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Abstract Chronic obstructive pulmonary disease (COPD) is an irreversible and progressive chronic inflammatory lung disease which affects millions of people worldwide. Activated fibroblasts are observed to accumulate in lung of COPD patients and promote COPD progression through aberrant extracellular matrix (ECM) deposition. In this study, we identified that miR-1307-5p expression was significantly increased in lung fibroblasts derived from COPD patients. Mechanistically, we found that upregulation of miR-1307-5p promoted TGF-β induced lung fibroblast activation and transdifferentiation. We also identified FBXL16 as a direct target for miR-1307-5p mediated myofibroblast activation in COPD. Knockdown of FBXL16 by siRNA prominently increased the expression of myofibroblast markers in MRC-5 fibroblasts after TGF-β administration. Ectopic expression of FBXL16 in MRC-5 counteracted miR-1307-5p agomir-induced fibroblast transdifferentiation. Furthermore, We found that miR-1307-5p promoted pulmonary fibroblast transdifferentiation through FBXL16 regulated HIF1α degradation. In general, our findings indicate that miR-1307-5p is important for COPD pathogenesis, and may serve as a potential target for COPD treatment.

Abstract Background To explore the associations of computed tomography (CT) image features with the serum cryptococcal antigen (CrAg) titers measured by the lateral flow assay (LFA) in localized pulmonary cryptococcosis patients. Methods A retrospective analysis of patients with pathologically confirmed pulmonary cryptococcosis admitted to the First Affiliated Hospital of Xiamen University from January 2016 to December 2022 was performed. Clinical data, CT results, serum CrAg-LFA test results, and follow-up data were collected and analyzed. Results A total of 107 patients with localized pulmonary cryptococcosis were included, of which 31 had a single lesion in chest CT and the other 76 had multiple lesions. The positivity rate was (94.74% vs 64.52%) and titers of serum CrAg-LFA (1.77 ± 0.87 vs 0.91 ± 0.98) in the multiple lesion group were higher than those in the single lesion group, respectively. Multivariate linear regression analysis showed that the serum CrAg titers were positively associated with the number of lesions (β, 0.08; 95% CI, 0.05 to 0.12) and the lesion size (β, 0.40; 95% CI, 0.31 to 0.50) after adjusting other covariates. The serum CrAg-LFA titers of 60 pulmonary cryptococcosis patients showed a decreasing trend with the reduction in pulmonary lesion size after effective therapy. Conclusion In pulmonary cryptococcosis patients, the number and size of lung lesions are positively correlated with the titers of the serum CrAg-LFA test. The CrAg-LFA test could be a useful tool for the diagnosis, severity assessment, and therapeutic monitoring of localized pulmonary cryptococcosis patients.

Rapidly obtaining the coverage characteristics of leaching solution in In-situ Leaching Area of Sandstone Uranium Mines is a necessary condition for optimizing well locations reasonably. In the presented study, the improved algorithm of the Fast Marching Method (FMM) was studied for rapidly solving coverage characteristics to replace the groundwater numerical simulator. First, the effectiveness of the FMM was verified by simulating diffusion characteristics of the leaching solution in In-situ Leaching Area. Second, based on the radial flow pressure equation and the interaction mechanism of the front diffusion of production and injection well flow field, an improved FMM which is suitable for In-situ Leaching Mining, was developed to achieve the co-simulation of production and injection well. Finally, the improved algorithm was applied to engineering practice to guide the design and production. The results show that the improved algorithm can efficiently solve the coverage characteristics of leaching solution, which is consistent with those obtained from traditional numerical simulators. In engineering practice, the improved FMM can be used to rapidly analyze the leaching process, delineate Leaching Blind Spots, and evaluate the rationality of well pattern layout. Furthermore, it can help to achieve iterative optimization and rapid decision-making of production and injection well locations under large-scale mining area models.

Abstract Background The association between sarcopenia and cardiovascular disease (CVD) is well known. However, the clinical diagnosis of sarcopenia is complex and not suitable for early clinical identification and prevention of CVD. Relative muscle strength (RMS) is a relatively quantitative and straightforward indicator, but its association with CVD remains unclear. Hence, the objective of this research was to investigate the correlation between RMS and CVD incidence. Methods This was a cross-sectional study, using data from the China Health and Retirement Longitudinal Study (CHARLS) in 2011. CVD events were assessed through self-reported physician diagnoses. The RMS was determined by dividing the maximum grip strength by the appendicular skeletal muscle mass (ASM). This study used multivariate logistic regression and restricted cubic spline (RCS) curves to explore the correlation between RMS and CVD incidence. Additionally, we conducted subgroup analyses to provide additional evidence supporting the association between the two variables. Results A total of 8,733 people were included in our study, with 1,152 (13.19%) CVD patients and 7,581 (86.81%) non-CVD patients. When the data were grouped according to quartiles (Q) of RMS, the inverse association between CVD and RMS remained statistically significant even after controlling for all potential confounding factors. Compared with participants in Q1 of RMS, the ORs (95% CIs) of CVD among those in Q2-Q4 were 0.99 (0.83, 1.17), 0.81 (0.67, 0.98), and 0.70 (0.57, 0.85), respectively. Moreover, the RCS results showed a negative linear correlation between the RMS and CVD incidence (P for nonlinearity = 0.555). Subgroup analysis revealed no significant interaction in any of the groups except for the sex group (P for interaction = 0.046). Conclusion Our study indicated a stable negative correlation between RMS and CVD incidence. RMS is helpful for the early identification and prevention of CVD.

Abstract This study aimed to retrospectively examine the computed tomography (CT) features of lung adenocarcinoma across different demographic groups. Preoperative chest CT findings from 1266 surgically resected lung adenocarcinoma cases were retrospectively analyzed. Lung adenocarcinomas were categorized based on CT characteristics into pure ground glass (pGGO), nodule-containing ground glass opacity (mGGO), and pure solid without containing ground glass opacity (pSD). These categories were correlated with sex, age, EGFR status, and five histopathological subtypes. The diameters of pGGO, mGGO, and pSD significantly increased across all patient groups (P 60 years) for both males (P = 0.002) and females (P = 0.027). The frequency of pSD was higher in the older age group for both sexes. A linear correlation between age and diameter was observed in the entire cohort as well as in the male and female groups (P

ObjectiveThis study integrates network pharmacology and metabolomics techniques to explore the potential regulatory mechanisms of Res on gouty arthritis (GA).MethodsNetwork pharmacology was used to predict the mechanism of Res in regulating GA, and methods such as HE staining, ELISA, immunohistochemistry, Real-time PCR, Western blot, and molecular docking were used to verify the role of NF-κB, MAPK, and JAK/STAT inflammatory signaling pathways in the MSU-induced GA rat model. In addition, non-targeted metabolomics techniques were combined to further investigate the mechanism of Res in treating GA.ResultsThe results of network pharmacology showed that Res may exert its therapeutic effects through the NF-κB signaling pathway. Animal experiments demonstrated that in the MSU-induced GA rat model, pathological damage, serum biochemical indicators, and levels of inflammatory factors were significantly increased, and the NF-κB signaling pathway was activated. The intervention of Res significantly reduced pathological damage, serum biochemical indicators, levels of inflammatory factors, and the activation of NF-κB, MAPK, and JAK/STAT signaling pathways in the model rats. Metabolomics results showed that Res could improve the metabolic trajectory deviations in serum and joint fluid of GA model rats. Through related metabolic pathway analysis, the most affected metabolic pathways were found to be Sphingolipid metabolism, Glycerophospholipid metabolism, Phenylalanine, tyrosine and tryptophan biosynthesis, Pantothenate and CoA, Citrate cycle (TCA cycle), and Arachidonic acid metabolism.ConclusionResveratrol can regulate the biosynthetic pathways of arachidonic acid, phenylalanine, tyrosine, and tryptophan, pantothenic acid and CoA biosynthesis pathways, TCA cycle, and other metabolic pathways, thereby regulating the NF-κB, MAPK, and JAK/STAT3 signaling pathways, and inhibiting the acute inflammatory response during GA attacks, showing characteristics of multi-pathway and multi-target action.

BackgroundShort video addiction (SVA) among college students is influenced by personality traits, namely, neuroticism and agreeableness. However, the role of depression and anxiety as mediators remains unclear.ObjectiveThis study aims to explore the mediating role of comorbid depression and anxiety in the relationship between different dimensions of university students’ personalities and SVA.MethodsThe SPSS PROCESS was utilized to analyze data from 804 university students across seven universities in China.ResultsThe findings show that neuroticism, agreeableness, and extraversion in the personalities of Chinese university students are all significantly linked to SVA; neuroticism and agreeableness in the personalities of university students have a greater impact on SVA; both neuroticism and agreeableness can first induce depression and then lead to anxiety and SVA, whereas only agreeableness can first lead to anxiety and then result in depression and SVA.ConclusionThis study uncovers the intricate relationship between personality traits and SVA among college students, emphasizing depression and anxiety as critical chain mediators in this relationship. It reveals that neuroticism and agreeableness significantly influence SVA through specific pathways involving depression and anxiety, indicating that interventions targeting these traits are essential.

