Spatial characteristics and restructuring model of the agro-cultural heritage site in the context of culture and tourism integration.

Tourism promotes the economic development of agro-cultural heritage sites while causing the problem of spatial alienation, so exploring the spatial alienation problems based on the integration of culture and tourism is of great significance for achieving the sustainable development of tourism in agro-cultural heritage sites. This study took the Yuanyang Hani Terrace agro-cultural heritage site as the research area, constructed the model of the spatial system of the agro-cultural heritage site based on the classical grounded theory, and analyzed the spatial characteristics of the agro-cultural heritage site. The results show that the spatial disorder of the agro-cultural heritage site is caused by the interaction of the imbalance of physical space, the fragmentation of cultural space and the complications of social space. Next, this study constructed the model for the spatial restructuring of the agro-cultural heritage site in the context of culture and tourism integration, with the integration of management systems as a guiding force, the integration of talent systems as a crucial force, the integration of agricultural, cultural and tourism resources as a core force, the integration of the cultural and tourism industries as a driving force, the integration of ecology and culture as a basic force, and the integration of digital scenes as an innovative force. This study expands and deepens the spatial theory of tourist destinations and the knowledge system of cultural heritage tourism, and provides a systematic implementation framework and management tools for the integration of culture and tourism and the high-quality development of agro-cultural heritage sites.

Structural and functional characterization of itaconyl-CoA hydratase and citramalyl-CoA lyase involved in itaconate metabolism of Pseudomonas aeruginosa.

Itaconate is a key anti-inflammatory/antibacterial metabolite in pathogen-macrophage interactions that induces adaptive changes in Pseudomonas aeruginosa-exposed airways. However, the impact and mechanisms underlying itaconate metabolism remain unclear. Our study reveals that itaconate significantly upregulates the expression of pyoverdine in P. aeruginosa and enhances its tolerance to tobramycin. Notably, the enzymes responsible for efficient itaconate metabolism, PaIch and PaCcl, play crucial roles in both utilizing itaconate and clearing its toxic metabolic intermediates. By using protein crystallography and molecular dynamics simulations analyses, we have elucidated the unique catalytic center and substrate-binding pocket of PaIch, which contribute to its highly efficient catalysis. Meanwhile, analysis of PaCcl has revealed how interactions between domains regulate the conformational changes of the active sites and binding pockets, influencing the catalytic process. Overall, our research uncovers the significance and mechanisms of PaIch and PaCcl in the efficient metabolism of itaconate by P. aeruginosa.

Hamiltonian energy in a modified Hindmarsh-Rose model.

This paper investigates the Hamiltonian energy of a modified Hindmarsh-Rose (HR) model to observe its effect on short-term memory. A Hamiltonian energy function and its variable function are given in the reduced system with a single node according to Helmholtz's theorem. We consider the role of the coupling strength and the links between neurons in the pattern formation to show that the coupling and cooperative neurons are necessary for generating the fire or a clear short-term memory when all the neurons are in sync. Then, we consider the effect of the degree and external stimulus from other neurons on the emergence and disappearance of short-term memory, which illustrates that generating short-term memory requires much energy, and the coupling strength could further reduce energy consumption. Finally, the dynamical mechanisms of the generation of short-term memory are concluded.

Gut microbiome-metabolites axis: A friend or foe to colorectal cancer progression.

An expanding corpus of research robustly substantiates the complex interrelation between gut microbiota and the onset, progression, and metastasis of colorectal cancer. Investigations in both animal models and human subjects have consistently underscored the role of gut bacteria in a variety of metabolic activities, driven by dietary intake. These activities include amino acid metabolism, carbohydrate fermentation, and the generation and regulation of bile acids. These metabolic derivatives, in turn, have been identified as significant contributors to the progression of colorectal cancer. This thorough review meticulously explores the dynamic interaction between gut bacteria and metabolites derived from the breakdown of amino acids, fatty acid metabolism, and bile acid synthesis. Notably, bile acids have been recognized for their potential carcinogenic properties, which may expedite tumor development. Extensive research has revealed a reciprocal influence of gut microbiota on the intricate spectrum of colorectal cancer pathologies. Furthermore, strategies to modulate gut microbiota, such as dietary modifications or probiotic supplementation, may offer promising avenues for both the prevention and adjunctive treatment of colorectal cancer. Nevertheless, additional research is imperative to corroborate these findings and enhance our comprehension of the underlying mechanisms in colorectal cancer development.

