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Liver cirrhosis poses a significant global health burden, with over 100 million cases worldwide and 2 million annual deaths. Despite advances in prognostic tools like MELD 3.0, their performance remains suboptimal. The pan-immune-inflammation value (PIV), a novel biomarker of systemic inflammation, has shown prognostic utility in chronic diseases but remains underexplored in cirrhosis. This study evaluates PIV’s predictive value for mortality in critically ill cirrhotic patients and its synergy with MELD 3.0. Using data from the MIMIC-IV database, we analyzed 2,399 critically ill cirrhotic patients. PIV was calculated as neutrophils × platelets × monocytes/lymphocytes. Primary and secondary endpoints were 28-day and 365-day all-cause mortality, respectively. Multivariable Cox models, restricted cubic splines, and time-dependent ROC analyses, calibration curves, and clinical decision curve analyses were employed to assess associations and predictive performance. Patients in the highest PIV quartile (Q4) exhibited older age, more comorbidities, and worse metabolic profiles compared to Q1. PIV demonstrated a J-shaped association with mortality: Q4 had 0.51-fold higher 28-day mortality than Q1 (adjusted HR = 1.51, P  < 0.001). The PIV-MELD 3.0 composite model outperformed individual markers, with AUCs of 69.5 (95% CI:0.68–0.71) (28-day) and 69.4 (95% CI:0.69–0.70) (365-day). Non-linear analysis revealed a J-shaped threshold effect with cut-off values of 3.33 (28-day) and 3.13 (365-day). Calibration curves and sensitivity analysis confirmed the superiority of the PIV combined with the MELD 3.0 model. Finally, sensitivity, subgroup, and external validation analyses further demonstrated the robustness of the association between PIV and mortality risk. PIV independently predicts short- and long-term mortality in cirrhotic patients, exhibiting a dose-response relationship. Integration with MELD 3.0 enhances risk stratification, offering a cost-effective tool for clinical decision-making. Prospective studies are warranted to validate these findings.

Background Diet may influence susceptibility of human papillomavirus (HPV) infection by affecting inflammation and immunity. However, the association between HPV infection and the inflammatory potential of diet has not been investigated. The research aimed to examine the correlation between HPV status and the dietary inflammatory index (DII ® ). Methods We utilized data from the National Health and Nutrition Examination Survey (NHANES) 2003–2016 to investigate the correlation between DII and HPV status among 9,256 women aged 18–59 years. DII scores were calculated based on 24-hour dietary recall interviews. The association between HPV status and DII was analyzed using weighted logistic regression and restricted cubic spline (RCS). Results Women with HPV infection exhibited higher DII scores than those without HPV infection. An increased likelihood of HPV infection was found to be significantly associated with higher DII scores (OR = 1.05, 95% CI: 1.01–1.09, P  = 0.021), after full multivariate adjustment. Compared with the lowest tertile of DII scores, the ORs (95% CIs) for HPV infection were 1.20 (1.01, 1.42) and 1.27 (1.07, 1.51) for the second and third tertiles, respectively ( P for trend = 0.006). RCS analysis showed a U-shaped relationship between DII and HPV infection, with a breakpoint identified at 0.13. Conclusions Our findings suggest that a pro-inflammatory diet is associated with an increased likelihood of HPV infection among women in the United States. Dietary interventions to reduce inflammation may help prevent HPV infection and related diseases.

In view of the large randomness, redundant path nodes, and low search efficiency of RRT-connect in a complex obstacle environment, this study intends to develop a path-planning method combining RRT-connect and Informed RRT*. First, to solve the problem of large sampling randomness, the Informed RRT* algorithm is combined to adopt a simpler rectangle and limit the sampling range to the rectangle. Second, for the poor quality of the search path, the dynamic step size is used for growth extension, the reverse greedy algorithm is used to delete redundant nodes, the spline curve is used to smooth the path such that the position meets the cubic spline curve and the speed meets the quadratic spline curve, and the final path is optimized. Finally, the proposed algorithm is verified in the simulation and real world using a self-developed quadrupedal robot. Compared with the original RRT-connect algorithm, the first solution time, total number of nodes, and initial path cost were reduced by more than 11%, 8.5%, and 2.5%, respectively.

