N6-methyladenosine-driven miR-143/145-KLF4 circuit orchestrates the phenotypic switch of pulmonary artery smooth muscle cells.

Pulmonary hypertension (PH) is characterized by vascular remodeling predominantly driven by a phenotypic switching in pulmonary artery smooth muscle cells (PASMCs). However, the underlying mechanisms for this phenotypic alteration remain incompletely understood. Here, we identified that RNA methyltransferase METTL3 is significantly elevated in the lungs of hypoxic PH (HPH) mice and rats, as well as in the pulmonary arteries (PAs) of HPH rats. Targeted deletion of Mettl3 in smooth muscle cells exacerbated hemodynamic consequences of hypoxia-induced PH and accelerated pulmonary vascular remodeling in vivo. Additionally, the absence of METTL3 markedly induced phenotypic switching in PASMCs in vitro. Mechanistically, METTL3 depletion attenuated m6A modification and hindered the processing of pri-miR-143/145, leading to a downregulation of miR-143-3p and miR-145-5p. Inhibition of hnRNPA2B1, an m6A mediator involved in miRNA maturation, similarly resulted in a significant reduction of miR-143-3p and miR-145-5p. We demonstrated that miR-145-5p targets Krüppel-like factor 4 (KLF4) and miR-143-3p targets fascin actin-bundling protein 1 (FSCN1) in PASMCs. The decrease of miR-145-5p subsequently induced an upregulation of KLF4, which in turn suppressed miR-143/145 transcription, establishing a positive feedback circuit between KLF4 and miR-143/145. This regulatory circuit facilitates the persistent suppression of contractile marker genes, thereby sustaining PASMC phenotypic switch. Collectively, hypoxia-induced upregulation of METTL3, along with m6A mediated regulation of miR-143/145, might serve as a protective mechanism against phenotypic switch of PASMCs. Our results highlight a potential therapeutic strategy targeting m6A modified miR-143/145-KLF4 loop in the treatment of PH.

Netographic narratives of user-generated travelogues on tourist destination image of Thailand.

The image of a tourist destination is considered a vital aspect of international travel experiences, yet research in this area remains limited. Adopting a combination of netography and qualitative research methodology, this study aims to contribute to the scientific knowledge of destination image development in Thailand by analysing online travelogues to evaluate how Chinese tourists interpret the idea of destination image. To achieve this goal, 146,641 words of Chinese internet comments containing the keyword "Thailand" from four major media sources and Chinese bloggers were gathered and analysed using netography methodology. The findings showed that there was a rise in public interest, in public forums, in the destination image of Thailand among Chinese outbound tourists. The study's results may provide important fundamental theoretical insights and inspire further investigation into the issue of destination image construction.

The perceived value of local knowledge tourism: dimension identification and scale development.

Introduction: Local knowledge tourism encompasses the rich cultural heritage, historical narratives, and traditional practices of a specific destination. Despite its significance in enhancing the tourist experience, there is a dearth of research examining the subjective perceptions and values of visitors engaging in local knowledge tourism. Consequently, there is a pressing need to explore the composition of perceived tourist values in this unique context. Methods: Due to the exploratory nature of this research, a constructivist grounded theory and content analysis are applied to analyze the data. Results: This study identifies and conceptualizes five distinct dimensions of perceived values in local knowledge tourism: functional value, emotional value, social value, cognitive value, and self-actualization value. Furthermore, an 18-item scale is developed to measure these dimensions quantitatively. Discussion: This research makes several significant contributions: (1) it expands the scope of perceived value research within the tourism domain and enhances our understanding of the tourist experience in local knowledge tourism; (2) it provides a reliable instrument for future quantitative investigations into the behavior and mindset of local knowledge tourists; and (3) it offers theoretical foundations and practical insights for destination managers seeking to develop tourism products tailored to the preferences and expectations of local knowledge tourists.

Roboethics of tourism and hospitality industry: A systematic review.

