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Hainan Province is a major domestic tourism destination in China, with rural tourism playing a key role in its development. This study analyzes the spatial distribution of 154 rural tourism sites across Hainan, examining regional balance, hotspots, and influencing factors such as transportation infrastructure, economic conditions, and A-level tourist attractions. Results show a clear spatial clustering of sites, with a strong concentration in the east and more dispersed patterns in the west. Economic growth and tourism sector development are identified as key factors influencing the "coconut-level" ratings. The study offers policy recommendations to promote sustainable rural tourism, including leveraging regional advantages, enhancing transportation connectivity, and improving tourism services and infrastructure. It also calls for investment in grassroots tourism projects and strengthening regional complementarity to foster balanced and equitable growth. These findings provide valuable insights for policymakers and tourism planners seeking to integrate rural tourism into broader sustainable development strategies., Competing Interests: Declarations. Conflict of interest: The authors declare that they have no potential conflict of interests., (© 2025. The Author(s).)

Carbapenem-resistant Pseudomonas aeruginosa (CRPA) is a global threat, but the mechanism of non-carbapenemase carbapenem resistance is still unclear. In the current study, we investigated the contributions of point mutations in mexR , oprD , and ftsI to carbapenem resistance in P. aeruginosa during in vivo evolution studies with consecutive clinical isolates. Real-time qPCR and Electrophoretic Mobility Shift Assay demonstrated that MexR (Gln55Pro) mutation increased MexAB efflux pump genes expression by altering MexR's binding capacity, leading to a four- to eight-fold increase in meropenem MIC in the Pae d1 Green ∆ mexR and PAO1∆ mexR mutants. The OprD (Trp415*) truncation affected porin structure, and the constructed mutant Pae d1 Green oprD Trp415* increased meropenem MIC by 16-fold (from 0.25 to 4 µg/mL). The contribution of ftsI mutation to meropenem resistance was confirmed by clinical linkage analysis and was estimated to cause a two-fold increase in meropenem MIC by comparing the resistant clinical isolate with the Pae d1 Green oprD Trp415*∆ mexR double mutant. The study found that the oprD Trp415* allele alone accounts for the imipenem MIC in clinical isolates, while the ∆ mexR and ftsI Arg504Cys alleles do not contribute to imipenem resistance. In conclusion, we identified and explored the contributions of mexR , oprD, and ftsI mutations to high level non-carbapenemase carbapenem resistance in P. aeruginosa . These findings highlight the interplay of different mutations in causing non-carbapenemase carbapenem-resistance in P. aeruginosa ., Importance: The emergence of carbapenem-resistant Pseudomonas aeruginosa (CRPA) poses a significant global health threat, complicating treatment options for infections caused by this pathogen. Understanding the mechanisms behind non-carbapenemase carbapenem resistance is critical for developing effective therapeutic strategies. This study provides crucial insights into how specific point mutations in key genes- mexR , oprD , and ftsI -contribute to carbapenem resistance, particularly the MexR (Gln55Pro) mutation's effect on efflux pump expression and the OprD (Trp415*) truncation's impact on porin structure. The findings elucidate the complex interplay of these mutations, highlighting their roles in conferring high-level resistance, and underscore the imperative for continued research to inform therapeutic strategies against CRPA infections., Competing Interests: The authors declare no conflict of interest.

Protein phosphorylation plays an important role in immune signaling transduction in plant resistance to pathogens. Wheat stripe rust, caused by Puccinia striiformis f. sp. tritici (Pst), severely devastates wheat production. Nonetheless, the molecular mechanism of wheat resistance to stripe rust remains limited. In this study, quantitative phosphoproteomics was employed to investigate the protein phosphorylation changes in wheat challenged by Pst. A total of 1537 and 2470 differentially accumulated phosphoproteins (DAPs) were identified from four early infection stage (6, 12, 18 and 24 h post-inoculation) in incompatible and compatible wheat-Pst interactions respectively. KEGG analysis revealed that Oxidative Phosphorylation, Phosphatidylinositol Signaling, and MAPK signaling processes are distinctively enriched in incompatible interaction, while Biosynthesis of secondary metabolites and RNA degradation process were significantly enriched in compatible interactions. In particular, abundant changes in phosphorylation levels of chloroplast proteins were identified, suggesting the regulatory role of photosynthesis in wheat-Pst interaction, which is further emphasized by protein-protein interaction (PPI) network analysis. Motif-x analysis identified [xxxxSPxxxx] motif, likely phosphorylation sites for defensive response-related kinases, and a new [xxxxSSxxxx] motif significantly enriched in incompatible interaction. The results shed light on the early phosphorylation events contributing to wheat resistance against Pst. Moreover, our study demonstrated that the phosphorylation levels of Nucleoside diphosphate kinase TaNAPK1 are upregulated at 12 hpi with CYR23 and at 24 hpi with CYR31. Transient silencing of TaNAPK1 was able to attenuate wheat resistance to CYR23 and CYR31. Our study provides new insights into the mechanisms underlying Pst-wheat interactions and may provide database to find potential targets for the development of new resistant varieties., (© 2024. The Author(s).)

