilities, such as text generation, semantic understanding, contextual comprehension, key information extraction, reasoning, and logical thinking. By implementing this framework, we demonstrated a $15\%\sim {30\%}$ improvement in the top-3 accuracy for anomaly detection tasks under adverse conditions, compared with baseline approaches.

This study introduces a novel approach to improve crop classification accuracy in airborne synthetic aperture radar (SAR) time-series imagery, focusing on overcoming the challenges posed by the incidence angle effect. The approach aims to innovate the integration of transfer learning and variational mode decomposition techniques. Transfer learning effectively addresses disparities in data distribution caused by varying incidence angles encountered in airborne SAR. Variational mode decomposition extracts robust temporal features, significantly reducing sensitivity to incidence angle variations. The approach is further enhanced by incorporating incidence angle information into the transfer learning model's training phase. The experimental results demonstrate the effectiveness of the method, which, under comparable sample conditions, achieves a remarkable improvement in accuracy (Kappa +25.05%) compared with the conventional methods. This improvement is particularly notable for crops, such as oats and soybeans, which are considerably influenced by the incidence angle effect, with Kappa increases of 27.92% and 39.30%, respectively. This study not only develops an effective strategy for crop classification in the context of airborne SAR imagery but also provides references for the effective use of new technologies from various fields in the field of remote sensing application.

Abstract Background Stem cell transplantation shows great potential to improve the long-term survival of cirrhosis patients. However, therapeutic effects may not be homogeneous across the whole study population. This study constructed an easy-to-use nomogram to improve prognostic prediction and aid in treatment decision making for cirrhotic patients. Methods From August 2005 to April 2019, 315 patients with decompensated cirrhosis receiving autologous peripheral blood stem cell (PBSC) transplantation were enrolled in this study. They were randomly classified into training (2/3) and validation (1/3) groups. A predictive model was developed using Cox proportional hazard models and subsequently validated. The predictive performance of the model was evaluated and also compared with other prognostic models. Results Age, creatinine, neutrophil-to-lymphocyte ratio, and Child–Turcotte–Pugh class were included in the nomogram as prognostic variables. The nomogram showed high discrimination power concerning the area under receiver operating characteristic curves (3/5-year AUC: 0.742/0.698) and good consistency suggested by calibration plots. Patients could be accurately stratified into poor- and good-outcome groups regarding liver-transplantation free survival after receiving PBSC therapy (P

Abstract Atherosclerosis is one of the leading causes of death worldwide. miR-26 is a potential biomarker of atherosclerosis. Standardized diagnostic tests for miR-26 (MIR26-DX) have been developed, but the fastest progress has been in predicting the efficacy of IFN-α therapy for hepatocellular carcinoma (HCC, phase 3). MiR-26 slows atherosclerosis development by suppressing ACC1/2, ACLY, ACSL3/4, ALDH3A2, ALPL, BMP2, CD36, COL1A1, CPT1A, CTGF, DGAT2, EHHADH, FAS, FBP1, GATA4, GSK3β, G6PC, Gys2, HMGA1, HMGB1, LDLR, LIPC, IL-1β, IL-6, JAG2, KCNJ2, MALT1, β-MHC, NF-κB, PCK1, PLCβ1, PYGL, RUNX2, SCD1, SMAD1/4/5/7, SREBF1, TAB3, TAK1, TCF7L2, and TNF-α expression. Many agents targeting these genes, such as the ACC1/2 inhibitors GS-0976, PF-05221304, and MK-4074; the DGAT2 inhibitors IONIS-DGAT2Rx, PF-06427878, PF-0685571, and PF-07202954; the COL1A1 inhibitor HT-100; the stimulants 68Ga-CBP8 and RCT-01; the CPT1A inhibitors etomoxir, perhexiline, and teglicar; the FBP1 inhibitors CS-917 and MB07803; and the SMAD7 inhibitor mongersen, have been investigated in clinical trials. Interestingly, miR-26 better reduced intima-media thickness (IMT) than PCSK9 or CT-1 knockout. Many PCSK9 inhibitors, including alirocumab, evolocumab, inclisiran, AZD8233, Civi-007, MK-0616, and LIB003, have been investigated in clinical trials. Recombinant CT-1 was also investigated in clinical trials. Therefore, miR-26 is a promising target for agent development. miR-26 promotes foam cell formation by reducing ABCA1 and ARL4C expression. Multiple materials can be used to deliver miR-26, but it is unclear which material is most suitable for mass production and clinical applications. This review focuses on the potential use of miR-26 in treating atherosclerosis to support the development of agents targeting it.

Abstract Background Claudin-18.2 (CLDN18.2) has emerged as an alluring therapeutic target against gastrointestinal tumors in recent years. However, a thorough understanding of its regulatory mechanism in gastric cancer remains elusive. Methods We presented a comprehensive study comprising 185 gastric cancer patients, which included 112 cases with high CLDN18.2 expression and 73 cases with low CLDN18.2 expression as determined by immunohistochemistry. After overdressed CLDN18.2 in AGS and NUGC4 cell lines, we elucidated the functions of CLDN18.2 in connecting gastric cancer cells and cancer-associated fibroblasts (CAFs) through an in vitro adhesion models and in vivo lung colonization models. The molecular mechanism underlying CLDN18.2-mediated interaction between gastric cancer cells and CAFs was identified through RNA sequencing and protein-proximity labeling techniques in vivo. Results In our own cohort, a correlation was observed between high levels of CLDN18.2 expression and advanced cancer stage, poor prognosis, and heightened infiltration of CAFs. We elucidated a pivotal role of CLDN18.2 in mediating adhesion between gastric cancer cells and CAFs, which leads to the adhesion of cancer cells to stroma tissue and facilitates the clustering of cancer cells and CAFs into embolus, enhancing gastric cancer’s metastatic progression and the risk of embolic death. Mechanistically, it was discovered that CAFs can activate adhesion and metastasis-related signaling pathways in CLDN18.2-positive gastric cancer cells. Furthermore, using an in vivo protein-proximity labeling approach, we identified S100 calcium binding protein A4 (S100A4) as a distinctive marker of CAFs that interacts with CLDN18.2 to enhance gastric cancer progression. Conclusions Our findings illuminated the role of the CLDN18.2-mediated interaction between cancer cells and CAFs in promoting gastric cancer progression and embolism, thereby providing insight into potential therapeutic avenues for CLDN18.2 positive cancers. Video Abstract

A transonic hump with a Mach number (M∞) of 0.875 was utilized to compare the prediction capabilities of RANS, URANS, IDDES, and IDDES-SLA for shock-induced separation. The results matched the experimental data concerning pressure, friction coefficients, velocity distribution, and other parameters. The improved delayed detached eddy simulation with a modified sub-grid scale (IDDES-SLA) method performed the best amongst tested numerical methods, demonstrating differences of 1.3% and 4.1% from the experimental results for separation and reattachment locations, respectively. The primary difference between IDDES and IDDES-SLA is reflected in detailed data, such as velocity and high-frequency characteristics, although both methods exhibit similar simulation capabilities for the main structural features of the flow field. The POD and PSD analyses of the flow field results demonstrated that the IDDES-SLA method was more capable of resolving higher modes of flow field.