This study aims to give a comprehensive analysis of customers' acceptance and use of AI gadgets and its relevant ethical issues in the tourism and hospitality business in the era of the Internet of Things. Adopting a PRISMA methodology for Systematic Reviews and Meta-Analyses, the present research reviews how tourism and hospitality scholars have conducted research on AI technology in the field of tourism and the hospitality industry. Most of the journal articles related to AI issues published in Web of Science, ScienceDirect.com and the journal websites were considered in this review. The results of this research offer a better understanding of AI implementation with roboethics to investigate AI-related issues in the tourism and hospitality industry. In addition, it provides decision-makers in the hotel industry with practical references on service innovation, participation in the design of AI devices and AI device applications, meeting customer needs, and optimising customer experience. The theoretical implications and practical interpretations are further identified.

Pro-Poor Hydraulic Governmentality: Sustainable Water Management and Local Livelihoods in Mekong Delta.

This article considers and adds empirical nuances to the recent conceptualization of pro-poor water management. Using the concept of pro-poor hydraulic governmentality along the Vietnam-Cambodia border of ThÆ°ong PhÆ°oc commune, we argue that water management is linked to local rural livelihoods in a complex and dynamic pro-poor mechanism. While certain policies organize local populations according to cost-effectiveness ignoring local customs, the practicalities of dealing with such constraints are much more ambivalent. This article demonstrates the structural pro-poor complexity among sand excavation, riverbank landslides, water management, local livelihoods, and populace resettlement. The government's resettlement plans and the perceptions of residents of these plans are intertwined with a wider political, economic, social, and cultural significance in the context of strong institutional power in Vietnam. Limitations and future research agenda are also indicated in the discussion and conclusion section.

Self-perception evolution among university student TikTok users: evidence from China.

The effects of short movies on social media platforms are gaining worldwide popularity and are now attracting global academic attention. Employing self-perception theory and qualitative research methodology, the study examines the influence of short video applications (TikTok) on app-user engagement and evaluates the self-perceived cognitive psychological understanding of Chinese university students. The findings show that identity, attitude change, emotional perception, and civic engagement are the most influential aspects of Chinese youths' self-perceptions. Furthermore, the positive and negative correlated components influence the distribution of short video values. Such tactical use of personality construction contributes to the present psychological research of Chinese university students.

Enterprise Operational Resilience with Digitalization Approach amid the COVID-19 Era: An Empirical Assessment.

The development of the COVID-19 pandemic has had a devastating impact on one Chinese city that has depended heavily on tourism, which is the core focus of the current study. This article uses phenomenological research methods in qualitative research to conduct semistructured and in-depth interviews with travel agency managers in China Highlights. Through the application of tourism resilience theory in the tourism crisis management domain, this article investigates the performance of China Highlights, a local tourism enterprise in Guilin, China, to restore the functioning and growth of the tourism industry in the postpandemic period. The results show that China's tourism industry is in the early stages of the fast growth stage of economic recovery, and tourism enterprises are faced with a significant challenge in determining how to make sound business choices during the pandemic and after the crisis has passed. It proposes that the tourism resilient theory can serve as a modern crisis management model to facilitate tourism enterprises to revive their performance in times of hardship.

Internationalization, cultural appreciation and institutional governmentality for quality control in transnational higher education cooperation: An empirical assessment.

This article examines the dynamic mechanism of cultural appreciation and institutional governmentality to ensure successful quality control in a transnational higher education collaboration context. Adopting participatory action research and a case study approach, this paper investigates the quality control system in a Chinese tourism university. The present study finds that mutual cultural appreciation, responsible government guidance and institutional governmentality are essential quality control measures for transnational higher education cooperation. The quality control system is suggested to be established to enrich and improve the quality standards of joint international higher education collaboration. This study proposes to expand the international influence and recognition of China-foreign education collaboration through quality international exchange and cooperation.

Pathogenic Mechanisms of Pulmonary Arterial Hypertension: Homeostasis Imbalance of Endothelium-Derived Relaxing and Contracting Factors.