Owing to its tyrosinase inhibitory activity, α-arbutin has been added to several skin care products as a skin-lightening agent. However, the protective effect of α-arbutin against ultraviolet A (UVA)-induced photoaging has not been well investigated. The present study was designed to investigate the photoprotective effect and mechanism of α-arbutin against UVA-induced photoaging. In vitro experiments, HaCaT cells were treated with UVA at a dose of 3 J/cm2 to evaluate the anti-photoaging effect of α-arbutin. α-Arbutin was found to exhibit a strong antioxidant effect by increasing glutathione (GSH) level and inhibiting reactive oxygen species (ROS) production. Meanwhile, α-arbutin markedly improved the expression of sirtuin 3 (SIRT3) and peroxisome proliferator-activated receptor γ coactivator 1 α (PGC-1α) proteins, initiating downstream signaling to increase mitochondrial membrane potential and mediate mitochondrial biogenesis, and improve mitochondrial structure significantly. In vivo analysis, the mice with shaved back hair were irradiated with a cumulative UVA dose of 10 J/cm2 and a cumulative ultraviolet B (UVB) dose of 0.63 J/cm2. The animal experiments demonstrated that α-arbutin increased the expression of SIRT3 and PGC-1α proteins in the back skin of mice, thereby reducing UV-induced skin damage. In conclusion, α-arbutin protects HaCaT cells and mice from UVA damage by regulating SIRT3/PGC-1α signaling pathway.

Abstract Gene therapy has witnessed substantial advancements in recent years, becoming a constructive tactic for treating various human diseases. This review presents a comprehensive overview of these developments, with a focus on their diverse applications in different disease contexts. It explores the evolution of gene delivery systems, encompassing viral (like adeno‐associated virus; AAV) and nonviral approaches, and evaluates their inherent strengths and limitations. Moreover, the review delves into the progress made in targeting specific tissues and cell types, spanning the eye, liver, muscles, and central nervous system, among others, using these gene technologies. This targeted approach is crucial in addressing a broad spectrum of genetic disorders, such as inherited lysosomal storage diseases, neurodegenerative disorders, and cardiovascular diseases. Recent clinical trials and successful outcomes in gene therapy, particularly those involving AAV and the clustered regularly interspaced short palindromic repeats (CRISPR)–CRISPR‐associated proteins, are highlighted, illuminating the transformative potentials of this approach in disease treatment. The review summarizes the current status of gene therapy, its prospects, and its capacity to significantly ameliorate patient outcomes and quality of life. By offering comprehensive analysis, this review provides invaluable insights for researchers, clinicians, and stakeholders, enriching the ongoing discourse on the trajectory of disease treatment.

Abstract Objective PD-L1 was an important biomarker in lung adenocarcinoma. The study was to confirm the most important factor affecting the expression of PD-L1 remains undetermined. Methods The clinical records of 1045 lung adenocarcinoma patients were retrospectively reviewed. The High-Resolution Computed Tomography (HRCT) scanning images of all the participants were analyzed, and based on the CT characteristics, the adenocarcinomas were categorized according to CT textures. Furthermore, PD-L1 expression and Ki67 index were detected by immunohistochemistry. All patients underwent EGFR mutation detection. Results Multivariate logistic regression analysis revealed that smoking (OR: 1.73, 95% CI: 1.04–2.89, p = 0.004), EGFR wild (OR: 1.52, 95% CI: 1.11–2.07, p = 0.009), micropapillary subtypes (OR: 2.05, 95% CI: 1.46–2.89, p 3 cm and CT textures of pSD showed a correlation with high expression of PD-L1. Further analysis revealed that smoking, micropapillary subtype, and EGFR wild type were also associated with high Ki67 expression. Moreover, high Ki67 expression was observed more frequently in tumors of size > 3 cm than in tumors with ≤ 3 cm size as well as in CT texture of pSD than lesions with GGO components. In addition, multivariate logistic regression analysis revealed that only lesions with micropapillary components correlated with pSD (OR: 3.96, 95% CI: 2.52–5.37, p

Abstract We investigate the weak decays of the triply heavy baryon $$\Omega _{QQQ}$$ Ω QQQ in the light-front quark model. Since $$\Omega _{QQQ}$$ Ω QQQ consists of three indistinguishable identical heavy quarks, the commonly adopted quark–diquark picture does not seem to be valid anymore. Instead, we employ the three-quark picture for baryons where the three quarks are regarded as individual quarks. We calculate the hadronic form factors for the transitions and give predictions for the decay widths of the semi-leptonic decay modes $$\Omega _{ccc}\rightarrow \Xi _{cc}/ \Omega _{cc}+ l^+\nu _l$$ Ω ccc → Ξ cc / Ω cc + l + ν l , $$\Omega _{bbb}\rightarrow \Xi _{bb}+ l^-\bar{\nu }_l$$ Ω bbb → Ξ bb + l - ν ¯ l and the non-leptonic decay modes $$\Omega _{ccc}\rightarrow \Xi _{cc}/\Omega _{cc}+ M$$ Ω ccc → Ξ cc / Ω cc + M , $$\Omega _{bbb}\rightarrow \Xi _{bb}+ M$$ Ω bbb → Ξ bb + M . Our study can be a guide for future experiments to discover the triply heavy baryons.

Abstract Background Multi-b-value diffusion-weighted imaging (DWI) with different postprocessing models allows for evaluating hepatocellular carcinoma (HCC) proliferation, spatial heterogeneity, and feasibility of treatment strategies. We assessed synergistic effects of bufalin+sorafenib in orthotopic HCC-LM3 xenograft nude mice by using intravoxel incoherent motion (IVIM), diffusion kurtosis imaging (DKI), a stretched exponential model (SEM), and a fractional-order calculus (FROC) model. Methods Twenty-four orthotopic HCC-LM3 xenograft mice were divided into bufalin+sorafenib, bufalin, sorafenib treatment groups, and a control group. Multi-b-value DWI was performed using a 3-T scanner after 3 weeks’ treatment to obtain true diffusion coefficient Dt, pseudo-diffusion coefficient Dp, perfusion fraction f, mean diffusivity (MD), mean kurtosis (MK), distributed diffusion coefficient (DDC), heterogeneity index α, diffusion coefficient D, fractional order parameter β, and microstructural quantity μ. Necrotic fraction (NF), standard deviation (SD) of hematoxylin-eosin staining, and microvessel density (MVD) of anti-CD31 staining were evaluated. Correlations of DWI parameters with histopathological results were analyzed, and measurements were compared among four groups. Results In the final 22 mice, f positively correlated with MVD (r = 0.679, p = 0.001). Significantly good correlations of MK (r = 0.677), α (r = -0.696), and β (r= -0.639) with SD were observed (all p < 0.010). f, MK, MVD, and SD were much lower, while MD, α, β, and NF were higher in bufalin plus sorafenib group than control group (all p < 0.050). Conclusion Evaluated by IVIM, DKI, SEM, and FROC, bufalin+sorafenib was found to inhibit tumor proliferation and angiogenesis and reduce spatial heterogeneity in HCC-LM3 models. Relevance statement Multi-b-value DWI provides potential metrics for evaluating the efficacy of treatment in HCC. Key points • Bufalin plus sorafenib combination may increase the effectiveness of HCC therapy. • Multi-b-value DWI depicted HCC proliferation, angiogenesis, and spatial heterogeneity. • Multi-b-value DWI may be a noninvasive method to assess HCC therapeutic efficacy. Graphical Abstract

Background The M-type phospholipase A2 receptor (PLA2R)-associated primary membranous nephropathy (PMN) is an immune-related disease in adults with increasing morbidity and variable treatment response, in which inflammation may contribute to the multifactorial immunopathogenesis. The relationship between fibrinogen-albumin ratio (FAR), serving as a novel inflammatory biomarker, and PMN is still unclear. Therefore, this study aims to clarify the association between FAR and disease activity and therapy response of PMN.Methods 110 biopsy-proven phospholipase A2 receptor (PLA2R) -associated PMN participants with nephrotic syndrome from January 2017 to December 2021 were recruited in the First Affiliated Hospital of Nanjing Medical University. The independent risk factors of non-remission (NR) and the predictive ability of FAR were explored by Cox regression and receiver-operating characteristic (ROC) curve analysis. According to the optimal cutoff value, study patients were categorized into the low-FAR group (≤the cutoff value) and the high-FAR group (>the cutoff value). Spearman’s correlations were used to examine the associations between FAR and baseline clinicopathological characteristics. Kaplan-Meier method was used to assess the effects of FAR on remission.Results In the entire study cohort, 78 (70.9%) patients reached complete or partial remission (CR or PR). The optimal cutoff value of FAR for predicting the remission outcome (CR + PR) was 0.233. The Kaplan-Meier survival analysis demonstrated that the high-FAR group (>0.233) had a significantly lower probability to achieve CR or PR compared to the low-FAR group (≤0.233) (Log Rank test, p = 0.021). Higher levels of FAR were identified as an independent risk factor for NR, and the high-FAR group was associated with a 2.27 times higher likelihood of NR than the low-FAR group (HR 2.27, 95% CI 1.01, 5.13, p = 0.048). These relationships remained robust with further analysis among calcineurin inhibitors (CNIs)-receivers. In the multivariate Cox regression model, the incidence of NR was 4.00 times higher in the high-FAR group than in the low-FAR group (HR 4.00, 95% CI 1.41, 11.31, p = 0.009). Moreover, ROC analysis revealed the predictive value of FAR for CR or PR with a 0.738 area under curve (AUC), and the AUC of anti-PLA2R Ab was 0.675. When combining FAR and anti-PLA2R Ab, the AUC was boosted to 0.766.Conclusions FAR was significantly correlated with proteinuria and anti-PLA2R Ab in PMN. As an independent risk factor for NR, FAR might serve as a potential inflammation-based prognostic tool for identifying cases with poor treatment response, and the best predictive cutoff value for outcomes was 0.233.