Slt2 is an important component of the Slt2-MAPK pathway and plays critical regulatory roles in growth, cell wall integrity, melanin biosynthesis, and pathogenicity of plant fungi. AaSlt2, an ortholog of the Saccharomyces cerevisiae Slt2 gene, was identified from A. alternata in this study, and its function was clarified by knockout of the gene. The ΔAaSlt2 strain of A. alternata was found to be defective in spore morphology, vegetative growth, and sporulation. Analysis of gene expression showed that expression of the AaSlt2 gene was significantly up-regulated during infection structure formation of A. alternata on hydrophobic and pear wax extract-coated surfaces. Further tests on onion epidermis confirmed that spore germination was reduced in the ΔAaSlt2 strain, together with decreased formation of appressorium and infection hyphae. Moreover, the ΔAaSlt2 strain was sensitive to cell wall inhibitors, and showed significantly reduced virulence on pear fruit. Furthermore, cell wall degradation enzyme (CWDE) activities, melanin accumulation, and toxin biosynthesis were significantly lower in the ΔAaSlt2 strain. Overall, the findings demonstrate the critical involvement of AaSlt2 in growth regulation, stress adaptation, infection structure formation, and virulence in A. alternata.

Background/Objectives: Physiologically based pharmacokinetic (PBPK) absorption models are instrumental for assessing drug absorption prior to clinical food effect studies, though discrepancies in predictive and actual outcomes are observed. This study focused on immediate release formulations of weakly basic water-insoluble compounds, namely rivaroxaban, ticagrelor, and PB-201, to investigate factors that could improve the predictive accuracy of PBPK models regarding food effects. Methods: Comprehensive in vitro experimental results provided the basis for the development of mechanistic absorption models, which were then combined with mechanistic disposition models to predict the systemic exposure of the model drugs in both fasted and fed states. Results: The developed PBPK models showed moderate to high predictive accuracy for food effects in Caucasian populations. For the Chinese population, the ticagrelor model’s initial overestimation of fed-state absorption was addressed by updating the permeability parameters from Caco-2 cell assays to those derived from parallel artificial membrane permeability assays in FaSSIF and FeSSIF media. This refinement was also applied to the rivaroxaban and ticagrelor models, leading to a more accurate representation of absorption in Caucasians. Conclusions: This study highlights the importance of apparent permeability in enhancing the predictive accuracy of PBPK absorption models for weakly basic water-insoluble compounds. Furthermore, the precipitation of PB-201 in the two-stage transfer experiments suggests that precipitation may not be a universal phenomenon for such compounds in vivo. Consequently, the precipitation rate constant, a theoretically essential parameter, should be determined based on experimental evidence to avoid overparameterization and ensure robust predictive accuracy of PBPK models.

Laser damage in films under long-term high-temperature conditions is a significant concern for advancing laser applications. This study focused on HfO2 films prepared using the sol–gel method with HfCl4 as a precursor. It examined the effects of temperature on various properties of the films, including their optical properties, microstructure, surface morphology, absorption, and laser-induced damage threshold (LIDT). The prepared film demonstrated desirable characteristics at the high temperature of 423 K, such as high transmittance, low absorption, and high LIDT. As the duration of its high-temperature exposure increased, the LIDT of the films gradually decreased. An intriguing finding was that the film’s LIDT exhibited an exponential decay pattern with prolonged heating time. This observation could be attributed to the power-law increase in defects on both the internal and surface areas of the film as the duration of high-temperature exposure lengthened. Moreover, even after a 15-day heating period at 423 K, the film maintained an LIDT of 12.9 J/cm2, indicating its potential applicability in practical high-temperature environments. This study provided a general pattern and a universal formula for understanding the laser damage of sol–gel films at high temperatures over time. Furthermore, it opened possibilities for future developments of laser films suitable for extreme environments.

Rice (Oryza sativa L.), a globally staple food crop, frequently encounters growth, developmental, and yield limitations due to phosphate deficiency. LOW PHOSPHATE ROOT1/2 (LPR1/2) are essential genes in plants that regulate primary root growth and respond to local phosphate deficiency signals under low phosphate stress. In rice, five LPR genes, designated OsLPR1–OsLPR5 based on their sequence identity with AtLPR1, have been identified. OsLPR3 and OsLPR5 are specifically expressed in roots and induced by phosphate deficiency, contributing to rice growth, development, and the maintenance of phosphorus homeostasis under low phosphate stress. In contrast, OsLPR2 is uniquely expressed in shoots, suggesting it may have distinct functions compared with other family members. This study employed Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-associated protein 9 (CRISPR/Cas9) gene editing technology to generate oslpr2 mutant transgenic lines and subsequently investigated the effect of OsLPR2 gene knockout on rice growth, phosphate utilization, and salt stress tolerance in the seedling stage, as well as the effect of OsLPR2 gene knockout on rice development and agronomic traits in the maturation stage. The results indicated that the knockout of OsLPR2 did not significantly impact rice seedling growth or phosphate utilization, which contrasts significantly with its homologous genes, OsLPR3 and OsLPR5. However, the mutation influenced various agronomic traits at maturity, including plant height, tiller number, and seed setting rate. Moreover, the OsLPR2 mutation conferred enhanced salt stress tolerance in rice. These findings underscore the distinct roles of OsLPR2 compared with other homologous genes, establishing a foundation for further investigation into the function of the OsLPR family and the functional differentiation among its members.

Light is a key factor affecting the growth and quality formation of Dendrobium officinale Kimura et Migo. In this study, we used D. officinale under different light conditions as experimental materials to explore the key genes that regulate its polysaccharide content. In addition, we cloned the UGPase gene and validated the gene by bioinformatics analysis and real-time quantitative PCR. Compared with the natural light control group, 494, 1630 and 599 differentially expressed genes were screened under different light quality conditions of red, blue and yellow, respectively. GO and KEGG enrichment analyses of these differentially expressed genes showed that the differentially expressed genes were enriched in the light signal transduction process under different light quality conditions. Bioinformatics analyses showed that the sequences of the genes were highly conserved with the sequences of the UGPase genes of other species, and had the highest sequence similarity with Phalaenopsis, which is also a member of the orchid family. Real-time quantitative PCR results showed that red light had the most significant promoting effect on the UGPase gene of D. officinale. In this study, we applied high-throughput sequencing technology to establish a transcriptome database of D. officinale under different light conditions and obtained a large amount of transcriptional information about D. officinale. The related genes affecting the quality of D. officinale were analysed at the transcriptional level, and the D. officinale UGPase gene was cloned, and its expression was analysed in different tissues and under different light conditions.