Pulmonary arterial hypertension (PAH) is a progressive and fatal disease. Sustained pulmonary vasoconstriction and concentric pulmonary vascular remodeling contribute to the elevated pulmonary vascular resistance and pulmonary artery pressure in PAH. Endothelial cells regulate vascular tension by producing endothelium-derived relaxing factors (EDRFs) and endothelium-derived contracting factors (EDCFs). Homeostasis of EDRF and EDCF production has been identified as a marker of the endothelium integrity. Impaired synthesis or release of EDRFs induces persistent vascular contraction and pulmonary artery remodeling, which subsequently leads to the development and progression of PAH. In this review, the authors summarize how EDRFs and EDCFs affect pulmonary vascular homeostasis, with special attention to the recently published novel mechanisms related to endothelial dysfunction in PAH and drugs associated with EDRFs and EDCFs.

Geographic proximity, supply chain and organizational glocalized survival: China's e-commerce investments in Indonesia.

Chinese e-commerce companies are in the ascendant into the overseas market, while still lack adequate academic attention. Adopting case study and public policy approaches, this article applies the symbiosis theory, based on the fundamentals of the development data of Chinese e-commerce companies in the Indonesia market, to construct an evaluation model and proposes a strategic orientation to reaching an embedded survival and further development. Through understanding the structural characteristics and developing status of different types of Chinese e-commerce companies going overseas, a detailed investigation to the Chinese e-commerce companies investing in Indonesia has been conducted. Findings show that the production capacity cooperation stage of the two countries has a trend of asymmetric symbiosis gradually developing towards symmetric symbiosis. To promote a continuous economic cooperation between China and Indonesia, this article proposes that the national-level collaboration policies, cross-border e-commerce value chain, as well as organizational-level coordination are the key sectors for reaching the vision of symmetric symbiosis between the two countries. Sectors in infrastructure, trade, capital, and people's mindset intimacy also contribute to construct a symbiosis mechanism for capacity cooperation between the two nations.

Hypoxia-Inducible Factor 2-Alpha Mediated Gene Sets Differentiate Pulmonary Arterial Hypertension.

OBJECTIVES: HIF2α is of vital importance in the regulation of endothelial dysfunction, cell proliferation, migration, and pulmonary vascular remodeling in pulmonary hypertension. Our previous studies demonstrated that conditional and inducible deletion of HIF2α in mouse lung endothelial cells, dramatically protected the mice against vascular remodeling and the development of pulmonary arterial hypertension (PAH). Here, we provide a novel transcriptome insight into the impact of HIF2α in PAH pathogenesis and the potential to use HIF2α-mediated gene sets to differentiate PAH human subjects. METHODS: Using transcriptome data, we first tapped the value of the difference in gene expression profile between wild type (WT) and Hif2a knockdown (KD) cell lines. We considered the deregulated genes between WT and Hif2a-KD cells as HIF2α influenced genes. By examining the lung tissue transcriptome data set with nine controls and eight PAH patients, we evaluated the HIF2α regulatory network in PAH pathogenesis to further determine the identification ability of HIF2α-mediated gene sets in human PAH subjects. On the other hand, using peripheral blood mononuclear cells (PBMCs) transcriptome data from PAH patients and healthy controls, we further validated the potential of the HIF2α-mediated PBMC gene sets as a possible diagnostic tool for PAH. To verify the ability of HIF2α-mediated gene sets for the identification of PAH, endothelial cell-specific Phd2 knockout mice with spontaneous pulmonary hypertension were used for reverse validation experiments. RESULTS: 19 identified GO biological process terms were significantly correlated with the genes down-regulated in Hif2a-KD cells, all of which are strongly related to the PAH pathogenesis. We further assessed the discriminative power of these HIF2α-mediated gene sets in PAH human subjects. We found that the expression profile of the HIF2α-mediated gene sets in lung tissues and PBMCs were differentiated both between controls and PAH patients. Further, a significant positive correlation was observed between hypoxia and Phd2 deficiency mediated gene set expression profiles. As expected, 7 of the 19 significantly down-regulated GO terms in Hif2a-KD cells were found to overlap with the up-regulated GO gene sets in Phd2 EC-/- mice compared to WT controls, suggesting opposing effects of HIF2α and PHD2 on PAH pathogenesis. CONCLUSION: HIF2α-mediated gene sets may be used to differentiate pulmonary arterial hypertension.

Inositol pyrophosphates promote the interaction of SPX domains with the coiled-coil motif of PHR transcription factors to regulate plant phosphate homeostasis.