Role of methylglyoxal and glyoxalase in the regulation of plant response to heavy metal stress.

KEY MESSAGE: Methylglyoxal and glyoxalase function a significant role in plant response to heavy metal stress. We update and discuss the most recent developments of methylglyoxal and glyoxalase in regulating plant response to heavy metal stress. Methylglyoxal (MG), a by-product of several metabolic processes, is created by both enzymatic and non-enzymatic mechanisms. It plays an important role in plant growth and development, signal transduction, and response to heavy metal stress (HMS). Changes in MG content and glyoxalase (GLY) activity under HMS imply that they may be potential biomarkers of plant stress resistance. In this review, we summarize recent advances in research on the mechanisms of MG and GLY in the regulation of plant responses to HMS. It has been discovered that appropriate concentrations of MG assist plants in maintaining a balance between growth and development and survival defense, therefore shielding them from heavy metal harm. MG and GLY regulate plant physiological processes by remodeling cellular redox homeostasis, regulating stomatal movement, and crosstalking with other signaling molecules (including abscisic acid, gibberellic acid, jasmonic acid, cytokinin, salicylic acid, melatonin, ethylene, hydrogen sulfide, and nitric oxide). We also discuss the involvement of MG and GLY in the regulation of plant responses to HMS at the transcriptional, translational, and metabolic levels. Lastly, considering the current state of research, we present a perspective on the future direction of MG research to elucidate the MG anti-stress mechanism and offer a theoretical foundation and useful advice for the remediation of heavy metal-contaminated environments in the future.

Synchronization of inertial complex-valued memristor-based neural networks with time-varying delays.

The synchronization of inertial complex-valued memristor-based neural networks (ICVMNNs) with time-varying delays was explored in the paper with the non-separation and non-reduced approach. Sufficient conditions required for the exponential synchronization of the ICVMNNs were identified with the construction of comprehensive Lyapunov functions and the design of a novel control scheme. The adaptive synchronization was also investigated based on the derived results, which is easier to implement in practice. What's more, a numerical example that verifies the obtained results was presented.

Pattern selection mechanism from the equilibrium point and limit cycle.

The outbreak of infectious diseases often exhibits periodicity, and this periodic behavior can be mathematically represented as a limit cycle. However, the periodic behavior has rarely been considered in demonstrating the cluster phenomenon of infection induced by diffusion (the instability modes) in the SIR model. We investigate the emergence of Turing instability from a stable equilibrium and a limit cycle to illustrate the dynamical and biological mechanisms of pattern formation. We identify the Hopf bifurcation to demonstrate the existence of a stable limit cycle using First Lyapunov coefficient in our spatiotemporal diffusion-driven SIR model. The competition between different instability modes induces different types of patterns and eventually spot patterns emerge as stable patterns. We investigate the impact of susceptible, infected, and recovered individuals on the type of patterns. Interestingly, these instability modes play a vital role in selecting the pattern formations, which is directly related to the number of observed spot patterns. Subsequently, we explain the dynamical and biological mechanisms of spot patterns to develop an effective epidemic prevention strategy.

Silencing lncRNA-DARS-AS1 suppresses nonsmall cell lung cancer progression by stimulating miR-302a-3p to inhibit ACAT1 expression.