BackgroundPatients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) usually present with multisystemic dysfunction with a wide range of clinical manifestations. When the tests for common mitochondrial DNA (mtDNA) point mutations are negative and the mtDNA defects hypothesis remains, urine epithelial cells can be used to screen the mitochondrial genome for unknown mutations to confirm the diagnosis.Case presentationA 66-year-old Chinese woman presented with symptoms of MELAS and was initially misdiagnosed with acute encephalitis at another institution. Although genetic analysis of blood lymphocyte DNA was negative, brain imaging, including magnetic resonance imaging, magnetic resonance spectroscopy, and clinical and laboratory findings, were all suggestive of MELAS. Finally, the patient was eventually diagnosed with MELAS with the mtDNA 5783G>A mutation in the MT-TC gene with a urinary sediment genetic test.ConclusionThis case report expands the genetic repertoire associated with MELAS syndrome and highlights the importance that full mtDNA sequencing should be warranted beside the analysis of classical variants when a mitochondrial disorder is highly suspected. Furthermore, urine sediment genetic testing has played a crucial role in the diagnosis of MELAS.

Purpose: Nascent geographic atrophy (nGA) refers to specific features seen on OCT B-scans, which are strongly associated with the future development of geographic atrophy (GA). This study sought to develop a deep learning model to screen OCT B-scans for nGA that warrant further manual review (an artificial intelligence [AI]-assisted approach), and to determine the extent of reduction in OCT B-scan load requiring manual review while maintaining near-perfect nGA detection performance. Design: Development and evaluation of a deep learning model. Participants: One thousand eight hundred and eighty four OCT volume scans (49 B-scans per volume) without neovascular age-related macular degeneration from 280 eyes of 140 participants with bilateral large drusen at baseline, seen at 6-monthly intervals up to a 36-month period (from which 40 eyes developed nGA). Methods: OCT volume and B-scans were labeled for the presence of nGA. Their presence at the volume scan level provided the ground truth for training a deep learning model to identify OCT B-scans that potentially showed nGA requiring manual review. Using a threshold that provided a sensitivity of 0.99, the B-scans identified were assigned the ground truth label with the AI-assisted approach. The performance of this approach for detecting nGA across all visits, or at the visit of nGA onset, was evaluated using fivefold cross-validation. Main Outcome Measures: Sensitivity for detecting nGA, and proportion of OCT B-scans requiring manual review. Results: The AI-assisted approach (utilizing outputs from the deep learning model to guide manual review) had a sensitivity of 0.97 (95% confidence interval [CI] = 0.93–1.00) and 0.95 (95% CI = 0.87–1.00) for detecting nGA across all visits and at the visit of nGA onset, respectively, when requiring manual review of only 2.7% and 1.9% of selected OCT B-scans, respectively. Conclusions: A deep learning model could be used to enable near-perfect detection of nGA onset while reducing the number of OCT B-scans requiring manual review by over 50-fold. This AI-assisted approach shows promise for substantially reducing the current burden of manual review of OCT B-scans to detect this crucial feature that portends future development of GA. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The biotoxicity of perfluoroalkyl and polyfluoroalkyl substances (PFASs) to aquatic organisms has been widely concerned. However, studies on toxic effects of PFASs are usually evaluated directly by using laboratory exposure rather than laboratory validation based on data obtained in the field. In this study, wild catfish (Silurus meridinalis) was explored on the relationship between PFASs bioaccumulation and lipid disorders. Nine and thirteen lipid metabolites were significantly associated with perfluorooctane sulfonate (PFOS) and 6:2/8:2Cl-PFESA (trade name F-53B) exposures, respectively; and the correlated lipid metabolites were the fatty acid (FA) and conjugates, FA esters, steroids, and glycerophosphate subclasses. The effects of PFASs on lipid metabolism of fish and its mechanism were further analyzed through exposure experiments. Zebrafish (Danio rerio) of different sexes underwent PFOS and F-53B exposures for 21 days at 100 ng/L and 100 μg/L. By determining gene expression levels, hepatic lipid contents, and histopathological change, the adverse effects order on lipid metabolism in male or female was 100 μg/L F-53B > 100 μg/L PFOS > 100 ng/L F-53B > 100 ng/L PFOS; the stress response in male was more intensive than that in female. PFOS and F-53B activated the peroxisome proliferator-activated receptor pathway, promoting the processes of FA and total cholesterol (T-CHO) transport, FA β-oxidation, FA synthesis, and finally induced FA and T-CHO transportation from blood into liver, then accelerated FA to FA ester transformation, and CHO into steroids. Laboratory experiments confirmed the field analysis. This study innovatively explored the adverse effects of PFOS and F-53B on lipid metabolism and their mechanisms at field and laboratory levels, highlighting concerns regarding PFASs health risks.

Summary: Background: Benefits of Intermittent fasting (IF) on health-related outcomes have been found in a range of randomised controlled trials (RCTs). Our umbrella review aimed to systematically analyze and synthesize the available causal evidence on IF and its impact on specific health-related outcomes while evaluating its evidence quality. Methods: We comprehensively searched the PubMed, Embase, Web of Science, and Cochrane databases (from inception up to 8 January 2024) to identify related systematic reviews and meta-analyses of RCTs investigating the association between IF and human health outcomes. We recalculated the effect sizes for each meta-analysis as mean difference (MD) or standardized mean difference (SMD) with corresponding 95% confidence intervals (CIs). Subgroup analyses were performed for populations based on three specific status: diabetes, overweight or obesity, and metabolic syndrome. The quality of systematic reviews was evaluated using A Measurement Tool to Assess Systematic Reviews (AMSTAR), and the certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) system. This study is registered with PROSPERO (CRD42023382004). Findings: A total of 351 associations from 23 meta-analyses with 34 health outcomes were included in the study. A wide range of outcomes were investigated, including anthropometric measures (n = 155), lipid profiles (n = 83), glycemic profiles (n = 57), circulatory system index (n = 41), appetite (n = 9), and others (n = 6). Twenty-one (91%) meta-analyses with 346 associations were rated as high confidence according to the AMSTAR criteria. The summary effects estimates were significant at p