Purpose: To assess the relationship between flow and geometric parameters in optical coherence tomography angiography images and the risk of incident diabetic retinopathy (DR)., Methods: This prospective, observational cohort study recruited patients with Type 2 diabetes without DR in Guangzhou, China, and followed up annually. A commercially available optical coherence tomography angiography device (DRI OCT Triton; Topcon Inc, Tokyo, Japan) was used to obtain a variety of flow (foveal avascular zone area, vessel density, and vessel length density) and geometric (fractal dimension and blood vessel tortuosity) parameters in superficial capillary plexus (SCP) and deep capillary plexus. The odds ratio (OR) and its 95% confidence interval (CI) were calculated per 1-SD increase in each optical coherence tomography angiography parameter., Results: Over a follow-up of 1 year, 182 of 1,698 participants (10.7%) developed incident DR. After adjusting for conventional risk factors and image quality score, the higher risk of DR onset was significantly associated with the reduced parafoveal vessel density of SCP (OR = 0.81; 95% CI: 0.69, 0.96; P = 0.016), reduced parafoveal vessel length density of SCP (OR = 0.73; 95% CI: 0.59, 0.90; P = 0.003), reduced fractal dimension of SCP (OR = 0.73; 95% CI: 0.61, 0.87; P < 0.001), increased blood vessel tortuosity of SCP (OR = 1.39; 95% CI: 1.18, 1.64; P < 0.001), and increased blood vessel tortuosity of deep capillary plexus (OR = 1.19; 95% CI: 1.01, 1.40; P = 0.033)., Conclusion: Reduced vessel density and impaired vessel geometry posed higher susceptibility for DR onset in patients with Type 2 diabetes, supporting the adoption of optical coherence tomography angiography parameters as early monitoring indicators of the newly incident DR.

Purpose: The purpose of this study was to evaluate the associations between choroidal thickness (CT) and the 2-year incidence of referable diabetic retinopathy (RDR)., Methods: This was a prospective cohort study. Patients with type 2 diabetes in Guangzhou, China, aged 30 to 80 years underwent comprehensive examinations, including standard 7-field fundus photography. Macular CT was measured using a commercial swept-source optical coherence tomography (SS-OCT) device (DRI OCT Triton; Topcon, Tokyo, Japan). The relative risk (RR) with 95% confidence intervals (CIs) was used to quantify the association between CT and new-onset RDR. The prognostic value of CT was assessed using the area under the receiver operating characteristic curve (AUC), net reclassification improvement (NRI), and integrated discrimination improvement (IDI)., Results: A total of 1345 patients with diabetes were included in the study, and 120 (8.92%) of them had newly developed RDR at the 2-year follow-up. After adjusting for other factors, the increased RDR risk was associated with greater HbA1c (RR = 1.35, 95% CI = 1.17-1.55, P < 0.001), higher systolic blood pressure (SBP; RR = 1.02, 95% CI = 1.01-1.03, P = 0.005), lower triglyceride (TG) level (RR = 0.81, 95% CI = 0.69-0.96, P = 0.015), presence of diabetic retinopathy (DR; RR = 8.16, 95% CI = 4.47-14.89, P < 0.001), and thinner average CT (RR = 0.903, 95% CI = 0.871-0.935, P < 0.001). The addition of average CT improved NRI (0.464 ± 0.096, P < 0.001) and IDI (0.0321 ± 0.0068, P < 0.001) for risk of RDR, and it also improved the AUC from 0.708 (95% CI = 0.659-0.757) to 0.761 (95% CI = 0.719-0.804)., Conclusions: CT thinning measured by SS-OCT is an early imaging biomarker for the development of RDR, suggesting that alterations in CT play an essential role in DR occurrence.