Phosphorus is an essential nutrient taken up by organisms in the form of inorganic phosphate (Pi). Eukaryotes have evolved sophisticated Pi sensing and signaling cascades, enabling them to stably maintain cellular Pi concentrations. Pi homeostasis is regulated by inositol pyrophosphate signaling molecules (PP-InsPs), which are sensed by SPX domain-containing proteins. In plants, PP-InsP-bound SPX receptors inactivate Myb coiled-coil (MYB-CC) Pi starvation response transcription factors (PHRs) by an unknown mechanism. Here we report that a InsP8-SPX complex targets the plant-unique CC domain of PHRs. Crystal structures of the CC domain reveal an unusual four-stranded anti-parallel arrangement. Interface mutations in the CC domain yield monomeric PHR1, which is no longer able to bind DNA with high affinity. Mutation of conserved basic residues located at the surface of the CC domain disrupt interaction with the SPX receptor in vitro and in planta, resulting in constitutive Pi starvation responses. Together, our findings suggest that InsP8 regulates plant Pi homeostasis by controlling the oligomeric state and hence the promoter binding capability of PHRs via their SPX receptors.

A genetically validated approach for detecting inorganic polyphosphates in plants.

Inorganic polyphosphates (polyPs) are linear polymers of orthophosphate units linked by phosphoanhydride bonds. Polyphosphates represent important stores of phosphate and energy, and are abundant in many pro- and eukaryotic organisms. In plants, the existence of polyPs has been established using microscopy and biochemical extraction methods that are now known to produce artifacts. Here we use a polyP-specific dye and a polyP-binding domain to detect polyPs in plant and algal cells. To develop the staining protocol, we induced polyP granules in Nicotiana benthamiana and Arabidopsis cells by heterologous expression of Escherichia coli polyphosphate kinase 1 (PPK1). Over-expression of PPK1 but not of a catalytically impaired version of the enzyme leads to severe growth phenotypes, suggesting that ATP-dependent synthesis and accumulation of polyPs in the plant cytosol is toxic. We next crossed stable PPK1-expressing Arabidopsis lines with plants expressing the polyP-binding domain of E. coli exopolyphosphatase (PPX1c), which co-localized with PPK1-generated polyP granules. These granules were stained by the polyP-specific dye JC-D7 and appeared as electron-dense structures in transmission electron microscopy sections. Using the polyP staining protocol derived from these experiments, we screened for polyP stores in different organs and tissues of both mono- and dicotyledonous plants. While we could not detect polyP granules in higher plants, we could visualize the polyP-rich acidocalcisomes in the green alga Chlamydomonas reinhardtii.

Two bifunctional inositol pyrophosphate kinases/phosphatases control plant phosphate homeostasis.

Many eukaryotic proteins regulating phosphate (Pi) homeostasis contain SPX domains that are receptors for inositol pyrophosphates (PP-InsP), suggesting that PP-InsPs may regulate Pi homeostasis. Here we report that deletion of two diphosphoinositol pentakisphosphate kinases VIH1/2 impairs plant growth and leads to constitutive Pi starvation responses. Deletion of phosphate starvation response transcription factors partially rescues vih1 vih2 mutant phenotypes, placing diphosphoinositol pentakisphosphate kinases in plant Pi signal transduction cascades. VIH1/2 are bifunctional enzymes able to generate and break-down PP-InsPs. Mutations in the kinase active site lead to increased Pi levels and constitutive Pi starvation responses. ATP levels change significantly in different Pi growth conditions. ATP-Mg2+ concentrations shift the relative kinase and phosphatase activities of diphosphoinositol pentakisphosphate kinases in vitro. Pi inhibits the phosphatase activity of the enzyme. Thus, VIH1 and VIH2 relay changes in cellular ATP and Pi concentrations to changes in PP-InsP levels, allowing plants to maintain sufficient Pi levels.

Molecular characterization of CHAD domains as inorganic polyphosphate-binding modules.