Background: Renal hypoxia plays a key role in the progression of chronic kidney disease (CKD). Shen Shuai II Recipe (SSR) has shown good results in the treatment of CKD as a common herbal formula. This study aimed to explore the effect of SSR on renal hypoxia and injury in CKD rats. Methods: Twenty-five Wistar rats underwent 5/6 renal ablation/infarction (A/I) surgery were randomly divided into three groups: 5/6 (A/I), 5/6 (A/I) + losartan (LOS), and 5/6 (A/I) + SSR groups. Another eight normal rats were used as the Sham group. After 8-week corresponding interventions, blood oxygenation level-dependent functional magnetic resonance imaging (BOLD-fMRI) was performed to evaluate renal oxygenation in all rats, and biochemical indicators were used to measure kidney and liver function, hemoglobin, and proteinuria. The expression of fibrosis and hypoxia-related proteins was analyzed using immunoblotting examination. Results: Renal oxygenation, evaluated by BOLD-fMRI as cortical and medullary T2* values (COT2* and MET2*), was decreased in 5/6 (A/I) rats, but increased after SSR treatment. SSR also downregulated the expression of hypoxia-inducible factor-1α (HIF-1α) in 5/6 (A/I) kidneys. With the improvement of renal hypoxia, renal function and fibrosis were improved in 5/6 (A/I) rats, accompanied by reduced proteinuria. Furthermore, the COT2* and MET2* were significantly positively correlated with the levels of creatinine clearance rate (Ccr) and hemoglobin, but negatively associated with the levels of serum creatinine (SCr), blood urea nitrogen (BUN), serum cystatin C (CysC), serum uric acid (UA), 24-h urinary protein (24-h Upr), and urinary albumin:creatinine ratio (UACR). Conclusion: The degree of renal oxygenation reduction is correlated with the severity of renal injury in CKD. SSR can improve renal hypoxia to attenuate renal injury in 5/6 (A/I) rats of CKD.

BackgroundMultiple pigmented epithelial cysts at the edge of pupils, that is, iris flocculi, in both eyes, are rare ocular diseases. It has been demonstrated that this disease can be attributed to mutations in the smooth muscle α-actin 2 (ACTA2) gene, which mainly affects the function of smooth muscle cells (SMCs). SMCs are components of the iris, aorta, and several other systemic organs. In addition, iris flocculi are strongly correlated with familial thoracic aortic aneurysm and dissection (TAAD), which is caused by the mutation of amino acid 149 in the ACTA2 gene.Case descriptionA 6-month-old Chinese boy was found to have iris flocculi during ocular fundus screening for premature infants. His mother, a 30-year-old Chinese woman with a history of aortic dissection, underwent an ophthalmic examination and was found to have iris flocculi. Whole exome sequencing revealed a heterozygous c.445C > T (p. Arg149Cys) mutation in ACTA2 in both the boy and his mother. After his family history was traced, the boy’s grandfather was diagnosed with similar iris flocculi. Due to the absence of any ocular complications caused by iris flocculi in the cases, no special treatment was given, and regular follow-up was recommended.ConclusionWe reported one case of familial iris flocculi caused by a heterozygous missense mutation in ACTA2 (p. Arg149Cys) and presented multimodal optical images of both the iris and fundus in three consecutive generations. This case report enriched the clinical features of retinal vasculature and macula associated with the mutation in the amino acid 149 of the ACTA2 gene.

Programmed cell death (PCD) plays a crucial role in maintaining the normal structure and function of the digestive tract in the body. Infection with Helicobacter pylori (H. pylori) is an important factor leading to gastric damage, promoting the Correa cascade and accelerating the transition from gastritis to gastric cancer. Recent research has shown that several PCD signaling pathways are abnormally activated during H. pylori infection, and the dysfunction of PCD is thought to contribute to the development of gastric cancer and interfere with treatment. With the deepening of studies on H. pylori infection in terms of PCD, exploring the interaction mechanisms between H. pylori and the body in different PCD pathways may become an important research direction for the future treatment of H. pylori infection and H. pylori-related gastric cancer. In addition, biologically active compounds that can inhibit or induce PCD may serve as key elements for the treatment of this disease. In this review, we briefly describe the process of PCD, discuss the interaction between different PCD signaling pathways and the mechanisms of H. pylori infection or H. pylori-related gastric cancer, and summarize the active molecules that may play a therapeutic role in each PCD pathway during this process, with the expectation of providing a more comprehensive understanding of the role of PCD in H. pylori infection.

BackgroundThe incidence of uveitis has risen with the use of targeted therapies, particularly prevalent in the administration of immune checkpoint inhibitors and MAP-kinase pathway inhibitors. We report the first case of VKH-like uveitis linked to Donafenib employed for the primary hepatocellular carcinoma, highlighting the necessity of ophthalmological follow-up in patients undergoing treatment with Donafenib.Case presentationA 55-year-old man developed VKH-like symptoms, including sporadic white patches, tinnitus, headache, and mild bilateral vision reduction, after 18 months of treatment with Donafenib and Sintilimab for hepatocellular carcinoma. Based on ophthalmological examinations that fundus fluorescein angiography images demonstrating multiple focal areas of pinpoint hyperfluorescence, along with pooling indicative of neurosensory detachment and disc leakage in both eyes, choroid thickening in swept-source optical coherence tomography, and “sunset-glow” fundus appearance, a tentative diagnosis of VKH-like uveitis was made. Initially, his best-corrected visual acuity (BCVA) was 20/200 in the right eye and 20/80 in the left eye. Upon discontinuing Donafenib and starting a 3-month course of oral glucocorticoids, his BCVA improved to 20/30 in the right eye and 20/40 in the left eye.ConclusionTargeted drugs have been commonly used for cancer treatment in recent years, but challenges of ocular side effects emerged gradually. To optimize patient outcomes, regular ophthalmological follow-ups are essential for those undergoing treatment with targeted therapies like Donafenib.

Purpose: Age-related macular degeneration (AMD) is a chronic and progressive macular degenerative disease that culminates in a gradual deterioration of central vision. Despite its prevalence, the key biomarkers for AMD have not yet been fully elucidated. In this study, we aimed to efficiently identify biomarkers crucial for diagnosing AMD.Methods: Three datasets pertaining to retinal pigment epithelium (RPE)/choroid tissues associated with AMD were selected from the GEO database. The GSE50195 dataset was utilized to conduct weighted gene co-expression network analysis (WGCNA) for identifying module genes linked to AMD. KEGG and GO enrichment analyses were subsequently conducted on these module genes. GSE29801 and GSE135092 datasets were subjected to differential expression analysis to pinpoint the DEGs intersecting with the module genes. Subsequently, wet AMD (wAMD) and dry AMD (dAMD) mouse models were developed, from which RPE/choroid tissues were harvested to validate the hub genes via RT-qPCR and Western blot.Results: Using the WGCNA, we selected the “antiquewhite4” module (r = 0.91 and p = 7e-07), which contains a total of 325 genes. Through the intersection of module genes with DEGs, nine hub genes were identified. Pathways involved in complement and coagulation cascades, ECM–receptor interactions, unsaturated fatty acid biosynthesis, and fatty acid elongation play important roles in AMD. Notably, CDH18 demonstrated notable variance across all three datasets. Post validation using RT-qPCR experiments revealed a significant downregulation of CDH18 in both dAMD and wAMD. EGLN3 was expressed at low levels in wAMD. In dAMD, EYA2, LTB, and PODXL were significantly downregulated, whereas APOC1 was notably upregulated. Western blot confirmed that CDH18 was lowly expressed in dAMD and wAMD mouse models.Conclusion: CDH18 was identified as the key gene involved in the pathogenesis of AMD. An imbalance of the complement and coagulation cascades is a potential mechanism of AMD. This study provides a novel idea for diagnosing and treating AMD in the future.

Preclinical evidence has firmly established a bidirectional interaction among the lung, gut, and gut microbiome. There are many complex communication pathways between the lung and intestine, which affect each other's balance. Some metabolites produced by intestinal microorganisms, intestinal immune cells, and immune factors enter lung tissue through blood circulation and participate in lung immune function. Altered gut–lung–microbiome interactions have been identified in rodent models and humans of several lung diseases such as pulmonary fibrosis, chronic obstructive pulmonary disease, lung cancer, asthma, etc. Emerging evidence suggests that microbial therapies can prevent and treat respiratory diseases, but it is unclear whether this association is a simple correlation with the pathological mechanisms of the disease or the result of causation. In this review, we summarize the complex and critical link between the gut microbiota and the lung, as well as the influence and mechanism of the gut microbiota on respiratory diseases, and discuss the role of interventions such as prebiotics and fecal bacteria transplantation on respiratory diseases. To provide a reference for the rational design of large-scale clinical studies, the direct application of microbial therapy to respiratory-related diseases can reduce the incidence and severity of diseases and accompanying complications.

