A dynamic nomogram to predict invasive fungal super-infection during healthcare-associated bacterial infection in intensive care unit patients: an ambispective cohort study in China.

Objectives: Invasive fungal super-infection (IFSI) is an added diagnostic and therapeutic dilemma. We aimed to develop and assess a nomogram of IFSI in patients with healthcare-associated bacterial infection (HABI). Methods: An ambispective cohort study was conducted in ICU patients with HABI from a tertiary hospital of China. Predictors of IFSI were selected by both the least absolute shrinkage and selection operator (LASSO) method and the two-way stepwise method. The predictive performance of two models built by logistic regression was internal-validated and compared. Then external validity was assessed and a web-based nomogram was deployed. Results: Between Jan 1, 2019 and June 30, 2023, 12,305 patients with HABI were screened in 14 ICUs, of whom 372 (3.0%) developed IFSI. Among the fungal strains causing IFSI, the most common was C.albicans (34.7%) with a decreasing proportion, followed by C.tropicalis (30.9%), A.fumigatus (13.9%) and C.glabrata (10.1%) with increasing proportions year by year. Compared with LASSO-model that included five predictors (combination of priority antimicrobials, immunosuppressant, MDRO, aCCI and S.aureus), the discriminability of stepwise-model was improved by 6.8% after adding two more predictors of COVID-19 and microbiological test before antibiotics use (P<0.01).And the stepwise-model showed similar discriminability in the derivation (the area under curve, AUC=0.87) and external validation cohorts (AUC=0.84, P=0.46). No significant gaps existed between the proportion of actual diagnosed IFSI and the frequency of IFSI predicted by both two models in derivation cohort and by stepwise-model in external validation cohort (P=0.16, 0.30 and 0.35, respectively). Conclusion: The incidence of IFSI in ICU patients with HABI appeared to be a temporal rising, and our externally validated nomogram will facilitate the development of targeted and timely prevention and control measures based on specific risks of IFSI.

The biotic effects of lignite on humic acid components conversion during chicken manure composting.

Targeted regulation of composting to convert organic matter into humic acid (HA) holds significant importance in compost quality. Owing to its low carbon content, chicken manure compost often requires carbon supplements to promote the humification progress. The addition of lignite can increase HA content through biotic pathways, however, its structure was not explored. The Parallel factor analysis revealed that lignite can significantly increase the complexity of highly humified components. The lignite addition improved phenol oxidase activity, particularly laccase, during the thermophilic and cooling phases. The abundance and transformation functions of core bacteria also indicated that lignite addition can influence the activity of microbial transformation of HA components. The structural equation model further confirmed that lignite addition had a direct and indirect impact on enhancing the complexity of HA components through core bacteria and phenol oxidase. Therefore, lignite addition can improve HA structure complexity during composting through biotic pathways.

Experimental study on the effects of pressure loss on uniformity, application rate and velocity on different working conditions using the dynamic fluidic sprinkler.

An experiment was conducted to determine the effects of pressure loss, combined spacing, and. coefficients of uniformity on the dynamic fluidic sprinkler. Spline interpolation was used to convert the radial water volume into grid-type data and various pressure conditions were used to simulate the three-dimensional water distribution under square and triangular combinations of sprinklers. For each of the combinations of the sprinklers, experiments were performed at operating pressures of 0.15, 0.2, 0.25, and 0.3 MPa, respectively. To find the optimum spatial distribution of sprinklers, three different sprinkler intervals, 1R, 1.2R, and 1.4R, were performed for the square and triangular combinations. The droplet size distributions were also measured along a radial transect from the sprinkler for each operational pressure using the Thies Clima Laser Precipitation Monitor. The results demonstrated that the average values of the inclination angles of the water droplet trajectory curves were 60.78° and 68.85° as the pressure rose from 0.15 MPa to 0.3 MPa. When the pressure exceeds 0.2 MPa, the square combination's distribution uniformity coefficients of 25% low and high values were higher than those of the triangle combination. Triangular combination coefficients of uniformity (CU) values initially decreased and then increased as sprinkler spacing increased, with the CU value under 1.4R spacing reaching 73.85%. At a 1.2R interval, the CU value of a triangular combination was 8.49% lower than that of a square combination, which is a significant difference. Peak irrigation values for the square combination, when the pressure was changed from 0.1 to 0.3 MPa, were 29.97, 22.9, 19.8, 19.91, and 19.21 mm h-1, respectively. The CU values at 0.2, 0.25, and 0.3 MPa decreased at rates of 0.07%, 1.36%, and 0.8%, respectively, when the pressure was reduced by 10%.

A review of microplastic transport in coastal zones.