Psoriasis and type 2 diabetes mellitus (T2DM) share similar inflammatory pathways in their pathogenesis. The stimulator of interferon genes (STING)-interferon regulatory factor 3 (IRF3) pathway has recently been shown to play an important role in immune and metabolic diseases. In this study, we investigated the activation of the STING-IRF3 pathway in human immortalized keratinocytes (HaCaT) cells treated with palmitic acid (PA) and imiquimod (IMQ). Additionally, we detected the STING-IRF3 pathway in diabetic mice with imiquimod (IMQ)-induced psoriasis and assessed the potential of STING inhibitor C-176. Furthermore, skin samples from patients with psoriasis and diabetes were collected for immunohistochemical analysis. The results indicated that the STING-IRF3 pathway was activated in HaCaT cells. Moreover, the STING pathway was also found to be induced in the skin tissue of diabetic mice with psoriasis; the inflammatory responses were ameliorated by treatment with C-176. In the skin tissue samples of patients with psoriasis and diabetes, immunohistochemistry showed that the expression levels of STING and phosphorylated IRF3 were also significantly increased. Thus, we conclude that the STING-IRF3 pathway is involved in the inflammatory response in the manifestation of psoriasis with T2DM. Inhibition of the activation of the STING pathway can ameliorate the development of psoriasis in diabetes and could be targeted for the development of therapeutic agents for these conditions., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Exosomes participate in many physiological and pathological processes by regulating cell-to-cell communication. This affects the etiology and development of diseases, such as osteoarthritis (OA). Although exosomes in the OA tissue microenvironment are involved in the progression of OA, exosomes derived from therapeutic cells represent a new therapeutic strategy for OA treatment. Recent studies have shown that exosomes participate in OA treatment by regulating the proliferation, apoptosis, inflammation, and extracellular matrix synthesis of chondrocytes. However, studies in this field are scant. This review summarizes the therapeutic properties of exosomes on chondrocytes in OA and their underlying molecular mechanisms. We also discuss the challenges and prospects of exosome-based OA treatment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Xian Bo, Chen, Chang, Hao Ran, Hui Hui, Ya Kun, Wu Kun, Hai Tao and Wen Dan.)

With matrine(MAT) as the model drug, to prepare nano graphene oxide(NGO)-based MAT in situ gel(MAT-NGO-gel), a kind of drug for tumor treatment in combination with phototheraphy, and investigate the physicochemical properties and anti-tumor effects in vivo of MAT-NGO-gel. First, HPLC method was established to measure the content of MAT in the gel. The ultrasonic method was used to load MAT onto the surface of NGO, and then poloxamer 188 and poloxamer 407 were chosen as the main materials to prepare MAT-NGO-gel. The optimum prescription was selected with the gelation temperature as the index. Finally, the drug loading rate, micromorphology, phototherrmal conversion characteristics and drug release in vitro of MAT-NGO-gel were characterized. In the optimized prescription, the concentration of poloxamer 188 and poloxamer 407 was 2% and 20% respectively, and the mass ratio of NGO and MAT was 1∶1. The gelation temperature and drug loading rate of MAT-NGO-gel prepared by the optimal prescription process was 37.5 ℃ and 16.7%. Under 808 nm laser irradiation, MAT-NGO-gel showed obvious concentration-and time-dependent photothermal conversion characteristics. In vitro release experiments showed that MAT-NGO-gel had temperature-dependent release characteristics. The pharmacodynamics of MAT solution, NGO-gel and MAT-NGO-gel were studied by using S180 tumor-bearing mice and 808 nm laser. The relative tumor volume and body weight of the tumor-bearing mice were plotted over time. After the experiment, the tumor tissues of each group were taken and the histopathological changes were observed by HE staining. The results of pharmacodynamic studies demonstrated that when compared with NS group and NGO-gel group, the body weights of mice in MAT-NGO-gel group and MAT-NGO-gel + laser group were higher, and the relative tumor volume growth was slower. The results of HE stained pathological sections showed that the tumor cells count for the mice in MAT-NGO-gel group and MAT-NGO-gel + laser group was significantly reduced, with obvious nuclear fragmentation and nucleolysis in these two groups. These results suggested that MAT-NGO-gel, especially combined with 808 nm laser, had stronger anti-tumor activity in vivo. The prescription process of MAT-NGO-gel in this experiment was stable and feasible. As compared with MAT solution, MAT-NGO-gel showed obvious sustained and temperature-dependent drug release characteristics. MAT-NGO-gel had much more obvious anti-tumor activity in vivo when combined with 808 nm laser irradiation. This study could provide certain theoretical basis for the therapy of malignant tumor with multiple mechanisms.