Introduction: Fuqi Guben Gao (FQGBG) is a botanical drug formulation composed of FuZi (FZ; Aconitum carmichaelii Debeaux [Ranunculaceae; Aconiti radix cocta]), Wolfberry (Lycium barbarum L. [Solanaceae; Lycii fructus]), and Cinnamon (Neolitsea cassia (L.) Kosterm. [Lauraceae; Cinnamomi cortex]). It has been used to clinically treat nocturia caused by kidney-yang deficiency syndrome (KYDS) for over 30 years and warms kidney yang. However, the pharmacological mechanism and the safety of FQGBG in humans require further exploration and evaluation.Methods: We investigated the efficacy of FQGBG in reducing urination and improving immune organ damage in two kinds of KYDS model rats (hydrocortisone-induced model and natural aging model), and evaluated the safety of different oral FQGBG doses through pharmacokinetic (PK) parameters, metabonomics, and occurrence of adverse reactions in healthy Chinese participants in a randomized, double-blind, placebo-controlled, single ascending dose clinical trial. Forty-two participants were allocated to six cohorts with FQGBG doses of 12.5, 25, 50, 75, 100, and 125 g. The PKs of FQGBG in plasma were determined using a fully validated LC-MS/MS method.Results: FQGBG significantly and rapidly improved the symptoms of increased urination in both two KYDS model rats and significantly resisted the adrenal atrophy in hydrocortisone-induced KYDS model rats. No apparent increase in adverse events was observed with dose escalation. Major adverse drug reactions included toothache, thirst, heat sensation, gum pain, diarrhea, abdominal distension, T-wave changes, and elevated creatinine levels. The PK results showed a higher exposure level of benzoylhypaconine (BHA) than benzoylmesaconine (BMA) and a shorter half-life of BMA than BHA. Toxic diester alkaloids, aconitine, mesaconitine, and hypaconitine were below the lower quantitative limit. Drug-induced metabolite markers primarily included lysophosphatidylcholines, fatty acids, phenylalanine, and arginine metabolites; no safety-related metabolite changes were observed.Conclusion: Under the investigated dosing regimen, FQGBG was safe. The efficacy mechanism of FQGBG in treating nocturia caused by KYDS may be related to the improvement of the hypothalamus-pituitary-adrenal axis function and increased energy metabolism.Clinical Trial Registration:https://www.chictr.org.cn/showproj.html?proj=26934, identifier ChiCTR1800015840.

Effective protection and rational utilization of coastal zones have become an important way for sustainable development in coastal areas. The paper summarized the achievements and existing problems based on a review of research on protection and utilization in the coastal zones of Hainan Island, and explained the important significance of effective protection and rational utilization of coastal zones. Based on the coastal geology and coastal dynamics on the control mechanism of coastline, this paper deeply analyzed the unique and fragile ecological characteristics, human activities impact, and abundant tourism resources in the coastal zones of Hainan Island. It revealed the importance of coastal dynamic processes and coastal zones, and how the atmosphere, ocean, and land interact. A new concept of effective protection and rational utilization in the coastal zones of Hainan Island had been proposed, and a top strategic model for effective protection and rational utilization in the coastal zones of Hainan Island had been constructed. In order to promote the effective protection and rational utilization in the coastal zones of Hainan Island, it is necessary to take balance of nature as the basis, strengthen the investigation and research on the dynamic process of the coastal zones, scientifically assess the carrying capacity of tourist destinations, timely carry out resource data mining, monitoring and early warning, and start the declaration and construction of marine world natural heritage in Hainan Island, explore the "Hainan Model" with "legislation first, overall planning, macroeconomic regulation, scientific support, financial support, unified management, and public participation" as the core.

Abstract By integrating land use and transportation systems, transit-oriented development (TOD) focuses on transit and land development, development potential, and the balance between transportation and land use. The TOD level assessment not only helps optimize existing TODs but also guides TOD planning. Based on previous literature, methods for assessing TOD around rail transit stations can be roughly divided into three categories: TOD index, the node-place model, and the data envelopment analysis (DEA) model. The TOD index aggregates indicators from different dimensions into a single value for evaluation. The node-place model emphasizes transportation, land use, and the balance between them, as well as expansion factors. And the DEA model is suitable for situations without input indicator weights or consideration of different units of measurement. TOD indicators are the basis of the evaluation, and in both the TOD index and node-place models, indicator weights are mostly determined by using subjective methods. Furthermore, a limited number of studies to date have pre-evaluated the implementation of TOD at rail stations under construction or in planning. This paper aims to assess the level of TOD areas at the rail transit station level, which can help in constructing the evaluation index system, selecting TOD stations, and optimizing them.

Abstract Glaucoma is a complex neurodegenerative disorder characterized by the progressive loss of retinal ganglion cells (RGC) and optic nerve axons, leading to irreversible visual impairment. Despite its clinical significance, the underlying mechanisms of glaucoma pathogenesis remain poorly understood. In this study, we aimed to unravel the multifaceted nature of glaucoma by investigating the interaction between T cells and retinas. By utilizing clinical samples, murine glaucoma models, and T cell transfer models, we made several key findings. Firstly, we observed that CD4+ T cells from glaucoma patients displayed enhanced activation and a bias towards T helper (Th) 1 responses, which correlated with visual impairment. Secondly, we identified the infiltration of Th1 cells into the retina, where they targeted RGC and integrated into the pro-inflammatory glial network, contributing to progressive RGC loss. Thirdly, we discovered that circulating Th1 cells upregulated vascular cell adhesion protein 1 (VCAM-1) on retinal microvessels, facilitating their entry into the neural retina. Lastly, we found that Th1 cells underwent functional reprogramming before reaching the retina, acquiring a phenotype associated with lymphocyte migration and neurodegenerative diseases. Our study provides novel insights into the role of peripheral CD4+ T cells in glaucoma pathogenesis, shedding light on the mechanisms underlying their infiltration into the retina and offering potential avenues for innovative therapeutic interventions in this sight-threatening disease. Graphical Abstract

Abstract Chronic obstructive pulmonary disease (COPD) is a leading aging related cause of global mortality. Small airway narrowing is recognized as an early and significant factor for COPD development. Senescent fibroblasts were observed to accumulate in lung of COPD patients and promote COPD progression through aberrant extracellular matrix (ECM) deposition and senescence-associated secretory phenotype (SASP). On the basis of our previous study, we further investigated the the causes for the increased levels of miR-377-3p in the blood of COPD patients, as well as its regulatory function in the pathological progression of COPD. We found that the majority of up-regulated miR-377-3p was localized in lung fibroblasts. Inhibition of miR-377-3p improved chronic smoking-induced COPD in mice. Mechanistically, miR-377-3p promoted senescence of lung fibroblasts, while knockdown of miR-377-3p attenuated bleomycin-induced senescence in lung fibroblasts. We also identified ZFP36L1 as a direct target for miR-377-3p that likely mediated its pro senescence activity in lung fibroblasts. Our data reveal that miR-377-3p is crucial for COPD pathogenesis, and may serve as a potential target for COPD therapy.

Abstract The relationship between serum uric acid and lung function has been controversial. This study aims to determine whether there is an independent relationship between serum uric acid and lung function in the National Health and Nutrition Examination Survey (NHANES) from 2007 to 2012. Serum uric acid was considered the exposure variable, and lung function (FEV1 and FVC) was the outcome variable. Multivariable linear regression was conducted with adjustments for potential confounders. The total number of participants from NHANES (2007–2012) was 30,442, of which 7514 were included in our analysis after applying exclusion criteria. We observed that serum uric acid was negatively associated with FEV1 and FVC after adjusting for confounders (β for FEV1 [− 24.77 (− 36.11, − 13.43)] and FVC [− 32.93 (− 47.42, − 18.45)]). Similarly, serum uric acid showed a negative correlation with FEV1 and FVC after adjusting for confounding variables both in male and female populations. The relationship between serum uric acid and FEV1 and FVC remained consistent and robust in various subgroups within both male and female populations, including age, race, BMI, alcohol consumption, smoking status, and income-poverty ratio. Serum uric acid is negatively associated with FEV1 and FVC in the US general healthy population. This negative relationship is significant in both the male and female populations.

Abstract Background Numerous studies have affirmed a robust correlation between residual cholesterol (RC) and the occurrence of cardiovascular disease (CVD). However, the current body of literature fails to adequately address the link between alterations in RC and the occurrence of CVD. Existing studies have focused mainly on individual RC values. Hence, the primary objective of this study is to elucidate the association between the cumulative RC (Cum-RC) and the morbidity of CVD. Methods The changes in RC were categorized into a high-level fast-growth group (Class 1) and a low-level slow-growth group (Class 2) by K-means cluster analysis. To investigate the relationship between combined exposure to multiple lipids and CVD risk, a weighted quantile sum (WQS) regression analysis was employed. This analysis involved the calculation of weights for total cholesterol (TC), low-density lipoprotein (LDL), and high-density lipoprotein (HDL), which were used to effectively elucidate the RC. Results Among the cohort of 5,372 research participants, a considerable proportion of 45.94% consisted of males, with a median age of 58. In the three years of follow-up, 669 participants (12.45%) had CVD. Logistic regression analysis revealed that Class 2 individuals had a significantly reduced risk of developing CVD compared to Class 1. The probability of having CVD increased by 13% for every 1-unit increase in the Cum-RC according to the analysis of continuous variables. The restricted cubic spline (RCS) analysis showed that Cum-RC and CVD risk were linearly related (P for nonlinearity = 0.679). The WQS regression results showed a nonsignificant trend toward an association between the WQS index and CVD incidence but an overall positive trend, with the greatest contribution from TC (weight = 0.652), followed by LDL (weight = 0.348). Conclusion Cum-RC was positively and strongly related to CVD risk, suggesting that in addition to focusing on traditional lipid markers, early intervention in patients with increased RC may further reduce the incidence of CVD.