Antimicrobial resistance has been seriously threatening human health, and discovering new antimicrobial agents from the natural resource is still an important pathway among various strategies to prevent resistance. Guanidine-containing polyhydroxyl macrolides, containing a polyhydroxyl lactone ring and a guanidyl side chain, can be produced by many actinomycetes and have been proved to possess many bioactivities, especially broad-spectrum antibacterial and antifungal activities. To explore the potential of these compounds to be developed into new antimicrobial agents, a review on their structural diversities, spectroscopic characterizations, bioactivities, acute toxicities, antimicrobial mechanisms, and the structure-activity relationship was first performed based on the summaries and analyses of related publications from 1959 to 2019. A total of 63 guanidine-containing polyhydroxyl macrolides were reported, including 46 prototype compounds isolated from 33 marine and terrestrial actinomycetes and 17 structural derivatives. Combining with their antimicrobial mechanisms, structure-activity relationship analyses indicated that the terminal guanidine group and lactone ring of these compounds are vital for their antibacterial and antifungal activities. Further, based on their bioactivities and toxicity analyses, the discovery of guanidyl side-chain targeting to lipoteichoic acid of Staphylococcus aureus indicated that these compounds have a great potency to be developed into antimicrobial and anti-inflammatory drugs.

Pharmacokinetics provides a scientific basis for drug product design, dosage regimen planning, understanding the body's action on the drug, and relating the time course of the drug in the body to its pharmacodynamics and/or toxic effects. Recently, naringin, a natural flavonoid, was approved for clinical trials as a first-class new drug product by the China Food and Drug Administration, owing to its nonclinical efficacy in relieving cough, reducing sputum, and low toxicity. Previous reports focused on the pharmacokinetic studies of naringin or its active metabolite naringenin in rats, which were scattered and insufficient because naringin was coadministered with mixtures such as herbs, fruits, and other traditional medicines. The purpose of this study was to evaluate the pharmacokinetics and metabolism of naringin and naringenin, following oral and intravenous administration of naringin in rats, dogs, and humans, which can be beneficial for new drug development. Separate bioanalytical methods were developed and validated to determine the concentrations of naringin and its active metabolite naringenin in biological samples obtained from rats, dogs, and humans. Comprehensive nonclinical and clinical data were used to estimate the pharmacokinetic parameters of naringin and naringenin. Experiments included single-dose studies (oral and intravenous administration), multiple-dose studies, and an assessment of food-effects. Furthermore, the metabolism of naringin and naringenin was studied in rat and human liver and kidney microsomes. All biological samples were analyzed using liquid chromatography-tandem mass spectrometry. The pharmacokinetic parameters of naringin and naringenin were calculated and the results show an insignificant influence of high-fat diet and insignificant accumulation of the drugs after multiple dosing. Twelve metabolites were detected in the liver and kidney microsomes of rats and humans; naringin metabolism was a complex process simultaneously catalyzed by multiple human enzymes. All evaluated species demonstrated differences in the pharmacokinetics and metabolism of naringin and naringenin. The results can be used to design a dosage regimen, deepen understanding of mechanisms, and accelerate new drug development. http://www.chinadrugtrials.org.cn/eap/main, identifiers CTR20130704 and CTR20190127.

Citri grandis Exocarpium (Chinese name Huajuhong, HJH) is a traditional Chinese medicinal herb widely used in traditional medicines and foods in China due to its efficacy in treating coughs and excessive phlegm. This study employed HS-SPME-GC-MS to analyze the volatile compounds in HJH samples from different regions, with the aim of distinguishing samples from Huazhou from those of other origins and exploring their potential relationship with ecological factors. A multidimensional strategy was utilized to analyze the relationships between volatile oils, climatic factors, and soil elements, examining how volatile compounds responded to ecological factors. From 47 batches of HJH samples across various regions, eight significantly different volatile compounds were identified, serving as chemical markers for HJH from Huazhou. The findings elucidate the impact of ecological factors on the volatile compounds of HJH, highlighting environmental factors relating to the authenticity of HJH from Huazhou. The results indicate that the authenticity of HJH is shaped by the unique climatic and soil environments of Huazhou.

Extracellular vesicles (EVs)-mediated epithelium-macrophage crosstalk has been proved to maintain lung homeostasis in cigarette smoke-induced lung diseases such as chronic obstructive pulmonary disease (COPD). In our previous study, we found that EVs derived from cigarette smoke extract (CSE) treated BEAS-2B promoted M1 macrophage polarization, which probably accelerated the development of inflammatory responses. Naringenin has been proved to suppress M1 macrophage polarization, but whether naringenin regulates macrophage polarization mediated by EVs has not been reported. In this study, we firstly found that EVs derived from naringenin and CSE co-treated BEAS-2B significantly inhibited the expression of CD86 and CD80 and the secretion of tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1β, inducible nitric oxide synthase (iNOS), and IL-12 in macrophage induced by EVs derived from CSE-treated BEAS-2B. Further research revealed that naringenin downregulated BEAS-2B-derived EVs miR-21-3p which targeted phosphatase and tensin homolog deleted on chromosome ten/protein kinase B (PTEN/AKT) cascade in macrophages and then suppressed M1 macrophage polarization. Subsequent proteomics suggested that naringenin decreased BEAS-2B-derived EVs poly ADP-ribose polymerase (PARP)1 expression thereby suppressing M1 macrophage polarization probably. Our study provides novel pharmacological references for the mechanism of naringenin in the treatment of cigarette smoke-induced lung inflammatory diseases.