Long noncoding RNAs (LncRNAs) have been gaining attention as potential therapeutic targets for lung cancer. In this study, we investigated the expression and biological behavior of lncRNA DARS-AS1, its predicted interacting partner miR-302a-3p, and ACAT1 in nonsmall cell lung cancer (NSCLC). The transcript level of DARS-AS1, miR-302a-3p, and ACAT1 was analyzed using qRT-PCR. Endogenous expression of ACAT1 and the expression of-and changes in-AKT/ERK pathway-related proteins were determined using western blotting. MTS, Transwell, and apoptosis experiments were used to investigate the behavior of cells. The subcellular localization of DARS-AS1 was verified using FISH, and its binding site was verified using dual-luciferase reporter experiments. The binding of DARS-AS1 to miR-302a-3p was verified using RNA co-immunoprecipitation. In vivo experiments were performed using a xenograft model to determine the effect of DARS-AS1 knockout on ACAT1 and NSCLC. lncRNA DARS-AS1 was upregulated in NSCLC cell lines and tissues and the expression of lncRNA DARS-AS1 was negatively correlated with survival of patients with NSCLC. Knockdown of DARS-AS1 inhibited the malignant behaviors of NSCLC via upregulating miR-302a-3p. miR-302a-3p induced suppression of malignancy through regulating oncogene ACAT1. This study demonstrates that the DARS-AS1-miR-302a-3p-ACAT1 pathway plays a key role in NSCLC.

Effect of enhanced recovery after surgery with multidisciplinary collaboration on nursing outcomes after total knee arthroplasty.

BACKGROUND: There is a lack of studies on the effects of enhanced recovery after surgery (ERAS) with multidisciplinary collaboration on the nursing outcomes of total knee arthroplasty (TKA). AIM: To explore the effect of ERAS with multidisciplinary collaboration on nursing outcomes after TKA. METHODS: We retrospectively analyzed the clinical data of 80 patients who underwent TKA at a tertiary hospital between January 2021 and December 2022. The patients were divided into two groups according to the nursing mode: the ERAS group (n = 40) received ERAS with multidisciplinary collaboration, and the conventional group (n = 40) received routine nursing. The following indicators were compared between the two groups: length of hospital stay, hospitalization cost, intraoperative blood loss, hemoglobin level 24 h after surgery, visual analog scale (VAS) score for pain, range of motion (ROM) of the knee joint, Hospital for Special Surgery (HSS) knee score, and postoperative complications. RESULTS: The ERAS group had a significantly shorter length of hospital stay, lower hospitalization cost, less intraoperative blood loss, higher hemoglobin level 24 h after surgery, lower VAS score for pain, higher knee joint ROM, and higher HSS knee score than the conventional group (all P < 0.05). There was no significant difference in the incidence of postoperative complications between the two groups (P > 0.05). CONCLUSION: Multidisciplinary collaboration with ERAS can reduce blood loss, shorten hospital stay, and improve knee function in patients undergoing TKA.

Bifurcation and pattern dynamics in the nutrient-plankton network.

This paper used a Holling-IV nutrient-plankton model with a network to describe algae's spatial and temporal distribution and variation in a specific sea area. The stability and bifurcation of the nonlinear dynamic model of harmful algal blooms (HABs) were analyzed using the nonlinear dynamic theory and de-eutrophication's effect on algae's nonlinear dynamic behavior. The conditions for equilibrium points (local and global), saddle-node, transcritical, Hopf-Andronov and Bogdanov-Takens (B-T) bifurcation were obtained. The stability of the limit cycle was then judged and the rich and complex phenomenon was obtained by numerical simulations, which revealed the robustness of the nutrient-plankton system by switching between nodes. Also, these results show the relationship between HABs and bifurcation, which has important guiding significance for solving the environmental problems of HABs caused by the abnormal increase of phytoplankton.

Activation and induction of antigen-specific T follicular helper cells play a critical role in recombinant SARS-CoV-2 RBD vaccine-induced humoral responses.

The role of follicular T helper (Tfh) cells in humoral response has been considered essential in recent years. Understanding how Tfh cells control complex humoral immunity is critical to developing strategies to improve the efficacy of vaccines against SARS-CoV-2 and other emerging pathogens. However, the immunologic mechanism of Tfh cells in SARS-CoV-2 receptor binding domain (RBD) vaccine strategy is limited. In this study, we expressed and purified recombinant SARS-CoV-2 RBD protein in Drosophila S2 cells for the first time and explored the mechanism of Tfh cells induced by RBD vaccine in humoral immune response. We mapped the dynamic of Tfh cell in lymph node and spleen following RBD vaccination and revealed the relationship between Tfh cells and humoral immune response induced by SARS-CoV-2 RBD vaccine through correlation analysis, blocking of IL-21 signaling pathway, and co-culture of Tfh with memory B cells. Recombinant RBD protein elicited a predominant Tfh1 and Tfh1-17 subset response and strong GC responses in spleen and lymph nodes, especially to enhanced vaccination. IL-21 secreted by Tfh cells affected the development and differentiation of B cells and played a key role in the humoral immune response. These observations will help us further understand the mechanism of protective immune response induced by COVID-19 vaccine and has guiding significance for the development of vaccines against newly emerging mutants.