Abstract Artificial intelligence (AI)-based diagnostic systems have been reported to improve fundus disease screening in previous studies. This multicenter prospective self-controlled clinical trial aims to evaluate the diagnostic performance of a deep learning system (DLS) in assisting junior ophthalmologists in detecting 13 major fundus diseases. A total of 1493 fundus images from 748 patients were prospectively collected from five tertiary hospitals in China. Nine junior ophthalmologists were trained and annotated the images with or without the suggestions proposed by the DLS. The diagnostic performance was evaluated among three groups: DLS-assisted junior ophthalmologist group (test group), junior ophthalmologist group (control group) and DLS group. The diagnostic consistency was 84.9% (95%CI, 83.0% ~ 86.9%), 72.9% (95%CI, 70.3% ~ 75.6%) and 85.5% (95%CI, 83.5% ~ 87.4%) in the test group, control group and DLS group, respectively. With the help of the proposed DLS, the diagnostic consistency of junior ophthalmologists improved by approximately 12% (95% CI, 9.1% ~ 14.9%) with statistical significance (P

Asthma is a chronic airway inflammation that is considered a serious public health concern worldwide. Nobiletin (5,6,7,8,3′,4′-hexamethyl flavonoid), an important compound isolated from several traditional Chinese medicines, especially Citri Reticulatae Pericarpium, is widely used for a number of indications, including cancer, allergic diseases, and chronic inflammation. However, the mechanism by which nobiletin exerts its anti-asthmatic effect remains unclear. In this research, we comprehensively demonstrated the anti-asthmatic effects of nobiletin in an animal model of asthma. It was found that nobiletin significantly reduced the levels of inflammatory cells and cytokines in mice and alleviated airway hyperresponsiveness. To explore the target of nobiletin, we identified PDE4B as the target of nobiletin through pharmacophore modeling, molecular docking, molecular dynamics simulation, SPR, and enzyme activity assays. Subsequently, it was found that nobiletin could activate the cAMP-PKA-CREB signaling pathway downstream of PDE4B in mouse lung tissues. Additionally, we studied the anti-inflammatory and anti-airway remodeling effects of nobiletin in LPS-induced RAW264.7 cells and TGF-β1-induced ASM cells, confirming the activation of the cAMP-PKA-CREB signaling pathway by nobiletin. Further validation in PDE4B-deficient RAW264.7 cells confirmed that the increase in cAMP levels induced by nobiletin depended on the inhibition of PDE4B. In conclusion, nobiletin exerts anti-asthmatic activity by targeting PDE4B and activating the cAMP-PKA-CREB signaling pathway.

ObjectiveTo explore the relationship between plasma lactoferrin (Lf) and glaucoma, assessing the clinical utility of Lf in glaucoma.MethodsA cross-sectional study involved 161 glaucoma patients and 115 healthy controls, with a follow-up of 14 subjects after approximately 2 years. Plasma Lf markers were quantified using ELISA, comparing levels between glaucoma patients and healthy controls, and analyzing plasma Lf across different glaucoma severity grades.ResultsGlaucoma patients had significantly elevated plasma Lf levels compared to healthy controls (p

BackgroundHigh sodium intake and fluid overhydration are common factors of and strongly associated with adverse outcomes in chronic kidney disease (CKD) patients. Yet, their effects on cardiac dysfunction remain unclear.AimsThe study aimed to explore the impact of salt and volume overload on cardiac alterations in non-dialysis CKD.MethodsIn all, 409 patients with CKD stages 1–4 (G1–G4) were enrolled. Daily salt intake (DSI) was estimated by 24-h urinary sodium excretion. Volume status was evaluated by the ratio of extracellular water (ECW) to total body water (TBW) measured by body composition monitor. Recruited patients were categorized into four groups according to DSI (6 g/day) and median ECW/TBW (0.439). Echocardiographic and body composition parameters and clinical indicators were compared. Associations between echocardiographic findings and basic characteristics were performed by Spearman’s correlations. Univariate and multivariate binary logistic regression analysis were used to determine the associations between DSI and ECW/TBW in the study groups and the incidence of left ventricular hypertrophy (LVH) and elevated left ventricular filling pressure (ELVFP). In addition, the subgroup effects of DSI and ECW/TBW on cardiac abnormalities were estimated using Cox regression.ResultsOf the enrolled patients with CKD, the median urinary protein was 0.94 (0.28–3.14) g/d and estimated glomerular filtration rate (eGFR) was 92.05 (IQR: 64.52–110.99) mL/min/1.73 m2. The distributions of CKD stages G1–G4 in the four groups was significantly different (p = 0.020). Furthermore, compared to group 1 (low DSI and low ECW/TBW), group 4 (high DSI and high ECW/TBW) showed a 2.396-fold (95%CI: 1.171–4.902; p = 0.017) excess risk of LVH and/or ELVFP incidence after adjusting for important CKD and cardiovascular disease risk factors. Moreover, combined with eGFR, DSI and ECW/TBW could identify patients with higher cardiac dysfunction risk estimates with an AUC of 0.704 (sensitivity: 75.2%, specificity: 61.0%). The specificity increased to 85.7% in those with nephrotic proteinuria (AUC = 0.713). The magnitude of these associations was consistent across subgroups analyses.ConclusionThe combination of high DSI (>6 g/d) and high ECW/TBW (>0.439) independently predicted a greater risk of LVH or ELVFP incidence in non-dialysis CKD patients. Moreover, the inclusion of eGFR and proteinuria improved the risk stratification ability of DSI and ECW/TBW in cardiac impairments in CKD.

This study aims to explore the relationships between renal function, hypoxia, and oxidative stress in chronic kidney disease (CKD). Seventy-six non-dialysis patients with CKD stages 1-5 and eight healthy subjects were included in the clinical research. They were divided into three groups: healthy subjects, CKD stages 1-3, and CKD stages 4-5. In the animal study, 16 rat models of CKD were established through 5/6 renal ablation/infarction (A/I) surgery, and 8 normal rats were split into 3 groups: Sham, CKD, and losartan groups. Blood oxygenation level-dependent magnetic resonance imaging (BOLD-MRI) was used to measure cortical and medullary T2* values (COT2* and MET2*) in all subjects and rats to evaluate renal oxygenation. Biochemical indicators were used to assess renal function and antioxidant capacity. Furthermore, the effects of losartan on renal fibrosis, hypoxia, and oxidative stress were examined using immunoblotting, colorimetric, and fluorometric assays. The results demonstrated significant positive associations between COT2* and MET2* with estimated glomerular filtration rate (eGFR). Patients with CKD stages 4-5 showed significantly lower serum superoxide dismutase (SOD) levels, which also had positive correlations with eGFR, COT2*, and MET2*. Furthermore, losartan treatment resulted in improved renal function and fibrosis, leading to increased levels of COT2*, MET2*, and SOD levels in 5/6 A/I rats. This was accompanied by reduced levels of hypoxia-inducible factor-1 alpha (HIF-1α) and malondialdehyde. Furthermore, losartan restored the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and suppressed the expression of Kelch-like ECH-associated protein 1 (Keap1) in 5/6 A/I kidneys. The study indicates that decline in renal oxygenation and antioxidant capacity is associated with the severity of renal failure in CKD. Losartan can potentially alleviate renal hypoxia and oxidative stress in the treatment of CKD via Keap1-Nrf2/HO-1 pathway.

BackgroundStickler syndrome is a hereditary connective tissue disorder associated with ocular, orofacial, musculoskeletal, and auditory impairments. Its main clinical characteristics include retinal detachment, hearing loss, and midface underdevelopment. In clinical practice, macrocyst is rarely reported in retinal detachment cases with Stickler syndrome.Case presentationWe report the case of a 7-year-old child who developed a rhegmatogenous retinal detachment (RRD) in the right eye, accompanied by multiple peripheral macrocysts. The detachment was successfully surgically repaired with vitrectomy, retinal laser photocoagulation, cryotherapy and silicone oil tamponade. During the operation, a mini-retinectomy in the outer layer of each macrocyst was made for vesicular drainage and retinal reattachment. Genetic testing identified a pathogenic point mutation variant (c.1693C>T; p.Arg565Cys) in exon 26 of the COL2A1 gene. Six-months after the operation, the retina remained attached with improvement of best corrected visual acuity to 20/200.ConclusionPatients with Stickler syndrome may develop RRD of different severity. Macrocyst is rarely reported in previous literature of Stickler syndrome. In this case report, we share our experience in treating with multiple macrocysts in RRD and emphasize the importance of periodic follow-up for patients with Stickler syndrome.