Porcine epidemic diarrhea virus (PEDV) infection causes lethal watery diarrhea and high mortality in neonatal piglets, leading to huge economic losses in the global swine industry. Currently, the existing commercial vaccines cannot fully control PEDV, so it is urgent to develop effective antiviral agents to complement vaccine therapy. In the present study, we investigated the antiviral effect of Hypericum japonicum extract (HJ) against PEDV in vivo and in vitro . In in vitro assays, HJ could directly inactivate PEDV strains; moreover, it inhibited the proliferation of PEDV strains in Vero or IPI-FX cells at its non-cytotoxic concentrations. Time of addition assays revealed that HJ mainly inhibited PEDV at the later stages of the viral life cycle. In in vivo , compared with the model group, HJ could reduce the viral titers in the intestines of infected piglets, and improve their intestinal pathological, indicating that HJ could protect the newborn piglets from highly pathogenic PEDV variant infection. Furthermore, this effect may be related to the fact that HJ can not only directly inhibit viruses, but also regulate the structure of intestinal microbiota. In conclusion, our results indicate that Hypericum japonicum could inhibit PEDV replication in vitro and in vivo and might possess the potential to develop as the anti-PEDV drug.

To improve the performance of the image semantic segmentation algorithm and make the algorithm achieve a better balance between accuracy and real-time performance when segmenting images, this paper proposes a real-time image semantic segmentation model based on an improved DeepLabv3+ network. First, the MobileNetV2 model with less computational overhead and number of parameters is selected as the backbone network to improve the segmentation speed; then, the Feature Enhancement Module (FEM) is introduced to several shallow features with different scale sizes in MobileNetV2, and then these shallow features are fused to improve the utilization rate of the model encoder on the edge information, to retain more detailed information and to improve the network’s feature representation ability for complex scenes; finally, to address the problem that the output feature maps of Atrous Spatial Pyramid Pooling (ASPP) module do not pay enough attention to detailed information after merging, the FEM attention mechanism is introduced on the feature maps processed by the ASPP module. The algorithm in this study achieves 76.45% for mean intersection over union (mIoU) accuracy with 29.18 FPS real-time performance in the PASCAL VOC2012 Augmented dataset; and 37.31% mIoU accuracy with 23.31 FPS real-time performance in the ADE20K dataset. The experimental results show that the algorithm in this study achieves a good balance between accuracy and real-time performance, and its image semantic segmentation performance is significantly improved compared to DeepLabv3+ and other existing algorithms.

Lipoteichoic acid (LTA) plays an essential role in bacterial growth and resistance to antibiotics, and LTA synthetase (LtaS) was considered as an attractive target for combating Gram-positive infections. Azalomycin F, a natural guanidyl-containing polyhydroxy macrolide, can target the LTA of Staphylococcus aureus. Using various technologies including enzyme-linked immunosorbent assay, transmission electron microscope, proteomics, and parallel reaction monitoring, here, the experimental results indicated that azalomycin F can accelerate the LTA release and disrupt the cell envelope, which would also lead to the feedback upregulation on the expressions of LtaS and other related enzymes. Simultaneously, the reconstituted enzyme activity evaluations showed that azalomycin F can significantly inhibit the extracellular catalytic domain of LtaS (eLtaS), while this was vague for LtaS embedded in the liposomes. Subsequently, the fluorescence analyses for five incubation systems containing azalomycin F and eLtaS or the LtaS-embedded liposome indicated that azalomcyin F can spontaneously bind to the active center of LtaS. Combining the mass spectroscopy analyses and the molecular dockings, the results further indicated that this interaction involves the binding sites of substrates and the LTA prolongation, especially the residues Lys299, Phe353, Trp354 and His416. All these suggested that azalomycin F has multiple antibacterial mechanisms against S. aureus. It can not only inhibit LTA biosynthesis through the interactions of its guanidyl side chain with the active center of LtaS but also disrupt the cell envelope through the synergistic effect of accelerating the LTA release, damaging the cell membrane, and electrostatically interacting with LTA. Simultaneously, these antibacterial mechanisms exhibit a synergistic inhibition effect on S. aureus cells, which would eventually cause the cellular autolysis.