ABSTRACTIn the era of Earth Observation (EO) big data, interactive spatiotemporal aggregation analysis is a critical tool for exploring geographic patterns. However, existing methods are inefficient and complex. Their interactive performance greatly depends on large-scale computing resources, especially data cube infrastructure. In this study, from a green computing perspective, we propose a lightweight data cube model based on the preaggregation concept, in which the frequency histogram of EO data is employed as a specific measure. The cube space was divided into lattice pyramids by the Google S2 grid system, and histogram statistics of the EO data were injected into in-memory cuboids. Therefore, exploratory aggregation analysis of EO datasets could be rapidly converted into multidimensional-view query processes. We implemented the prototype system on a local PC and conducted a case study of global vegetation index aggregation. The experiments showed that the proposed model is smaller, faster and consumes less energy than ArcGIS Pro and XCube, and facilitates green computing strategies involving a cube infrastructure. Due to the standalone mode, larger dataset will result in longer cube building time with indexing latency. The efficiency of the approach comes at the expense of accuracy, and the inherent uncertainties were examined in this paper.

Skin cutaneous melanoma (SKCM) is one of the most malignant forms of skin cancer, characterized by its high metastatic potential and low cure rate in advanced stages. Despite advancements in clinical therapies, the overall cure rate for SKCM remains low due to its resistance to conventional treatments. Inflammation is associated with the activation and regulation of inflammatory responses and plays a crucial role in the immune system. It has been implicated in various physiological and pathological processes, including cancer. However, the mechanisms of inflammasome activation in SKCM remain largely unexplored. In this study, we quantified the expression level of six inflammasome-related gene sets using transcriptomic data from SKCM patients. As a result, we found that inflammasome features were closely associated with various clinical characteristics and served as a favorable prognostic factor for patients. A functional enrichment analysis revealed the oncogenic role of inflammasome features in SKCM. Unsupervised clustering was applied to identify immune clusters and inflammatory subtypes, revealing a significant overlap between immune cluster 4 and SKCM subtype 2. The CASP1, GSDMD, NLRP3, IL1B, and IL18 features could predict immune checkpoint blockade therapy response in various SKCM cohorts. In conclusion, our study highlighted the significant association between the inflammasome and cancer treatment. Understanding the role of inflammasome signaling in SKCM pathology can help identify potential therapeutic targets and improve patient prognosis.

The water oxidation reaction in photosystem II (PS II) produces most of the molecular oxygen in the atmosphere, which sustains life on Earth, and in this process releases four electrons and four protons that drive the downstream process of CO2 fixation in the photosynthetic apparatus. The catalytic center of PS II is an oxygen-bridged Mn4Ca complex (Mn4CaO5) which is progressively oxidized upon the absorption of light by the chlorophyll of the PS II reaction center, and the accumulation of four oxidative equivalents in the catalytic center results in the oxidation of two waters to dioxygen in the last step. The recent emergence of X-ray free-electron lasers (XFELs) with intense femtosecond X-ray pulses has opened up opportunities to visualize this reaction in PS II as it proceeds through the catalytic cycle. In this review, we summarize our recent studies of the catalytic reaction in PS II by following the structural changes along the reaction pathway via room-temperature X-ray crystallography using XFELs. The evolution of the electron density changes at the Mn complex reveals notable structural changes, including the insertion of OX from a new water molecule, which disappears on completion of the reaction, implicating it in the O—O bond formation reaction. We were also able to follow the structural dynamics of the protein coordinating with the catalytic complex and of channels within the protein that are important for substrate and product transport, revealing well orchestrated conformational changes in response to the electronic changes at the Mn4Ca cluster.

Abstract Circular RNAs (circRNAs) play key roles in colorectal cancer (CRC) progression, but little is known about the biological functions of hsa_circRNA_001676 in CRC. Therefore, we explored the potential role of hsa_circRNA_001676 in CRC development. RT-qPCR was performed to determine hsa_circRNA_001676, miR-556-3p and Ras-GTPase-activating SH3 domain-binding-proteins 2 (G3BP2) levels in CRC tissues. Meanwhile, to evaluate the roles of hsa_circRNA_001676, miR-556-3p and G3BP2 on CRC, functional analysis of cell proliferation, migration and stemness were then performed. Our results showed that compared to normal tissues, hsa_circRNA_001676 and G3BP2 level was elevated, but miR-556-3p level was reduced in CRC tissues. Additionally, luciferase reporter results showed that hsa_circRNA_001676 was shown to target miR-556-3p, and G3BP2 was targeted by miR-556-3p. Hsa_circRNA_001676 or G3BP2 overexpression promoted CRC cell proliferation and migration. Conversely, miR-556-3p overexpression suppressed CRC cell proliferation and migration. Moreover, deficiency of hsa_circRNA_001676 or G3BP2 repressed the CRC cell proliferation, migration and stemness. Meanwhile, hsa_circRNA_001676 deficiency obviously reduced tumor growth and stemness in a CRC mouse xenograft model. Furthermore, hsa_circRNA_001676 deficiency notably reduced G3BP2 level, but elevated miR-556-3p level in tumor tissues from tumor-bearing mice. Mechanistically, hsa_circRNA_001676 targeted miR-556-3p to increase G3BP2 level, contributing to the progression of CRC. Collectively, hsa_circRNA_001676 was able to accelerate proliferation, migration and stemness in CRC through regulating miR-556-3p/G3BP2 axis, suggesting that hsa_circRNA_001676 may become a potential therapeutic target in treating CRC.

Ordovician karst water in the North China coalfield is a green energy source that integrates water and heat. Therefore, it is of great significance for the exploration and development of geothermal resources to clarify the formation and evolution characteristics of the recharge source, geothermal reservoir environment, flow and circulation affected by coal mining. The Huaibei coalfield, one of the typical North China type coalfield, was selected as the study area on the basis of full understanding of its geological, hydrogeological and geothermal geological conditions. The hydrochemistry and isotope data and the previous study results were jointly employed to reveal the hydrochemical characteristics of geothermal water and the mechanism of water-rock interactions. Also, they were used to identify the recharge source of geothermal water, evaluate the temperature of geothermal reservoir and the depth of geothermal water circulation, and propose the formation and evolution model of geothermal water in the study area. The results show that the geothermal water of the Zhahe mining district is mainly recharged by precipitation infiltration, and the hydrochemical type and water-rock interaction are dominated by HCO3−Ca and leaching dissolution respectively, indicating that the geothermal water in this area has a rapid renewal rate and a short circulation path. In the Suxian and Linhuan mining districts, the geothermal water is only recharged by precipitation with evaporation infiltration in some areas and is obviously mixed with ancient groundwater. There are various hydrochemical types including SO4−Ca, SO4−Ca·Mg, HCO3·SO4−Ca·Mg, SO4−Ca·Na, Cl·SO4−Na, Cl−Na, etc. Meanwhile, the water-rock interactions are dominated by leaching and dissolution and cation alternating adsorption (positive and negative), accompanied by dedolomitization, indicating that the geothermal water in this area has a long residence time, a long circulation path, and a more closed reservoir environment. The thermal reservoir temperature range from 34.8 to 69.1℃ according to the calculation of quartz and improved SiO2 geothermometer, and the circulation depth range from 881 to 2281 m. The formation and evolution of karst geothermal water in the Huaibei coalfield is obviously controlled by structure, and there are significant spatial differences in geothermal water circulation and renewal capacity, reservoir temperature, circulation depth and hydrochemical environment. Therefore, the development and utilization of karst geothermal resources should comprehensively consider the regional characteristics.