The incidence rate of Parkinson's disease (PD) is increasing yearly. Neuronal apoptosis caused by abnormal protein phosphorylation is closely related to the pathogenesis of Parkinson's disease. At present, few PD-specific apoptosis pathways have been revealed. To investigate the effect of Baichanting (BCT) on apoptosis from the perspective of protein phosphorylation, α-syn transgenic mice were selected to observe the behavioral changes of the mice, and the apoptosis of substantia nigra cells were detected by the HE method and TUNEL method. Network pharmacology combined with phosphorylation proteomics was used to find relevant targets for BCT treatment of PD and was further verified by PRM and western blotting. BCT improved the morphology of neurons in the substantia nigra and reduced neuronal apoptosis. The main enriched pathways in the network pharmacology results were apoptosis, the p53 signaling pathway and autophagy. Western blot results showed that BCT significantly regulated the protein expression levels of BAX, Caspase-3, LC3B, P53 and mTOR and upregulated autophagy to alleviate apoptosis. Using phosphorylated proteomics and PRM validation, we found that Pak5, Grin2b, Scn1a, BcaN, L1cam and Braf are closely correlated with the targets of the web-based pharmacological screen and may be involved in p53/mTOR-mediated autophagy and apoptosis pathways. BCT can inhibit the activation of the p53/mTOR signaling pathway, thereby enhancing the autophagy function of cells, and reducing the apoptosis of neurons which is the main mechanism of its neuroprotective effect.

Background: /aims: Atherosclerosis (AS) is the common pathological basis of a variety of cardiovascular diseases (CVD), and has become the main cause of human death worldwide, and the incidence is increasing and younger trend. Ginsenoside Rb1 (Rb1), an important monomer component of the traditional Chinese herb ginseng, known for its ability to improve blood lipid disorders and anti-inflammatory. In addition, Rb1 was proved to be an effective treatment for AS. However, the effect of Rb1 on AS remains to be elucidated. The aim of this study was to investigate the mechanisms of Rb1 in ameliorating AS induced by high-fat diet (HFD). Materials and methods: In this study, we developed an experimental AS model in Sprague-Dawley rats by feeding HFD with intraperitoneal injection of vitamin D3. The potential therapeutic mechanism of Rb1 in AS rats was investigated by detecting the expression of inflammatory factors, microbiome 16S rRNA gene sequencing, short-chain fatty acids (SCFAs) targeted metabolomics and untargeted metabolomics. Results: Rb1 could effectively alleviate the symptoms of AS and suppress the overexpression of inflammation-related factors. Meanwhile, Rb1 altered gut microbial composition and concentration of SCFAs characterized by Bacteroidetes, Actinobacteria, Lactobacillus, Prevotella, Oscillospira enrichment and Desulfovibrio depletion, accompanied by increased production of acetic acid and propionic acid. Moreover, untargeted metabolomics showed that Rb1 considerably improved faecal metabolite profiles, particularly arachidonic acid metabolism and primary bile acid biosynthesis. Conclusion: Rb1 ameliorated the HFD-induced AS, and the mechanism is related to improving intestinal metabolic homeostasis and inhibiting systemic inflammation by regulating gut microbiota.

Abstract Background Blinding drugs through simulation techniques is an important means to control the subjective bias of investigators and subjects. However, clinical trials face significant challenges in the placebo production of drugs, and many trials cannot be double-blinded. Objective This study was conducted to ascertain the consistency between non-blind and blind evaluation results in clinical trials and to pioneer strategies to control information bias, particularly in trials where double-blinding is not feasible. Methods In this investigation, a randomized controlled trial (RCT) studying diabetic foot infections (DFIs) was utilized as a representative case. In this trial, the grading of DFIs, as per guidelines by the Infectious Disease Society of America (IDSA) and International Working Group on Diabetic Foot (IWGDF), was used as the primary efficacy indicator. A sample of sixteen patients was randomly chosen from the RCT, and DFI grading was assessed jointly by both non-blinded investigators and blinded center-reading investigators. A consistency test was then deployed to compare the evaluation results, forming the basis for our proposed strategies for effective blinded evaluation. In addition, other perspectives were collected at the end of this study, including with those involved in designing and conducting the recent blinded evaluation trial. Results Five subjects were excluded due to the quality of photos or the lack of post-treatment visits. The post-treatment IDSA/IWGDF grading results were compared in 11 subjects (experimental group=6, control group=5), and the consistency test showed inconsistent results between the non-blinded and center reading blinded evaluations (Kappa=0.248, p=0.384). In the experimental group, three cases were judged as grade 1 in the non-blinded evaluation and grade 2 in the central reading blinded evaluation; in the control group, three cases were judged as grade 2 in the non-blinded evaluation and grade 1 in the central reading blinded evaluation. The sum of these two cases in 22 post-treatment determinations was 27% (6/22). Furthermore, researchers propose several strategies for implementing blinded evaluations in clinical trials after this trial, which encompass aspects such as staff allocation, training, participant management, trial drug administration, efficacy indicator collection, and safety event management. Conclusions The study highlighted that evaluations from non-blinded site investigators may potentially exaggerate the efficacy of the experimental group and that deep wounds can present challenges for observation via center-reading photos. These findings underline the vital necessity for objective assessment in open clinical trials, especially those where wound observation serves as the primary efficacy indicator. The study suggests the adoption of independent blinded investigators at each site, complemented by a comprehensive set of standard operating procedures for blinding evaluation. These measures could serve as an effective counterbalance to subjective bias, thereby augmenting the credibility and consistency of results in open clinical trials. The implications of these findings and recommendations could be of great significance for the design and execution of future open clinical trials, potentially bolstering the quality of clinical research in this area. Trial registration ChiCTR2000041443. Registered on December 2020

Abstract The measurements on a few pentaquarks states $$P_c(4440)$$ P c ( 4440 ) , $$P_c(4457)$$ P c ( 4457 ) and $$P_{cs}(4459)$$ P cs ( 4459 ) excite our new interests about their structures. Since the masses of $$P_c(4440)$$ P c ( 4440 ) and $$P_c(4457)$$ P c ( 4457 ) are close to the threshold of $$\Sigma _c{\bar{D}}^*$$ Σ c D ¯ ∗ , in the earlier works, they were regarded as molecular states of $$\Sigma _c{\bar{D}}^*$$ Σ c D ¯ ∗ with quantum numbers $$I(J^P)=\frac{1}{2}(\frac{1}{2}^-)$$ I ( J P ) = 1 2 ( 1 2 - ) and $$\frac{1}{2}(\frac{3}{2}^-)$$ 1 2 ( 3 2 - ) , respectively. In a similar way $$P_{cs}(4459)$$ P cs ( 4459 ) is naturally considered as a $$\Xi _c{\bar{D}}^*$$ Ξ c D ¯ ∗ bound state with $$I=0$$ I = 0 . Within the Bethe-Salpeter (B-S) framework we systematically study the possible bound states of $$\Lambda _c\bar{D}^*$$ Λ c D ¯ ∗ , $$\Sigma _c{\bar{D}}^*$$ Σ c D ¯ ∗ , $$\Xi _c{\bar{D}}^*$$ Ξ c D ¯ ∗ and $$\Xi _c'{\bar{D}}^*$$ Ξ c ′ D ¯ ∗ . Our results indicate that $$\Sigma _c{\bar{D}}^*$$ Σ c D ¯ ∗ can form a bound state with $$I(J^P)=\frac{1}{2}(\frac{1}{2}^-)$$ I ( J P ) = 1 2 ( 1 2 - ) , which corresponds to $$P_c(4440)$$ P c ( 4440 ) . However for the $$I(J^P)=\frac{1}{2}(\frac{3}{2}^-)$$ I ( J P ) = 1 2 ( 3 2 - ) system the attraction between $$\Sigma _c$$ Σ c and $${\bar{D}}^*$$ D ¯ ∗ is too weak to constitute a molecule, so $$P_{c}(4457)$$ P c ( 4457 ) may not be a bound state of $$\Sigma _c{\bar{D}}^*$$ Σ c D ¯ ∗ with $$I(J^P)=\frac{1}{2}(\frac{3}{2}^-)$$ I ( J P ) = 1 2 ( 3 2 - ) . As $$\Xi _c{\bar{D}}^*$$ Ξ c D ¯ ∗ and $$\Xi _c'{\bar{D}}^*$$ Ξ c ′ D ¯ ∗ systems we take into account of the mixing between $$\Xi _c$$ Ξ c and $$\Xi '_c$$ Ξ c ′ and the eigenstets should include two normal bound states $$\Xi _c{\bar{D}}^*$$ Ξ c D ¯ ∗ and $$\Xi _c'{\bar{D}}^*$$ Ξ c ′ D ¯ ∗ with $$I(J^P)=\frac{1}{2}(\frac{1}{2}^-)$$ I ( J P ) = 1 2 ( 1 2 - ) and a loosely bound state $$\Xi _c{\bar{D}}^*$$ Ξ c D ¯ ∗ with $$I(J^P)=\frac{1}{2}(\frac{3}{2}^-)$$ I ( J P ) = 1 2 ( 3 2 - ) . The conclusion that two $$\Xi _c{\bar{D}}^*$$ Ξ c D ¯ ∗ bound states exist, supports the suggestion that the observed peak of $$P_{cs}(4459)$$ P cs ( 4459 ) may hide two states $$P_{cs}(4455)$$ P cs ( 4455 ) and $$P_{cs}(4468)$$ P cs ( 4468 ) . Based on the computations we predict a bound state $$\Xi _c'{\bar{D}}^*$$ Ξ c ′ D ¯ ∗ with $$I(J^P)=\frac{1}{2}(\frac{1}{2}^-)$$ I ( J P ) = 1 2 ( 1 2 - ) but not that with $$I(J^P)=\frac{1}{2}(\frac{3}{2}^-)$$ I ( J P ) = 1 2 ( 3 2 - ) . Further more accurate experiments will test our approach and results.