We have used the additive manufacturing technology of selective laser sintering (SLS), together with post SLS heat treatment, to produce porous three dimensional scaffolds from the glass-ceramic apatite-wollastonite (A-W). The A-W scaffolds were custom-designed to incorporate a cylindrical central channel to increase cell penetration and medium flow to the center of the scaffolds under dynamic culture conditions during in vitro testing and subsequent in vivo implantation. The scaffolds were seeded with human bone marrow mesenchymal stromal cells (MSCs) and cultured in spinner flasks. Using confocal and scanning electron microscopy, we demonstrated that MSCs formed and maintained a confluent layer of viable cells on all surfaces of the A-W scaffolds during dynamic culture. MSC-seeded, with and without osteogenic pre-differentiation, and unseeded A-W scaffolds were implanted subcutaneously in MF1 nude mice where osteoid formation and tissue in-growth were observed following histological assessment. The results demonstrate that the in vivo biocompatibility and osteo-supportive capacity of A-W scaffolds can be enhanced by SLS-custom design, without the requirement for osteogenic pre-induction, to advance their potential as patient-specific bone replacement materials., (© 2015 Wiley Periodicals, Inc.)

Objective: This study aimed to investigate the effects of hirudin on the expression of transforming growth factor (TGF-β1) and basic fibroblast growth factor (bFGF) in human gingival fibroblasts (HGFs) in vitro, as well to explore its func- tion in the mechanism of gingival remodeling., Methods: After culturing was performed with classic tissue-explant method, HGFs were derived from normal gingival and gingival hyperplasia tissues followed by orthodontic treatments with different concentrations of hirudin. The mRNA and protein expression levels of TGF-β1 and bFGF were respectively detected by real time quantity polymerase chain reaction and immunocytochemistry., Results: Compared with normal HGFs, TGF-β1 expression promoted collagen synthesis of fibroblasts, whereas bFGF collagen synthesis was decreased in hyperplasia HGFs without hirudin (P < 0.05). Hirudin significantly upregulated the expression levels of bFGF but downregulated TGF-β1 in hyperplasia HGFs (P < 0.05)., Conclusion: Orthodontic force may influence the balance of collagen synthesis and degradation in HGFs. Hirudin may modulate the balance of HGF collagen metabolism, thereby promoting gingival remodeling.

Listeria monocytogenes (LM) is a zoonotic pathogen that widely adapts to various environments. Recent studies have found that noncoding RNAs (ncRNAs) play regulatory roles in LM responses to environmental stress. To understand the role of ncRNA rli87 in the response regulation, a rli87 deletion strain LM-Δrli87 was constructed by homologous recombination and tested for stress responses to high temperature, low temperature, high osmotic pressure, alcohol, acidity, alkaline and oxidative environments, along with LM EGD-e strain (control). The results showed that compared with LM EGD-e, LM-Δrli87 grew faster (P < 0.05) at low temperature (30 °C), high temperature (42 °C), and in alkaline condition (pH = 9), similarly (P > 0.05) in acidic and high osmatic pressure (10% NaCl) conditions. When cultured in medium containing 3.8% ethanol, the growth was not significantly different between the two strains (P > 0.05). When cultured at pH 9, they had similar growth rates in the first 5 h (P > 0.05), but the rates were significantly different after 6 h (P < 0.05). The expression of rsbV, rsbW, hpt, clpP, and ctsR was upregulated in LM-∆rli87 compared with LM EGD-e at pH 9, indicating that the rli87 gene regulated the expression of the five genes in alkaline environment. Our results suggest that the rli87 gene has an important regulatory role in LM's response to temperature (30 and 42 °C), alkaline stresses., (© 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.)