Abstract Background Histone acetylation is involved in the regulation of stress responses in multiple organisms. Dermacentor silvarum is an important vector tick species widely distributed in China, and low temperature is a crucial factor restricting the development of its population. However, knowledge of the histone acetyltransferases and epigenetic mechanisms underlying cold-stress responses in this tick species is limited. Methods Histone acetyltransferase genes were characterized in D. silvarum, and their relative expressions were determined using qPCR during cold stress. The association and modulation of histone acetyltransferase genes were further explored using RNA interference, and both the H3K9 acetylation level and relative expression of KAT5 protein were evaluated using western blotting. Results Three histone acetyltransferase genes were identified and named as DsCREBBP, DsKAT6B, and DsKAT5. Bioinformatics analysis showed that they were unstable hydrophilic proteins, characterized by the conserved structures of CBP (ZnF_TAZ), PHA03247 super family, Creb_binding, and MYST(PLN00104) super family. Fluorescence quantitative PCR showed that the expression of DsCREBBP, DsKAT6B, and DsKAT5 increased after 3 days of cold treatment, with subsequent gradual decreases, and was lowest on day 9. Western blotting showed that both the H3K9 acetylation level and relative expression of KAT5 in D. silvarum increased after treatment at − 4, 4, and 8 °C for 3 and 6 days, whereas they decreased significantly after a 9-day treatment. RNA interference induced significant gene silencing, and the mortality rate of D. silvarum significantly increased at the respective semi-lethal temperatures. Conclusion These results imply that histone acetyltransferases play an important role in tick adaptation to low temperatures and lay a foundation for further understanding of the epigenetic regulation of histone acetylation in cold-stressed ticks. Further research is needed to elucidate the mechanisms underlying histone acetylation during cold stress in ticks. Graphical Abstract

Abstract Background Primary biliary cholangitis (PBC) is an autoimmune liver disease, whose etiology is yet to be fully elucidated. Currently, ursodeoxycholic acid (UDCA) is the only first-line drug. However, 40% of PBC patients respond poorly to it and carry a potential risk of disease progression. So, in this study, we aimed to explore new biomarkers for risk stratification in PBC patients to enhance treatment. Methods We first downloaded the clinical characteristics and microarray datasets of PBC patients from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified and subjected to enrichment analysis. Hub genes were further validated in multiple public datasets and PBC mouse model. Furthermore, we also verified the expression of the hub genes and developed a predictive model in our clinical specimens. Results A total of 166 DEGs were identified in the GSE79850 dataset, including 95 upregulated and 71 downregulated genes. Enrichment analysis indicated that DEGs were significantly enriched in inflammatory or immune-related process. Among these DEGs, 15 risk-related genes were recognized and further validated in the GSE119600 cohort. Then, TXNIP, CD44, ENTPD1, and PDGFRB were identified as candidate hub genes. Finally, we proceeded to the next screening with these four genes in our serum samples and developed a three-gene panel. The gene panel could effectively identify those patients at risk of disease progression, yielding an AUC of 0.777 (95% CI, 0.657–0.870). Conclusions In summary, combining bioinformatics analysis and experiment validation, we identified TXNIP, CD44, and ENTPD1 as promising biomarkers for risk stratification in PBC patients.

Building envelopes and indoor environments exhibit thermal inertia, forming a virtual energy storage system in conjunction with the building air conditioner (AC) system. This system represents a current demand response resource for building electricity use. Thus, this study centers on the CatBoost algorithm within machine learning (ML) technology, utilizing the LASSO regression model for feature selection and applying the Optuna framework for hyperparameter optimization (HPO) to develop a cost-optimal control method for minimizing building AC loads. This method addresses the challenges associated with traditional load forecasting and control methods, which are often impacted by environmental temperature, building parameters, and user behavior uncertainties. These methods struggle to accurately capture the complex dynamics and nonlinear relationships of AC operations, making it difficult to devise AC operation and virtual energy storage scheduling strategies effectively. The proposed method was applied and validated using a case study of an office building in Nanjing, China. The prediction results showed coefficient of variation in root mean square error (CV-RMSE) values of 6.4% and 2.2%. Compared with the original operating conditions, the indoor temperature remained within a comfortable range, the AC load was reduced by 5.25%, and the operating energy costs were reduced by 24.94%. These results demonstrate that the proposed method offers improved computational efficiency, enhanced model performance, and economic benefits.

Low temperature combined with low light (LL) is an important factor limiting pepper quality and yield. ‘Hang Jiao No. 2′ were used as experimental materials, and different concentrations of MeJA (T1 (0 μM), T2 (100 μM), T3 (150 μM), T4 (200 μM), T5 (250 μM) and T6 (300 μM)) were sprayed under LL stress to explore the positive effect of exogenous methyl jasmonate (MeJA) on peppers under LL stress. The photosynthetic properties, osmoregulatory substance, reactive oxygen species, antioxidant enzyme activities, and related gene expressions of the peppers were measured. Our results demonstrated that 200 μM MeJA treatment significantly increased chlorophyll content, light quantum flux per active RC electron transfer (Eto/RC), maximum captured photonic flux per active RC (TRo/RC), energy flux for electron transfer in the excitation cross section (Eto/CSm), energy flux captured by absorption in the excitation cross section (TRo/CSm), soluble protein, and soluble sugar content. Moreover, it significantly improved the maximum photochemical efficiency of PSII (Fv/Fm) and performance index based on absorbed light energy (PI (abs)) by 56.77% and 67.00%, respectively, and significantly decreased malondialdehyde (MDA) content and relative conductivity by 30.55% and 28.17%, respectively. Additionally, antioxidant enzyme activities were elevated, and the expression of the related genes was activated in pepper seedlings under stress, leading to a significant reduction in reactive oxygen species content. In conclusion, our findings confirmed that 200 μM MeJA could reduce the injury of LL to pepper leaves to the photosynthetic organs of pepper leaves, protect the integrity of the cell membrane, and further improve the tolerance of pepper seedlings to LL.