Transport of microplastics (MPs) in coastal zones is influenced not only by their own characteristics, but also by the hydrodynamic conditions and coastal environment. In this article, we first summarized the source, distribution and abundance of MPs in coastal zones around the world through the induction of in-situ observation literature, and then comprehensively reviewed the different transports of MPs in coastal zones, including sedimentation, vertical mixing, resuspension, drift and biofouling. Afterwards, we conducted a comparative analysis of relevant experimental literature, and found that the current experimental research on microplastic transport mainly focused on the settling velocity under static water and the transport distribution under dynamic water. Based on the relevant literature on numerical simulation of microplastic transport in coastal zones, it was also found that the Euler-Lagrange method is the most widely used. The main influencing factor in the Euler method is hydrodynamic, while the Lagrange method and Euler-Lagrange method is hydrodynamic and microplastic particle characteristics. Tides in hydrodynamics are mentioned the most frequently, and the role of turbulence in almost all the literature. The density of MPs is the most influencing factor on transport results, followed by size, while shape is only studied in small-scale models. Some literature has also found that the influence of biofilms is mainly reflected in the changes in the density and size of MPs.

Analysis of Factors Associated with Constipation in the Population with Obesity: Evidence from the National Health and Nutrition Examination Survey.

INTRODUCTION: Obesity and constipation are both global problems, but the factors associated with constipation in individuals with obesity are currently understudied. The aim of our study was to explore the factors associated with constipation in people with obesity. METHODS: From three cycles of the National Health and Nutrition Examination Survey (NHANES) 2005-2010, data from 14,048 persons aged ≥20 years were collected. Variables included demographics, lifestyle, comorbidities, and dietary data. Multiple logistic regression analysis was used to calculate adjusted prevalence odds ratio (OR) and assess the relationship between different variables and constipation in population with obesity. RESULTS: Using stool consistency definition, multivariate analysis revealed that education ≥12th grade (OR: 0.456; 95% CI: 0.300, 0.694; p = 0.00024), hypertension (OR: 0.505; 95% CI: 0.334, 0.763; p = 0.00119), polypharmacy (OR: 1.669; 95% CI: 1.104, 2.521; p = 0.01507), high cholesterol (OR: 0.400; 95% CI: 0.213, 0.750; p = 0.00430), and high dietary fiber (OR: 0.454; 95% CI: 0.245, 0.841; p = 0.01206) were substantially linked with constipation in the population with obesity. For constipation defined using stool frequency, multivariate regression analysis show constipation in people with obesity had a significant association with the female sex (OR: 2.684; 95% CI: 1.379, 5.223; p = 0.00366 multivariate), Mexican American (OR: 0.142; 95% CI, 0.033, 0.616; p = 0.00914 multivariate), hypertension (OR: 0.569; 95% CI: 0.324, 0.998; p = 0.04916), depression (OR: 2.280; 95% CI: 1.240, 4.195; p = 0.00803), occasional/often milk consumption (OR: 0.473; 95% CI: 0.286, 0.782; p = 0.00356), medium energy (OR: 0.318; 95% CI: 0.118, 0.856; p = 0.02338), polypharmacy (OR: 1.939; 95% CI: 1.115, 3.373; p = 0.01907), and medium moisture (OR: 0.534; 95% CI: 0.285, 0.999; p = 0.04959). In nonobese people, constipation was significantly associated with the female sex and high moisture but not with hypertension and polypharmacy. CONCLUSION: This study suggests that the population with obesity has many factors that affect constipation such as hypertension, polypharmacy, cholesterol, dietary fiber, depression, and so on, of which hypertension and polypharmacy were significant associated with constipation, regardless of definitions of constipation. Notably, hypertension might be associated with a reduced risk of constipation in people with obesity.

Emotional labour and turnover intention among nurses in China: Mediating effects of nurse-patient relationship and self-rated health.

AIM: This study tested the mediating role of the nurse-patient relationship and self-rated health in the effect of emotional labour on turnover intention among nurses in China. BACKGROUND: The underlying mechanism behind the effect of emotional labour on turnover intention remains inadequately understood. INTRODUCTION: Nurses with a high level of emotional labour are predisposed to experiencing poor health and tension in their relationships with patients, which may increase turnover intention. METHODS: A cross-sectional survey of 527 nurses in a public tertiary hospital in Qiqihar, located in China's Heilongjiang province, was conducted. Emotional labour and turnover intention were assessed using existing validated scales containing multiple items, while the nurse-patient relationship and self-rated health were assessed using single items, respectively. Baron and Kenny's causal steps and the Karlson/Holm/Breen method were adopted to test the mediating effects of the nurse-patient relationship and self-rated health in the association between emotional labour and turnover intention after adjusting for variations in sociodemographic and job characteristics. RESULTS: Emotional labour was positively associated with turnover intention. Self-rated poor health and a disharmonious nurse-patient relationship partially mediated the positive effect of emotional labour on turnover intention. CONCLUSIONS: Emotional labour significantly affects the turnover intention of nurses working in public tertiary hospitals in China, and this effect is partially mediated by self-rated health and the nurse-patient relationship. IMPLICATIONS FOR NURSING PRACTICE AND NURSING POLICY: Giving more attention to nurses' negative emotions and work attitudes is crucial. Developing comprehensive strategies for enhancing nurses' emotional management ability, promoting their physical and psychological well-being, and improving nurse-patient relationship to reduce nurses' turnover.