Exosomes are tiny vesicles that are actively secreted by a variety of cells, which regulate various physiological and pathological processes of the body by carrying proteins, lipids, miRNAs and other biological molecules. Exocrine microRNAs(miRNAs) stably exist in the body fluid circulation and participate in many pathological processes of organs. In organ fibrosis disease, the content of the exosomal miRNAs shows significant differential expression profile as compared with normal tissues, and promotes or inhibits organ fibrosis by regulating different signal pathways. It is considered to be the latest biological indicator for diagnosing organ fibrosis and judging its degree of fibrosis, and a new therapeutic target for fibrosis disease.

Abstract Despite a wealth of research linking the triglyceride glucose index (TyG index) to metabolic diseases. However, little evidence links the TyG index to all-cause or CVD mortality in middle-aged and elderly individuals with type 2 diabetes (T2D). This study analyzed data from 2998 patients with T2D who participated in the National Health and Nutrition Examination Survey (NHANES) between 1999 and 2018. The TyG index and mortality in middle-aged and elderly T2D patients were investigated using Cox regression models. The nonlinear association between the TyG index and mortality can be understood with the help of a restricted cubic spline (RCS). During a median follow-up period of 82 months, 883 fatalities were observed from all causes and 265 from CVD. The TyG index was found to have a U-shaped relationship with all-cause and CVD mortality in T2D, with cutoffs of 8.95 and 9, respectively, according to the RCS. After controlling for other factors, an increase of 1 unit in the TyG index was related to an increase of 33% in all-cause mortality and 50% in CVD mortality when TyG was ≥ 8.95 and 9. When TyG

In a community, due to the different characteristics of each species, their contributions to community beta diversity may vary. Quantifying the contribution of each species to overall beta diversity (SCBD) is essential for explaining the patterns of beta diversity. However, there is currently limited research linking SCBD with species functional traits, and how species functional traits influence SCBD remains unclear. This study is based on tree census data, species functional traits, and environmental variables from a 15 ha permanent monitoring plot in a tropical karst rainforest in south China. By calculating species-specific SCBD based on abundance and presence–absence data, as well as functional distinctiveness and species ecological niche characteristics (niche position and niche width), we applied structural equation modeling (SEM) to analyze how functional traits, distinctiveness, and niche characteristics jointly influence SCBD. The results revealed that SCBD based on abundance is positively correlated with occupancy and abundance, whereas SCBD based on presence–absence data exhibits a hump-shaped relationship with occupancy and abundance. Species ecological niche characteristics directly influence SCBD, with species occupying central ecological niches having a negative effect on SCBD and niche width having a positive effect. Functional traits and functional distinctiveness indirectly impact SCBD through their influence on species ecological niche characteristics. SEM models based on the presence–absence data provide higher explanatory power. In summary, in the seasonal rainforest communities of northern tropical karst regions in China, the combined effects of species’ functional traits, functional distinctiveness, and ecological niche characteristics determine SCBD. This not only contributes to a deeper understanding of how species traits influence β-diversity, making SCBD a more applicable tool for biodiversity conservation, but also allows for the development of more effective biodiversity protection strategies by elucidating the link between SCBD and ecosystem multifunctionality.

The advancement of virtual coupling technology in urban rail transit has facilitated the online coupling and decoupling of trains, enabling a range of flexible transportation configurations, including various route types and adjustable formations. This study targets the fluctuating passenger demands on urban rail lines, aiming to minimize both passenger travel and operational costs. The model integrates constraints associated with virtual coupling, train operations, rolling stock circulation, and the interaction between virtually coupled trains and passenger arrivals. New decision variables are introduced to depict the train formation state under virtual coupling scenarios. An integrated optimization model for train diagrams and rolling stock circulation under virtual coupling conditions is developed, employing a genetic-simulated annealing algorithm informed by train operation simulations. A case study on an urban rail line during the morning peak examines the optimization of train diagrams for full-length and short-turn routes. Findings confirm that virtual coupling technology effectively adapts to lines with uneven passenger flow distribution, significantly enhancing the match between supply and demand, equalizing spatial and temporal traffic variations, and harmonizing the quality of passenger services with operational efficiency.

Lianas are a crucial component of karst seasonal rainforests, yet research on them has predominantly focused on non-karst regions. Consequently, their abundance and species richness remain relatively understudied within karst ecosystems. We aimed to document the abundance and species richness of lianas and investigate their relationships with abiotic and biotic factors, based on data from a fully mapped 15 ha plot in a karst seasonal rainforest of Nonggang (SW China). Structural equation models (SEMs) were employed to estimate the path coefficients and variation of dependent variables, enabling a comprehensive analysis of the factors affecting the abundance and species richness of liana. Within the 15 ha plot, a total of 23,819 lianas were identified, encompassing 113 species from 34 families. These lianas constituted 24.16% of the total woody plant density and 33.44% of the species present, but only 4.32% of the total woody plant basal area. Lianas are primarily influenced by abiotic factors, especially elevation and phosphorus (P), with less impact from biotic factors. Our findings reveal that lianas, despite constituting a relatively small percentage of the total woody plant basal area, significantly contribute to the density and diversity of the forest. Notably, abiotic factors such as elevation and phosphorus availability predominantly shape the distribution and richness of lianas, highlighting the importance of these environmental variables. The findings offer valuable insights for future liana studies and the preservation of karst forests’ biodiversity.

Abstract Hypertension is the most prevalent chronic disease World-wide, and the leading preventable risk factor for cardiovascular disease (CVD). Few patients accomplish the objective of decreasing blood pressure and avoiding hypertensive target organ damage after treatments with antihypertensive agents which opens the door for other treatments, such as herbal-and antihypertensive combination therapy. Captopril (CAP), as a-pril which inhibits angiotensin converting enzyme has long been used in the management of hypertension and CVD. Gedan Jiangya Decoction (GJD) is known for antihypertensive effects in prior studies. The research is aimed to determine whether GJD in combination with captopril has antihypertensive, kidney protective, antioxidant, and vasoactive effects in spontaneously hypertensive rats (SHR). Regular measurements of systolic and diastolic blood pressure (SBP and DBP), and body weight were monitored weekly. H&E staining was utilized to examine histopathology. The combined effects were studied using ELISA, immunohistochemistry, and qRT-PCR. Significant reductions in SBP, DBP, aortic wall thickness, and improvement in renal tissue were observed following GJD + CAP treatment, with increased serum levels of NO, SOD, GSH-Px, and CAT and decreases in Ang II, ET-1, and MDA. Similarly, GJD + CAP treatment of SHR's significantly decreased ET-1 and AGTR1 mRNA and protein expression while increasing eNOS mRNA and protein expression in thoracic aorta and kidney tissue. In conclusion, the present investigation found that GJD + CAP treatment decreases SHR blood pressure, improves aorta remodeling and renal protection, and that this effect could be attributable, in part, due to antioxidant and vascular tone improvement.

Abstract Objective E2F1 has been confirmed to be highly expressed in a variety of cancers. To better understand the prognostic value of E2F1 in cancer patients, this study was conducted to comprehensively evaluate the prognostic value of E2F1 in cancer according to published data. Method PubMed, Web of Science and CNKI database were searched until May 31th, 2022 by using key words to retrieve the published essays on the role of E2F1 expression in the prognostic value of cancer. The essays were identified according to the inclusion and exclusion criteria. The pooled result of hazard ratio and 95% confidence interval was calculated with Stata17.0 software. Result A total of 17 articles were included in this study involved in 4481 cancer patients. The pooled results showed that higher E2F1 expression was significantly correlated with unfavorable overall survival (HR = 1.10, I 2 = 95.3%, *P Heterogeneity = 0.000) and disease-free survival (HR = 1.41, I 2 = 95.2%, *P Heterogeneity = 0.000) of cancer patients. Such a significant association of was maintained subgroup of sample size of patients (> 150: for OS, HR = 1.77, and for DFS, HR = 0.91; or