RUNX1 promotes proliferation and migration in non-small cell lung cancer cell lines via the mTOR pathway.

RUNX1, a member of the RUNX family of metazoan transcription factors, participates in the regulation of differentiation, proliferation, and other processes involved in growth and development. It also functions in the occurrence and development of tumors. However, the role and mechanism of action of RUNX1 in non-small cell lung cancer (NSCLC) are not yet clear. We used a bioinformatics approach as well as in vitro and in vivo assays to evaluate the role of RUNX1 in NSCLC as the molecular mechanisms underlying its effects. Using the TCGA, GEO, GEPIA (Gene Expression Profiling Interactive Analysis), and Kaplan-Meier databases, we screened the differentially expressed genes (DEGs) and found that RUNX1 was highly expressed in lung cancer and was associated with a poor prognosis. Immunohistochemical staining based on tissue chips from 110 samples showed that the expression of RUNX1 in lung cancer tissues was higher than that in adjacent normal tissues and was positively correlated with lymph node metastasis and TNM staging. In vitro experiments, we found that RUNX1 overexpression promoted cell proliferation and migration functions and affected downstream functional proteins by regulating the activity of the mTOR pathway, as confirmed by an analysis using the mTOR pathway inhibitor rapamycin. In addition, RUNX1 affected PD-L1 expression via the mTOR pathway. These results indicate that RUNX1 is a potential therapeutic target for NSCLC.

PHF23 promotes NSCLC proliferation, metastasis, and chemoresistance via stabilization of ACTN4 and activation of the ERK pathway.

At present, non-small cell lung cancer (NSCLC) is still one of the leading causes of cancer-related deaths. Chemotherapy remains the standard treatment for NSCLC. However, the emergence of chemoresistance is one of the major obstacles to lung cancer treatment. Plant homologous structural domain finger protein 23 (PHF23) plays crucial roles in multiple cell fates. However, the clinical significance and biological role of PHF23 in NSCLC remain elusive. The Cancer Genome Atlas data mining, NCBI/GEO data mining, and western blotting analysis were employed to characterize the expression of PHF23 in NSCLC cell lines and tissues. Statistical analysis of immunohistochemistry and the Kaplan-Meier Plotter database were used to investigate the clinical significance of PHF23. A series of in vivo and in vitro assays, including assays for colony formation, cell viability, 5-ethynyl-2'-deoxyuridine (EDU incorporation) and Transwell migration, flow cytometry, RT-PCR, gene set enrichment analysis, co-immunoprecipitation analysis, and a xenograft tumor model, were performed to demonstrate the effects of PHF23 on the chemosensitivity of NSCLC cells and to clarify the underlying molecular mechanisms. PHF23 is overexpressed in NSCLC cell lines and tissues. High PHF23 levels correlate with short survival times and a poor response to chemotherapy in NSCLC patients. PHF23 overexpression facilitates cell proliferation, migration and sensitizes NSCLC cells to Cisplatin and Docetaxel by promoting DNA damage repair. Alpha-actinin-4 (ACTN4), as a downstream regulator, interacts with PHD domain of PHF23. Moreover, PHF23 is involved in ACTN4 stabilization by inhibiting its ubiquitination level. These results show that PHF23 plays an important role in the development and progression of NSCLC and suggest that PHF23 may serve as a therapeutic target in NSCLC patients.

Tumor necrosis factor-like cytokine 1A plays a role in inflammatory bowel disease pathogenesis.