Due to the limited supply of autologous bone grafts, there is a need to develop more bone matrix materials to repair bone defects. Xenograft bone is expected to be used for clinical treatment due to its exact structural similarity to natural bone and its high biocompatibility. In this study, decellularized antler cancellous bone matrix (DACB) was first prepared, and then the extent of decellularization of DACB was verified by histological staining, which demonstrated that it retained the extracellular matrix (ECM). The bioactivity of DACB was assessed using C3H10T1/2 cells, revealing that DACB enhanced cell proliferation and facilitated cell adhesion and osteogenic differentiation. When evaluated by implanting DACB into nude mice, there were no signs of necrosis or inflammation in the epidermal tissues. The bone repair effect of DACB was verified in vivo using sika deer during the antler growth period as an animal model, and the molecular mechanisms of bone repair were further evaluated by transcriptomic analysis of the regenerated tissues. Our findings suggest that the low immunogenicity of DACB enhances the production of bone extracellular matrix components, leading to effective osseointegration between bone and DACB. This study provides a new reference for solving bone defects.

Abstract Anoikis is a unique form of apoptosis associated with vascularization and distant metastasis in cancer. Eliminating anoikis resistance in tumor cells could be a promising target for improving the prognosis of terminal cancer patients. However, current studies have not elaborated on the prognosis effect of anoikis-related long non-coding RNAs (lncRNAs) in cutaneous melanoma. Pre-processed data, including RNA sequences and clinical information, were retrieved from TCGA and GTEx databases. After a series of statistical analyses, anoikis-related lncRNAs with prognostic significance were identified, and a unique risk signature was constructed. Risk scores were further analyzed in relation to the tumor microenvironment, tumor immune dysfunction and exclusion, immune checkpoint genes, and RNA methylation genes. The indicators were also used to predict the potentially sensitive anti-cancer drugs. An anoikis-related lncRNAs risk signature consisting of LINC01711, POLH-AS1, MIR205HG, and LINC02416 was successfully established in cutaneous melanoma. Overall survival and progression-free survival of patients were strongly linked with the risk score, independently of other clinical factors. The low-risk group exhibited a more beneficial immunological profile, was less affected by RNA methylation, and was more sensitive to the majority of anti-cancer drugs, all of which indicated a better prognostic outcome. The 4 hub lncRNAs may be fundamental to studying the mechanism of anoikis in cutaneous melanoma and provide personalized therapy for salvaging drug resistance.

Abstract Supercritical airfoils are critical components in the design of commercial wide-body aircraft wings due to their ability to enhance aerodynamic performance in transonic flow regimes. However, traditional design methods for supercritical airfoils can be time-consuming and require significant manual effort, not to mention the high cost associated with computational fluid dynamics analysis. To address these challenges, this paper introduces a highly automated approach for supercritical airfoil design, called Evolutionary Generative Design (EvoGD). The EvoGD approach is based on the framework of Evolutionary Computation and employs a series of sophisticated data-driven generative models incorporated with physical information to iteratively refine initial airfoil shapes, resulting in improved aerodynamic performances and reduced constraint violations. Moreover, to speed up the evaluation of the generated airfoils, a series of accurate and efficient data-driven predictors are utilized. The efficacy of the EvoGD approach was demonstrated through experiments on a dataset of 501 supercritical airfoils, including one baseline design and 500 randomly perturbed airfoils. On average, the generated airfoils showed improved performance in terms of buffet lift coefficient, cruise lift-to-drag ratio, and thickness by 5%, 4%, and 1%, respectively. The best generated airfoil outperformed the baseline design in terms of critical buffet lift coefficient and cruise lift-to-drag ratio by 7.1% and 6.4%, respectively. The entire design process was completed in less than an hour on a personal computer, highlighting the high efficiency and scalability of the EvoGD approach.

Abstract Background Although most patients can recover from SARS-CoV-2 infection during the short-term, the long-term effects of COVID-19 on the brain remain explored. Functional MRI (fMRI) could potentially elucidate or otherwise contribute to the investigation of the long COVID syndrome. A lower fMRI response would be translated into decreased brain activity or delayed signal transferring reflecting decreased connectivity. This research aimed to investigate the long-term alterations in the local (regional) brain activity and remote (interregional) functional connection in recovered COVID-19. Methods Thirty-five previously hospitalized COVID-19 patients underwent 3D T1weighed imaging and resting-state fMRI at 6-month follow-up, and 36 demographic-matched healthy controls (HCs) were recruited accordingly. The amplitude of low-frequency fluctuation (ALFF) and seed-based functional connectivity (FC) was used to assess the regional intrinsic brain activity and the influence of regional disturbances on FC with other brain regions. Spearman correlation analyses were performed to evaluate the association between brain function changes and clinical variables. Results The incidence of neurosymptoms (6/35, 17.14%) decreased significantly at 6-month follow-up, compared with COVID-19 hospitalization stage (21/35, 60%). Compared with HCs, recovered COVID-19 exhibited higher ALFF in right precuneus, middle temporal gyrus, middle and inferior occipital gyrus, lower ALFF in right middle frontal gyrus and bilateral inferior temporal gyrus. Furthermore, setting seven abnormal activity regions as seeds, we found increased FC between right middle occipital gyrus and left inferior occipital gyrus, and reduced FC between right inferior occipital gyrus and right inferior temporal gyrus/bilateral fusiform gyrus, and between right middle frontal gyrus and right middle frontal gyrus/ supplementary motor cortex/ precuneus. Additionally, abnormal ALFF and FC were associated with clinical variables. Conclusions COVID-19 related neurological symptoms can self heal over time. Recovered COVID-19 presented functional alterations in right frontal, temporal and occipital lobe at 6-month follow-up. Most regional disturbances in ALFF were related to the weakening of short-range regional interactions in the same brain function.

Abstract In vehicular edge computing, the low-delay services are invoked by the vehicles from the edge clouds while the vehicles moving on the roads. Because of the insufficiency of computing capacity and storage resource for edge clouds, a single edge cloud cannot handle all the services, and thus the efficient service deployment strategy in multi edge clouds should be designed according to the service demands. Noticed that the service demands are dynamic in temporal, and the inter-relationship between services is a non-negligible factor for service deployment. In order to address the new challenges produced by these factors, a collaborative service on-demand dynamic deployment approach with deep reinforcement learning is proposed, which is named CODD-DQN. In our approach, the number of service request of each edge clouds are forecasted by a time-aware service demands prediction algorithm, and then the interacting services are discovered through the analysis of service invoking logs. On this basis, the service response time models are constructed to formulated the problem, aiming to minimize service response time with data transmission delay between services. Furthermore, a collaborative service dynamic deployment algorithm with DQN model is proposed to deploy the interacting services. Finally, the real-world dataset based experiments are conducted. The results show our approach can achieve lowest service response time than other algorithms for service deployment.