BackgroundOpen globe injuries (OGIs) are one of the leading causes of monocular vision loss, and the clinical characteristics of OGIs are region specific. The features and patterns of OGIs in Southwest China are poorly known and not well studied. Our study aimed to review the epidemiological and clinical characteristics of patients hospitalized for OGIs in Southwest China.MethodsA retrospective study of OGI patients admitted to the West China Hospital from January 1st, 2015, to December 31st, 2019, was performed. Demographic characteristics and injury details were recorded. The Birmingham Eye Trauma Terminology system and the ocular trauma score (OTS) were used.ResultsA total of 3,014 patients were included. The male-to-female ratio was 5.2:1, and the mean age was 35.6 ± 19.1 years. 15.2% of patients were from the ethnic groups. The highest-risk occupation was the farmer (30.3%), followed by the worker (28.5%). OGIs occurred more frequently in people with middle (37.0%) and primary school (33.1%) education levels. Types of injuries included 46.8% penetration, 21.2% rupture, 2.9% perforation, and 29.1% intraocular foreign body (IOFB). The injuries types differed between age and occupation groups (p

Introduction: Idiopathic pulmonary fibrosis is a chronic interstitial lung disease characterized by excessive deposition of extracellular matrix. Cannabidiol, a natural component extracted from plant cannabis, has been shown to have therapeutic effects on lung diseases, but its exact mechanism of action is unknown, hindering its therapeutic effectiveness.Methods: To establish a pulmonary fibrosis model, combined with UPLC-Q-TOF/MS metabolomics and 16S rDNA sequencing, to explore cannabidiol’s mechanism in treating pulmonary fibrosis. The rats were randomly divided into the control group, pulmonary fibrosis model group, prednisone treatment group, and cannabidiol low, medium, and high dose groups. The expression levels of HYP, SOD, and MDA in lung tissue and the expression levels of TNF-α, IL-1β, and IL-6 in serum were detected. Intestinal microbiota was detected using UPLC-QTOF/MS analysis of metabolomic properties and 16S rDNA sequencing.Results: Pathological studies and biochemical indexes showed that cannabidiol treatment could significantly alleviate IPF symptoms, significantly reduce the levels of TNF-α, IL-1β, IL-6, MDA, and HYP, and increase the expression level of SOD (p < 0.05). CBD-H can regulate Lachnospiraceae_NK4A136_group, Pseudomonas, Clostridia_UCG-014, Collinsella, Prevotella, [Eubacterium]_coprostanoligenes_group, Fusobacterium, Ruminococcus, and Streptococcus, it can restore intestinal microbiota function and reverse fecal metabolism trend. It also plays the role of fibrosis through the metabolism of linoleic acid, glycerol, linolenic acid, and sphingolipid.Discussion: Cannabidiol reverses intestinal microbiota imbalance and attenuates pulmonary fibrosis in rats through anti-inflammatory, antioxidant, and anti-fibrotic effects. This study lays the foundation for future research on the pathological mechanisms of IPF and the development of new drug candidates.

Carbapenem-resistant Escherichia coli (E. coli) strains are widely distributed and spreading rapidly, creating significant challenges for clinical therapeutics. NDM-5, a novel mutant of New Delhi Metallo-β-Lactamase-1 (NDM-1), exhibits high hydrolase activity toward carbapenems. Since the genetic backgrounds of clinically isolated carbapenem-resistant E. coli are heterogeneous, it is difficult to accurately evaluate the impact of blaNDM–5 on antibiotic resistance. Herein, E. coli BL21 was transformed with a plasmid harboring blaNDM–5, and the resultant strain was named BL21 (pET-28a-blaNDM–5). Consistent with the findings of previous studies, the introduction of exogenous blaNDM–5 resulted in markedly greater resistance of E. coli to multiple β-lactam antibiotics. Compared with BL21 (pET-28a), BL21 (pET-28a-blaNDM–5) exhibited reduced motility but a significant increase in biofilm formation capacity. Furthermore, transcriptome sequencing was conducted to compare the transcriptional differences between BL21 (pET-28a) and BL21 (pET-28a-blaNDM–5). A total of 461 differentially expressed genes were identified, including those related to antibiotic resistance, such as genes associated with the active efflux system (yddA, mcbR and emrY), pili (csgC, csgF and fimD), biofilm formation (csgD, csgB and ecpR) and antioxidant processes (nuoG). Finally, the pGS21a plasmid harboring blaNDM–5 was transformed into E. coli Rosetta2, after which the expression of the NDM-5 protein was induced using isopropyl-β-D-thiogalactoside (IPTG). Using glutathione-S-transferase (GST) pull-down assays, total proteins from E. coli were scanned to screen out 82 proteins that potentially interacted with NDM-5. Our findings provide new insight into the identified proteins to identify potential antibiotic targets and design novel inhibitors of carbapenem-resistant bacteria.

Purpose The purpose of this study was to investigate how aerobic exercise affects oxidative stress (OS) in patients with chronic kidney disease (CKD).Methods Retrieval dates range from the date the database was established to 19 July 2023, without languages being restricted. A meta-analysis and sensitivity analysis were conducted using RevMan 5.3 and Stata 16.0.Results The meta-analysis showed that, compared to usual activity or no exercise, aerobic exercise significantly reduced the oxidative markers malondialdehyde (MDA) (mean differences (MD) − 0.96 (95% CI −1.33, − 0.59); p

Abstract In this work, we study the weak decay between two heavy baryons $${\mathcal {B}}_i(\frac{1}{2}^+)\rightarrow {\mathcal {B}}_f(\frac{3}{2}^+)$$ B i ( 1 2 + ) → B f ( 3 2 + ) in the light-front quark model where three-quark picture is employed for baryon. We derive general form of transition amplitude of $$ {\mathcal {B}}_i(\frac{1}{2}^+)\rightarrow {\mathcal {B}}_f(\frac{3}{2}^+)$$ B i ( 1 2 + ) → B f ( 3 2 + ) , and analyze two specific cases of transitions: the weak decays of single heavy baryon $$\Sigma _{b} \rightarrow \Sigma _{c}^*$$ Σ b → Σ c ∗ and the decays of double-charmed baryon $$\Xi _{cc}\rightarrow \Sigma _{c}^*(\Xi _{c}^*)$$ Ξ cc → Σ c ∗ ( Ξ c ∗ ) . We compute the hadronic form factors for the transitions and apply them to study the decay widths of the semi-leptonic $${\mathcal {B}}_i(\frac{1}{2}^+)\rightarrow {\mathcal {B}}_f(\frac{3}{2}^+) l\bar{\nu }_l$$ B i ( 1 2 + ) → B f ( 3 2 + ) l ν ¯ l and non-leptonic $${\mathcal {B}}_i(\frac{1}{2}^+)\rightarrow {\mathcal {B}}_f(\frac{3}{2}^+)M$$ B i ( 1 2 + ) → B f ( 3 2 + ) M . Previously we studied the transition $$\Sigma _{b} \rightarrow \Sigma _{c}^*$$ Σ b → Σ c ∗ with the quark–diquark picture of baryon in the light-front quark model. Here we revisit this transition with three-quark picture of baryon. At the quark level, the transition $$\Sigma _{b} \rightarrow \Sigma _{c}^*$$ Σ b → Σ c ∗ is induced by the $$b\rightarrow c$$ b → c transition.The subsystem of the two unchanged light quarks which possesses definite and same spin in initial and final state can be viewed as a spectator, so the spectator approximation can be applied directly. For the weak decay of doubly charmed baryon $$\Xi _{cc}$$ Ξ cc , a c quark decays to a light quark $$q_1$$ q 1 , so both the initial state cc and final state $$q_1q_2$$ q 1 q 2 ( $$q_1$$ q 1 and the original $$q_2$$ q 2 in initial state may be the same flavor quarks) which possess definite spin are no longer spectators. A rearrangement of quarks for initial and final states is adopted to isolate the unchanged subsystem $$cq_2$$ c q 2 which can be viewed as the spectator approximately. Future measurements on these channels will constrain the nonperturbative parameter in the wavefunctions and test the model predictions.

Abstract Background The incidence of non-alcoholic fatty liver disease (NAFLD) has been on the rise in recent years, and there are no effective drugs to treat NAFLD; therefore, effective prevention and treatment of NAFLD have become a new challenge. Danggui Shaoyao Powder (DGSY) is a classic prescription commonly used in clinical practice and has been shown to reduce hepatic steatosis in patients with NAFLD. In addition, previous studies have shown that DGSY can alleviate hepatic steatosis and inflammation in NAFLD mice. Although clinical practice and basic studies have shown that DGSY is effective in NAFLD, high levels of clinical evidence are lacking. Therefore, a standardized RCT study protocol is required to evaluate its clinical efficacy and safety. Methods and analysis This study will be a randomized, double-blind, placebo-controlled, and single-center trial. According to the random number table, NAFLD participants will be randomly divided into the DGSY or placebo group for 24 weeks. The follow-up period will be 6 weeks after drug withdrawal. The primary outcome is the relative change in MRI-proton density fat fraction (MRI-PDFF) from baseline to 24 weeks. Absolute changes in serum alanine aminotransferase (ALT), liver stiffness measurement (LSM), body mass index (BMI), blood lipid, blood glucose, and insulin resistance index will be selected as secondary outcomes to comprehensively evaluate the clinical efficacy of DGSY in the treatment of NAFLD. The safety of DGSY will be evaluated by renal function, routine blood and urine tests, and electrocardiogram. Discussion This study will provide evidence-based medical corroboration for the clinical application of DGSY and promote the development and application of this classic prescription. Trial registration http://www.chictr.org.cn . Trial number: ChiCTR2000029144. Registered on 15 Jan 2020.