Deposition of β -amyloid (Aβ) peptides, cleavage products of β-amyloid precursor protein (APP) by β-secretase-1 (BACE1) and γ-secretase, is a neuropathological hallmark of Alzheimer's disease (AD). γ-Secretase inhibition is a therapeutical anti-Aβ approach, although changes in the enzyme's activity in AD brain are unclear. Cerebrospinal fluid (CSF) Aβ peptides are thought to derive from brain parenchyma and thus may serve as biomarkers for assessing cerebral amyloidosis and anti-Aβ efficacy. The present study compared active γ-secretase binding sites with Aβ deposition in aged and AD human cerebrum, and explored the possibility of Aβ production and secretion by the choroid plexus (CP). The specific binding density of [(3) H]-L-685,458, a radiolabeled high-affinity γ-secretase inhibitor, in the temporal neocortex and hippocampal formation was similar for AD and control cases with similar ages and post-mortem delays. The CP in post-mortem samples exhibited exceptionally high [(3) H]-L-685,458 binding density, with the estimated maximal binding sites (Bmax) reduced in the AD relative to control groups. Surgically resected human CP exhibited APP, BACE1 and presenilin-1 immunoreactivity, and β-site APP cleavage enzymatic activity. In primary culture, human CP cells also expressed these amyloidogenic proteins and released Aβ40 and Aβ42 into the medium. Overall, our results suggest that γ-secretase activity appears unaltered in the cerebrum in AD and is not correlated with regional amyloid plaque pathology. The CP appears to be a previously unrecognised non-neuronal contributor to CSF Aβ, probably at reduced levels in AD., (© 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.)

Background and Objective: It remains unclear whether angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) can inhibit neointimal hyperplasia after stent implantation in patients with coronary artery disease. The aim of this meta-analysis was therefore to evaluate the benefits of ARBs in patients after coronary stent implantation based on the currently available randomized controlled trials., Methods: We conducted a pooled analysis of randomized controlled trials to compare outcomes after stent implantation in patients administered ARBs with those not administered ARBs. We searched Ovid/MEDLINE, EMBASE, and the ISI web of knowledge using the terms 'angiotensin receptor blocker,' 'renin angiotensin system inhibitor,' 'angiotensin receptor antagonist,' 'stent,' 'angiograph,' 'percutaneous coronary intervention (PCI),' and 'coronary artery disease.' Published meta-analyses, review articles, and editorials were reviewed for potential studies of interest. The inclusion criteria were randomized controlled trials published in English, with a follow-up period of 6 months, comparing the outcomes after coronary stent implantation with and without the administration of any kind of ARB, reporting at least one outcome of interest (restenosis rate and late lumen loss). Data abstraction included study design, patient characteristics, follow-up period, type of ARB, type of stent, restenosis rate, and late lumen loss. Fixed-effects models were used to calculate the pooled relative risk for the restenosis rate and the standardized mean difference for late lumen loss., Results: Five studies were included, with a total number of 624 patients. Seventy-five of 314 patients in the ARB group were diagnosed with in-stent restenosis at the 6-month follow-up, compared with 87 of 310 patients in the control group (relative risk 0.85; 95% CI 0.65, 1.11; p = 0.23). Consistent with this, there was no significant difference in late lumen loss between the two groups (0.04 mm; 95% CI -0.15, 0.23; p = 0.66)., Conclusion: There is no evident benefit with the use of an ARB in terms of inhibition of neointimal hyperplasia in patients after coronary stent implantation.

Background and Aim of the Study: By investigating the expression and function of RhoA/Rho kinase pathway in the radial artery (RA), internal mammary artery (IMA), and great saphenous vein (GSV), this study aimed to elucidate the mechanism for a higher susceptibility of spasm in the RA and provide an effective drug candidate to prevent and treat RA spasm., Methods: RA, IMA, and GSV that would otherwise have been discarded were collected from 25 patients who underwent coronary artery bypass grafting. Eleven matched rings of RA, IMA, and GSV were used to evaluate the vasodilatory properties of 10(-7-)10(-4) mol/l of fasudil, a Rho-kinase inhibitor, by using in vitro organ chambers. Another 14 matched RA, IMA, and GSV were used to demonstrate the immunohistochemistry (IHC) of RhoA and mRNA of RhoA and Rho kinase., Results: The maximal vasodilation of RA to fasudil was significantly greater than IMA. RhoA protein IHC staining was different in IMA, RA, and GSV (RA > GSV >IMA). The expression of RhoA and Rho kinase mRNA in the RA was significantly greater than in the IMA., Conclusions: The expression of RhoA/Rho kinase mRNA and protein and function in the RA were significantly stronger than in the IMA, suggesting that RhoA/Rho kinase pathway may be one mechanism by which RA is more susceptible to spasm than IMA. Rho kinase inhibitors can be effective drug candidates to prevent and treat vasospasm.