Molecular Insights into the Specific Targeting of c-MYC G-Quadruplex by Thiazole Peptides.

Stabilization of a G-quadruplex (G4) in the promotor of the c-MYC proto-oncogene leads to inhibition of gene expression, and it thus represents a potentially attractive new strategy for cancer treatment. However, most G4 stabilizers show little selectivity among the many G4s present in the cellular complement of DNA and RNA. Intriguingly, a crescent-shaped cell-penetrating thiazole peptide, TH3, preferentially stabilizes the c-MYC G4 over other promotor G4s, but the mechanisms leading to this selective binding remain obscure. To investigate these mechanisms at the atomic level, we performed an in silico comparative investigation of the binding of TH3 and its analogue TH1 to the G4s from the promotors of c-MYC, c-KIT1, c-KIT2, and BCL2. Molecular docking and molecular dynamics simulations, combined with in-depth analyses of non-covalent interactions and bulk and per-nucleotide binding free energies, revealed that both TH3 and TH1 can induce the formation of a sandwich-like framework through stacking with both the top and bottom G-tetrads of the c-MYC G4 and the adjacent terminal capping nucleotides. This framework produces enhanced binding affinities for c-MYC G4 relative to other promotor G4s, with TH3 exhibiting an outstanding binding priority. Van der Waals interactions were identified to be the key factor in complex formation in all cases. Collectively, our findings fully agree with available experimental data. Therefore, the identified mechanisms leading to specific binding of TH3 towards c-MYC G4 provide valuable information to guide the development of new selective G4 stabilizers.

Inhibition of cinnamic acid and its derivatives on polyphenol oxidase: Effect of inhibitor carboxyl group and system pH.

Phenolic acids are promising inhibitors of polyphenol oxidase (PPO), but the effects of carboxyl group and pH on their inhibition effects are still unclear. In this study, methyl cinnamate, cinnamic acid and 4-carboxycinnamic acid were investigated by their inhibitory effects with pH varied from 6.8 to 5.0. Results showed that 4-carboxycinnamic acid had the strongest inhibitory effect on PPO, followed by cinnamic acid and methyl cinnamate. Acidic pH enhanced the inhibitory effects of cinnamic acid and its derivatives on PPO, and the enhancement degree, IC50 and Ki declining degree were followed as 4-carboxycinnamic acid > cinnamic acid > methyl cinnamate. Methyl cinnamate exhibited competitive inhibition on PPO, while cinnamic acid and 4-carboxycinnamic acid exhibited mixed-type inhibition. Inhibitors induced slight changes in the secondary and tertiary structures of PPO, which were enhanced by acidic pH. Molecular docking results showed that 4-carboxycinnamic acid exhibited the strongest binding ability, and the main interaction forces were around carboxyl groups, and acidic pH enhanced the binding effect through more interactions and lower binding energy. This study could provide new insights into industrial application of cinnamic acid and its derivatives for the control of enzymatic browning of fruits and vegetables.

Pharmacogenomics and adverse effects of anti-infective drugs in children.

Children, as a special group, have their own peculiarities in terms of individualized medication use compared to adults. Adverse drug reactions have been an important issue that needs to be addressed in the hope of safe medication use in children, and the occurrence of adverse drug reactions is partly due to genetic factors. Anti-infective drugs are widely used in children, and they have always been an important cause of the occurrence of adverse reactions in children. Pharmacogenomic technologies are becoming increasingly sophisticated, and there are now many guidelines describing the pharmacogenomics of anti-infective drugs. However, data from paediatric-based studies are scarce. This review provides a systematic review of the pharmacogenomics of anti-infective drugs recommended for gene-guided use in CPIC guidelines by exploring the relationship between pharmacogenetic frequencies and the incidence of adverse reactions, which will help inform future studies of individualized medication use in children.

Factors influencing nurse fatigue during COVID-19: regression vs. fuzzy-set qualitative comparative analysis.