Abstract Objectives This study was performed in the frame of a more extensive study dedicated to the integrated analysis of the single-cell transcriptome and chromatin accessibility datasets of peripheral blood mononuclear cells (PBMCs) with a large-scale GWAS of 45 complex traits in Chinese Holstein cattle. Lipopolysaccharide (LPS) is a crucial mediator of chronic inflammation to modulate immune responses. PBMCs include primary T and B cells, natural killer (NK) cells, monocytes (Mono), and dendritic cells (DC). How LPS stimulates PBMCs at the single-cell level in dairy cattle remains largely unknown. Data description We sequenced 30,756 estimated single cells and mapped 26,141 of them (96.05%) with approximately 60,075 mapped reads per cell after quality control for four whole-blood treatments (no, 2 h, 4 h, and 8 h LPS) by single-cell RNA sequencing (scRNA-seq) and single-cell sequencing assay for transposase-accessible chromatin (scATAC-seq). Finally, 7,107 (no), 9,174 (2 h), 6,741 (4 h), and 3,119 (8 h) cells were generated with ~ 15,000 total genes in the whole population. Therefore, the single-cell transcriptome and chromatin accessibility datasets in this study enable a further understanding of the cell types and functions of PBMCs and their responses to LPS stimulation in vitro.

Abstract The two most prevalent subtypes of epithelial ovarian carcinoma (EOC) are ovarian clear cell carcinoma (OCCC) and high-grade serous ovarian carcinoma (HGSC). Patients with OCCC have a poor prognosis than those with HGSC due to chemoresistance, implying the need for novel treatment target. In this study, we applied single-cell RNA sequencing (scRNA-seq) together with bulk RNA-seq data from the GEO (Gene Expression Omnibus) database (the GSE189553 dataset) to characterize and compare tumor heterogeneity and cell-level evolution between OCCC and HGSC samples. To begin, we found that the smaller proportion of an epithelial OCCC cell subset in the G2/M phase might explain OCCC chemoresistance. Second, we identified a possible pathogenic OCCC epithelial cell subcluster that overexpresses LEFTY1. Third, novel biomarkers separating OCCC from HGSC were discovered and subsequently validated on a wide scale using immunohistochemistry. Amine oxidase copper containing 1 (AOC1) was preferentially expressed in OCCC over HGSC, while S100 calcium-binding protein A2 (S100A2) was detected less frequently in OCCC than in HGSC. In addition, we discovered that metabolic pathways were enriched in the epithelial compartment of the OCCC samples. In vitro experiments verified that inhibition of oxidative phosphorylation or glycolysis pathways exerted direct antitumor effects on both OCCC and HGSC cells, while targeting glutamine metabolism or ferroptosis greatly attenuated chemosensitivity only in OCCC cells. Finally, to determine whether there were any variations in immune cell subsets between OCCC and HGSC, data from scRNA-seq and mass cytometry were pooled for analysis. In summary, our work provides the first holistic insights into the cellular and molecular distinctions between OCCC and HGSC and is a valuable source for discovering new targets to leverage in clinical treatments to improve the poor prognosis of patients with OCCC.

Abstract Corruption and anti-corruption efforts are intertwined with political and economic concerns. From an economic and political perspective, as the government strives to enhance its governance capabilities, it becomes crucial to consider the costs of anti-corruption supervision and the losses incurred from corruption. This evaluation is essential for formulating a scientifically sound anti-corruption strategy that maximizes government benefits. To address this issue, the paper presents a model that incorporates levels of supervision and associated costs. The findings reveal that in the case of homogeneous officials, the optimal level of supervisory input, which maximizes government benefit, is nearly zero when per capita income is low due to budgetary constraints on anti-corruption control. However, as per capita income reaches a certain threshold, the optimal level of supervisory input suddenly rises to its maximum and decreases as per capita income increases. Alternatively, if the government adopts a zero-tolerance approach towards corruption and provides adequate remuneration to its employees, ensuring that all competent authorities can resist corruption, then corruption can be eliminated. Moreover, when officials exhibit heterogeneity in terms of their honesty levels, certain conditions give rise to a middle per capita income range, resulting in an optimal level of supervisory input that leads to a phenomenon known as “partial corruption.” During this phase, the wages paid by the government to its employees promote honesty, preventing them from engaging in corruption. However, they are unable to curb the corrupt activities of more dishonest officials. To some extent, this model also explains the challenges associated with eradicating corruption in several middle-income countries.

Abstract PB‐201 is the second glucokinase activator in the world to enter the phase III clinical trials for the treatment of type 2 diabetes mellitus (T2DM). Combined with the efficacy advantages and the friendly absorption, distribution, metabolism, and excretion characteristics, the indication population of PB‐201 will be broad. Because the liver is the primary organ for PB‐201 elimination, and the elderly account for 20% of patients with T2DM, it is essential to estimate PB‐201 exposure in specific populations to understand the pharmacokinetic characteristics and avoid hypoglycemia. Despite the limited contribution of CYP3A4 to PB‐201 metabolism in vivo, the dual effects of nonspecific inhibitors/inducers on PB‐201 (substrate for CYP3A4 and CYP2C9 isoenzymes) exposure under fasted and fed states also need to be evaluated to understand potential risks of combination therapy. To grasp the unknown information, the physiologically‐based pharmacokinetic (PBPK) model was first developed and the influence of internal and external factors on PB‐201 exposure was evaluated. Results are shown that the predictive performance of the mechanistic PBPK model meets the predefined criteria, and can accurately capture the absorption and disposition characteristics. Impaired liver function and age‐induced changes in physiological factors may significantly increase the exposure under fasted state by 36%–158% and 48%–82%, respectively. The nonspecific inhibitor (fluconazole) and inducer (rifampicin) may separately increase/decrease PB‐201 systemic exposure by 44% and 58% under fasted state, and by 78% and 47% under fed state. Therefore, the influence of internal and external factors on PB‐201 exposure deserves attention, and the precision dose can be informed in future clinical studies based on the predicted results.