Inorganic polyphosphates (polyPs) are linear polymers of orthophosphate units linked by phosphoanhydride bonds. Here, we report that bacterial, archaeal, and eukaryotic conserved histidine α-helical (CHAD) domains are specific polyP-binding modules. Crystal structures reveal that CHAD domains are formed by two four-helix bundles, giving rise to a central pore surrounded by conserved basic surface patches. Different CHAD domains bind polyPs with dissociation constants ranging from the nano- to mid-micromolar range, but not nucleic acids. A CHAD-polyP complex structure reveals the phosphate polymer binding across the central pore and along the two basic patches. Mutational analysis of CHAD-polyP interface residues validates the complex structure. The presence of a CHAD domain in the polyPase ygiF enhances its enzymatic activity. The only known CHAD protein from the plant Ricinus communis localizes to the nucleus/nucleolus when expressed in Arabidopsis and tobacco, suggesting that plants may harbor polyPs in these compartments. We propose that CHAD domains may be used to engineer the properties of polyP-metabolizing enzymes and to specifically localize polyP stores in eukaryotic cells and tissues.

TWISTED DWARF1 Mediates the Action of Auxin Transport Inhibitors on Actin Cytoskeleton Dynamics.

Plant growth and architecture is regulated by the polar distribution of the hormone auxin. Polarity and flexibility of this process is provided by constant cycling of auxin transporter vesicles along actin filaments, coordinated by a positive auxin-actin feedback loop. Both polar auxin transport and vesicle cycling are inhibited by synthetic auxin transport inhibitors, such as 1-N-naphthylphthalamic acid (NPA), counteracting the effect of auxin; however, underlying targets and mechanisms are unclear. Using NMR, we map the NPA binding surface on the Arabidopsis thaliana ABCB chaperone TWISTED DWARF1 (TWD1). We identify ACTIN7 as a relevant, although likely indirect, TWD1 interactor, and show TWD1-dependent regulation of actin filament organization and dynamics and that TWD1 is required for NPA-mediated actin cytoskeleton remodeling. The TWD1-ACTIN7 axis controls plasma membrane presence of efflux transporters, and as a consequence act7 and twd1 share developmental and physiological phenotypes indicative of defects in auxin transport. These can be phenocopied by NPA treatment or by chemical actin (de)stabilization. We provide evidence that TWD1 determines downstream locations of auxin efflux transporters by adjusting actin filament debundling and dynamizing processes and mediating NPA action on the latter. This function appears to be evolutionary conserved since TWD1 expression in budding yeast alters actin polarization and cell polarity and provides NPA sensitivity.

Keeping it all together: auxin-actin crosstalk in plant development.

Polar auxin transport and the action of the actin cytoskeleton are tightly interconnected, which is documented by the finding that auxin transporters reach their final destination by active movement of secretory vesicles along F-actin tracks. Moreover, auxin transporter polarity and flexibility is thought to depend on transporter cycling that requires endocytosis and exocytosis of vesicles. In this context, we have reviewed the current literature on an involvement of the actin cytoskeleton in polar auxin transport and identify known similarities and differences in its structure, function and dynamics in comparison to non-plant organisms. By describing how auxin modulates actin expression and actin organization and how actin and its stability affects auxin-transporter endocytosis and recycling, we discuss the current knowledge on regulatory auxin-actin feedback loops. We focus on known effects of auxin and of auxin transport inhibitors on the stability and organization of actin and examine the functionality of auxin and/or auxin transport inhibitor-binding proteins with respect to their suitability to integrate auxin/auxin transport inhibitor action. Finally, we indicate current difficulties in the interpretation of organ, time and concentration-dependent auxin/auxin transport inhibitor treatments and formulate simple future experimental guidelines.

Preventive Counseling Services during Primary Care Visits: A Comparison of Health Centers versus Other Physician Offices.

We compared preventive counseling services provided by health centers versus other physician offices. Cross-sectional data came from the 2008 National Ambulatory Medical Care Survey, including 25,177 patient visits in physician offices and 3,345 patient visits in health centers. Despite serving disproportionately more vulnerable patients, health centers provided comparable rates of preventive counseling services, compared with other physician offices: health education (39% vs. 36%), disease management (34% vs. 41%), asthma education (21% vs. 13%), tobacco education (19% for both), and weight reduction education (6% vs. 9%) (p>.05 for all). Adjusted analyses showed no association between health care setting and preventive counseling.