The binding of tumor necrosis factor-like cytokine 1A (TL1A) to death receptor 3 (DR3) plays an important role in the interaction between dendritic cells (DCs) and T cells and contributes to intestinal inflammation development. However, the mechanism by which DCs expressing TL1A mediate helper T (Th) cell differentiation in the intestinal lamina propria (LP) during the pathogenesis of inflammatory bowel disease remains unclear. In this study, we found that TL1A/DR3 promoted Th1 and Th17 cell differentiation in T-T and DC-T cell interaction-dependent manners. TL1A-deficient CD4+ T cells failed to polarize into Th1/Th17 cells and did not cause colonic inflammation in a T cell transfer colitis model. Notably, TL1A was located in the cytoplasm and nuclei of DCs, positively regulated the DC-specific ICAM-grabbing nonintegrin/RAF1/nuclear factor κB signaling pathway, enhanced the antigen uptake ability of DCs, and promoted TLR4-mediated DC activation, inducing naive CD4+ T cell differentiation into Th1 and Th17 cells. Our work reveals that TL1A plays a regulatory role in inflammatory bowel disease pathogenesis.

Assessment of Purity, Stability, and Pharmacokinetics of NGP-1, a Novel Prodrug of GS441254 with Potential Anti-SARS-CoV-2 Activity, Using Liquid Chromatography.

SARS-CoV-2 is a highly contagious and pathogenic virus that first appeared in late December 2019 and caused a global pandemic in a short period. The virus is a single-stranded RNA virus belonging to the Coronaviridae family. Numerous treatments have been developed and tested in response to the pandemic, particularly antiviral drugs. Among them, GS441524 (GS441), a nucleoside antiviral drug, has demonstrated promising results in inhibiting SARS-CoV-2. Nevertheless, the limited oral bioavailability of GS441 restricts its application to patients with the virus. In this study, a novel prodrug of GS441 (NGP-1) with an isobutyl ester and cyclic carbonate structure was designed and synthesized. Its purity and the stability in different artificial digestive juices of NGP-1 was determined with HPLC-DAD methods. The pharmacokinetics of NGP-1 and GS441 were studied in rats via gavage administration. A new LC-MS/MS method was developed to quantitatively analyze GS441 in plasma samples. The results showed that the ka, Cmax, and MRT of converted GS441 from NGP-1 were 5.9, 3, and 2.5 times greater than those of GS441 alone. The Frel of NGP-1 was approximately four-fold that of GS441, with an AUC0-∞ of 9716.3 h·ng mL-1. As a prodrug of GS441, NGP-1 increased its lipophilicity, absorption, and bioavailability, indicating that it holds promise in improving the clinical efficacy of anti-SARS-CoV-2 medications.

Establishment of Novel Mouse Model of Dietary NASH Rapidly Progressing into Liver Cirrhosis and Tumors.

Non-alcoholic steatohepatitis (NASH), which is the most severe manifestation of non-alcoholic fatty liver disease (NAFLD), has been recognized as a major hepatocellular carcinoma (HCC) catalyst. However, the molecular mechanism of NASH-liver fibrosis-HCC sequence remains unclear and a specific and effective treatment for NASH has not yet been established. The progress in this field depends on the availability of reliable preclinical models which show the steady progression to NASH, liver cirrhosis, and HCC. However, most of the NASH mouse models that have been described to date develop NASH generally for more than 24 weeks and there is an uncertainty of HCC development. To overcome such shortcomings of experimental NASH studies, we established a novel NASH-HCC mouse model with very high reproducibility, generality, and convenience. We treated male C57BL/6J mice with a newly developed choline-deficient and methionine-restricted high-fat diet, named OYC-NASH2 diet, for 60 weeks. Treatment of OYC-NASH2 diet for 3 weeks revealed marked steatosis, lobular inflammation, and fibrosis, histologically diagnosed as NASH. Liver cirrhosis was observed in all mice with 48-week treatment. Liver nodules emerged at 12 weeks of the treatment, > 2 mm diameter liver tumors developed in all mice at 24 weeks of the treatment and HCC appeared after 36-week treatment. In conclusion, our rapidly progressive and highly reproducible NASH-liver cirrhosis-HCC model is helpful for preclinical development and research on the pathogenesis of human NAFLD-NASH-HCC. Our mouse model would be useful for the development of novel chemicals for NASH-HCC-targeted therapies.