Abstract Transient receptor potential (TRP) channels are sensors for a variety of cellular and environmental signals. Mammals express a total of 28 different TRP channel proteins, which can be divided into seven subfamilies based on amino acid sequence homology: TRPA (Ankyrin), TRPC (Canonical), TRPM (Melastatin), TRPML (Mucolipin), TRPN (NO-mechano-potential, NOMP), TRPP (Polycystin), TRPV (Vanilloid). They are a class of ion channels found in numerous tissues and cell types and are permeable to a wide range of cations such as Ca2+, Mg2+, Na+, K+, and others. TRP channels are responsible for various sensory responses including heat, cold, pain, stress, vision and taste and can be activated by a number of stimuli. Their predominantly location on the cell surface, their interaction with numerous physiological signaling pathways, and the unique crystal structure of TRP channels make TRPs attractive drug targets and implicate them in the treatment of a wide range of diseases. Here, we review the history of TRP channel discovery, summarize the structures and functions of the TRP ion channel family, and highlight the current understanding of the role of TRP channels in the pathogenesis of human disease. Most importantly, we describe TRP channel-related drug discovery, therapeutic interventions for diseases and the limitations of targeting TRP channels in potential clinical applications.

Abstract Aim The aim of the study was to investigate the correlation between fear of COVID‐19 and mental health of nurses and the effects of psychological capital and burnout in this relation. Design A cross‐sectional study. Methods The online surveys were conducted among mainland Chinese nurses. Participants (n = 445; average age 32.89 ± 6.76 years) completed an online‐questionnaire based on the Fear of COVID‐19 Scale, the Psychological Capital Scale, Maslach Burnout Inventory Human Services Survey for Medical Professionals Scale and the 12‐Item Short Form Health Survey. Data analysis was conducted by Pearson's correlation analysis, Harman single‐factor test and the bootstrap method for mediating effect testing. Results (1) The study demonstrated a significant direct effect of fear of COVID‐19 on nurses' mental health, as well as on mediating factors such as burnout and psychological capital. (2) Regression analyses confirmed that while psychological capital bolstered mental health, burnout undermined it, with fear of COVID‐19 further imposing a negative influence. (3) Fear of COVID‐19 exerted an effect on the mental health of nurses by the independent and chain intermediary functions of psychological capital and burnout, resulting in a total mediating effect of −0.233.

Abstract Background Inflammatory bowel diseases (IBDs) pose significant challenges in terms of treatment non‐response, necessitating the development of novel therapeutic approaches. Although biological medicines that target TNF‐α (tumour necrosis factor‐α) have shown clinical success in some IBD patients, a substantial proportion still fails to respond. Methods We designed bispecific nanobodies (BsNbs) with the ability to simultaneously target human macrophage‐expressed membrane TNF‐α (hmTNF‐α) and IL‐23. Additionally, we fused the constant region of human IgG1 Fc (hIgG1 Fc) to BsNb to create BsNb‐Fc. Our study encompassed in vitro and in vivo characterization of BsNb and BsNb‐Fc. Results BsNb‐Fc exhibited an improved serum half‐life, targeting capability and effector function than BsNb. It's demonstrated that BsNb‐Fc exhibited superior anti‐inflammatory effects compared to the anti‐TNF‐α mAb (infliximab, IFX) combined with anti‐IL‐12/IL‐23p40 mAb (ustekinumab, UST) by Transwell co‐culture assays. Notably, in murine models of acute colitis brought on by 2,4,6‐trinitrobenzene sulfonic acid（TNBS) and dextran sulphate sodium (DSS), BsNb‐Fc effectively alleviated colitis severity. Additionally, BsNb‐Fc outperformed the IFX&UST combination in TNBS‐induced colitis, significantly reducing colon inflammation in mice with colitis produced by TNBS and DSS. Conclusion These findings highlight an enhanced efficacy and improved biostability of BsNb‐Fc, suggesting its potential as a promising therapeutic option for IBD patients with insufficient response to TNF‐α inhibition. Key points A bispecific nanobody (BsNb) was created to target TNF‐α and IL‐23p19, exhibiting high affinity and remarkable stability. BsNb‐Fc inhibited the release of cytokines in CD4+T cells during co‐culture experiments. BsNb‐Fc effectively alleviated colitis severity in mouse model with acute colitis induced by DSS or TNBS, outperforming the IFX&UST combination.

BackgroundDiabetic peripheral neuropathy (DPN) contributes to disability and imposes heavy burdens, while subclinical DPN is lack of attention so far. We aimed to investigate the relationship between vitamin D and distinct subtypes of subclinical DPN in type 2 diabetes (T2DM) patients.MethodsThis cross-sectional study included 3629 T2DM inpatients who undertook nerve conduction study to detect subclinical DPN in Zhongshan Hospital between March 2012 and December 2019. Vitamin D deficiency was defined as serum 25-hydroxyvitamin D (25(OH)D) level

Acute generalized pustular psoriasis (GPP) is a serious illness. Despite various treatment methods, there is still lack of effective treatment plans for refractory cases with multiple comorbidities. This case report presents a 67-year-old woman with acute GPP, stage 4 chronic kidney disease (CKD), type 2 diabetes, and cardiovascular disease, in whom skin symptom disappearance and kidney function improvement were observed after the use of oral tacrolimus as the sole therapy. This is the first report on the application of tacrolimus in the treatment of acute GPP, especially refractory acute GPP. The successful treatment indicates that there are shared immune pathways between acute GPP and CKD, and the pathways can be interdicted by tacrolimus. Further studies are needed to optimize the therapy to maximize efficacy and minimize toxicity.

BackgroundPorcine deltacoronavirus (PDCoV), a novel swine enteropathogenic coronavirus, challenges the global swine industry. Currently, there are no approaches preventing swine from PDCoV infection.MethodsA new PDCoV strain named JS2211 was isolated. Next, the dimer receptor binding domain of PDCoV spike protein (RBD-dimer) was expressed using the prokaryotic expression system, and a novel nanoparticle containing RBD-dimer and ferritin (SC-Fe) was constructed using the SpyTag/SpyCatcher system. Finally, the immunoprotection of RBD-Fe nanoparticles was evaluated in mice.ResultsThe novel PDCoV strain was located in the clade of the late Chinese isolate strains and close to the United States strains. The RBD-Fe nanoparticles were successfully established. Immune responses of the homologous prime-boost regime showed that RBD-Fe nanoparticles efficiently elicited specific humoral and cellular immune responses in mice. Notably, high level PDCoV RBD-specific IgG and neutralizing antibody (NA) could be detected, and the histopathological results showed that PDCoV infection was dramatically reduced in mice immunized with RBD-Fe nanoparticles.ConclusionThis study effectively developed a candidate nanoparticle with receptor binding domain of PDCoV spike protein that offers protection against PDCoV infection in mice.