Epithelial TIPE1 Protein Guards against Colitis by Inhibiting TNF-α-Mediated Inflammation.

Intestinal epithelial cells (IECs) at the internal/external interface orchestrate the mucosal immune response, and IEC dysfunction has been linked to multiple inflammatory diseases, including inflammatory bowel disease. In this study, we found that a member of the TNF-α-induced protein 8 (TNFAIP8 or TIPE) family called TIPE1 is indispensable for maintaining epithelial cell barrier integrity and homeostasis under inflammatory conditions. TIPE1-deficient mice, or chimeric mice that were deficient in TIPE1 in their nonhematopoietic cells, were more sensitive to dextran sulfate sodium-induced experimental colitis; however, TIPE1 deficiency had no impact on the development of inflammation-associated and sporadic colorectal cancers. Mechanistically, TIPE1 prevented experimental colitis through modulation of TNF-α-dependent inflammatory response in IECs. Importantly, genetic deletion of both TIPE1 and its related protein TNFAIP8 in mice led to the development of spontaneous chronic colitis, indicating that both of these two TIPE family members play crucial roles in maintaining intestinal homeostasis. Collectively, our findings highlight an important mechanism by which TIPE family proteins maintain intestinal homeostasis and prevent inflammatory disorders in the gut.

Ionic Microgel Colloidal Crystals: Responsive Chromism in Dual Physical and Chemical Colors for High-End Information Security and Encryption.

Chromic materials play a decisive and escalating role in information security. However, it is challenging to develop chromic materials for encryption technologies that can hardly be imitated. Inspired by versatile metachrosis in nature, a series of coumarin-based 7-(6-bromohexyloxy)-coumarin microgel colloidal crystals (BrHC MGCC) with multiresponsive chromism are able to be assembled by ionic microgels in poly(vinyl alcohol) (PVA) solution followed by two cycles of freezing-thawing. The ionic microgels can be finely tailored by in situ quaternization with tunable size under varied temperatures and hydration energies of counterions as well as quenched luminescence under UV irradiation, which endows BrHC MGCC with intriguing chromism in the dual-channel coloration of physical structural color and chemical fluorescent color. Three types of BrHC MGCC exhibit various change ranges in structural coloration and similar quenching in fluorescence emission, which can be utilized for the development of the static-dynamic combined anticounterfeiting system with dual coloration. The information conveyed by the BrHC MGCC array presents dynamic variation versus temperature, while the static information can be only integrally read in both sunlight and a 365 nm UV lamp. The fabrication of a microgel colloidal crystal with dual coloration opens a facile and ecofriendly window for multilevel information security, camouflage, and a cumbersome authentication process.

The relationship between oxytocin and empathy for others' pain: Testing the mediating effect of first-hand pain sensitivity.

Although previous studies have shown that oxytocin attenuates first-hand pain sensitivity, studies of its effects on empathetic reactions to the observation of others' pain have yielded inconsistent and controversial results. Given the link between first-hand pain and empathy for others' pain, we hypothesized that oxytocin affects empathy for others' pain by modulating first-hand pain sensitivity. Using a double-blind, placebo-controlled, between-participant experimental design, healthy participants (n = 112) were randomly assigned to either an intranasal oxytocin or placebo group. Pain sensitivity was evaluated by pressure pain threshold, and empathetic responses were assessed by ratings in response to viewing video clips depicting others in physically painful scenarios. Results showed that pressure pain thresholds decreased over time in both groups, indicating increased sensitivity to first-hand pain after repeated measurements. However, this decrease was smaller for participants who received intranasal oxytocin, indicative of oxytocin-induced attenuation of first-hand pain sensitivity. In addition, although empathetic ratings were comparable between oxytocin and placebo groups, first-hand pain sensitivity fully mediated the impact of oxytocin on pain empathetic ratings. Thus, intranasal oxytocin can indirectly affect pain empathetic ratings by reducing first-hand pain sensitivity. These findings expand our understanding of the relationship among oxytocin, pain, and empathy.