Background: Nurses during COVID-19 who face significant stress and high infection risk are prone to fatigue, affecting their health and quality of patient care. A cross- sectional study of 270 nurses who went to epidemic area to support anti-epidemic was carried out via online survey during the COVID-19 pandemic on November 2021. Methods: A web-based cross-sectional survey of 270 nurses in China who traveled to Heihe City in Heilongjiang Province to combat the novel coronavirus epidemic. The researchers collected information on sociodemographic variables, anxiety, transition shock, professionalism, collaboration, hours of work per day, and fatigue. Regression and fuzzy-set Quality Comparative Analysis (fsQCA) evaluated the factors' impact on the nurses' fatigue. Results: Regression analysis showed that the psychological variables significant for fatigue, transition shock (ß = 0.687, p < 0.001) and anxiety (ß = 0.757, p < 0.001) were positively associated with fatigue, professionalism (ß = -0.216, p < 0.001) was negatively associated with fatigue, and among the work-related variables, cooperation (ß = -0.262, p < 0.001) was negatively related to fatigue. FsQCA analysis showed that combined effects of work hours, anxiety, and nurses' educational status caused most of the fatigue (raw coverage = 0.482, consistency = 0.896). Conclusion: This study provides two main findings, the one is the greater transition shock experienced during COVID-19 in a new environment, low levels of professionalism, anxiety, and poor nursing teamwork situations lead anti-epidemic nurses to increased fatigue. Second, the fsQCA results showed that anxiety is sufficient for fatigue and that nurses' educational status, daily working hours, and anxiety are the most effective combination of factors.

Anxiety and Insomnia Mediate the Association of Fear of Infection and Fatigue: A Cross-Sectional Survey of Nurses Deployed to a COVID-19 Epicenter in China.

Background: This study aimed to test the mediating role of anxiety and insomnia in the association between fear of infection and fatigue. Methods: A cross-sectional questionnaire survey was conducted on the nurses deployed to Heihe. A serial multiple mediation model was established to determine the role of anxiety and insomnia in the association between fear of infection and fatigue. Findings: Over half (53.0%) of the study participants reported experiencing fear of infection despite stringent personal protection measures. The scores of anxiety (11.87±5.19), insomnia (16.33±5.95), and fatigue (45.94±12.93) were moderately correlated, with a Pearson correlation coefficient ranging from 0.501 to 0.579. Anxiety, either alone or in combination with insomnia, mediated the association between fear of infection and fatigue. Conclusion: The findings suggest that anxiety and insomnia play a mediating role in the relationship between fear of infection and fatigue. These results emphasize the importance of implementing targeted mental health interventions and work arrangements to address the well-being of healthcare professionals.

Development and validation of a predictive model for depression risk in the U.S. adult population: Evidence from the 2007-2014 NHANES.

BACKGROUND: Depression is a prevalent mental health disorder with a complex etiology and substantial public health implications. Early identification of individuals at risk for depression is crucial for effective intervention and prevention efforts. This study aimed to develop a predictive model for depression by integrating demographic factors (age, race, marital status, income), lifestyle factors (sleep duration, physical activity), and physiological measures (hypertension, blood lead levels). A key objective was to explore the role of physical activity and blood lead levels as predictors of current depression risk. METHODS: Data were extracted from the 2007-2014 National Health and Nutrition Examination Survey (NHANES). We applied a logistic regression analysis to these data to assess the predictive value of the above eight factors for depression to create the predictive model. RESULTS: The predictive model had bootstrap-corrected c-indexes of 0.68 (95% CI, 0.67-0.70) and 0.66 (95% CI, 0.64-0.68) for the training and validation cohorts, respectively, and well-calibrated curves. As the risk of depression increased, the proportion of participants with 1.76 ~ 68.90 µg/L blood lead gradually increased, and the proportion of participants with 0.05 ~ 0.66 µg/L blood lead gradually decreased. In addition, the proportion of sedentary participants increased as the risk of depression increased. CONCLUSIONS: This study developed a depression risk assessment model that incorporates physical activity and blood lead factors. This model is a promising tool for screening, assessing, and treating depression in the general population. However, because the corrected c-indices of the predictive model have not yet reached an acceptable threshold of 0.70, caution should be exercised when drawing conclusions. Further research is required to improve the performance of this model.

JAG1 enhances angiogenesis in triple-negative breast cancer through promoting the secretion of exosomal lncRNA MALAT1.

Despite significant improvements in five-year survival rates due to early diagnosis and combination therapy, triple-negative breast cancer (TNBC) treatment remains a major challenge. Finding new and effective targets for diagnosis and drug therapy is urgent for TNBC patients. Jagged-1 (JAG1), one of the canonical ligands of the Notch signaling pathway, is involved in vascular budding and is a poor prognostic factor of TNBC. In this study, combined with quantitative real-time PCR, database analysis, animal experiments, and other means, JAG1 was confirmed to be related to the poor prognosis of TNBC patients. JAG1 was highly expressed in MDA-MB-231 Bone (231B) cells, with stronger invasion and metastasis ability than MDA-MB-231 (231) cells. Treatment of human vascular endothelial cells (HUVEC) with TNBC conditioned medium showed that TNBC JAG1 promoted the angiogenesis of HUVEC. Next, we detected the exosomes extracted from TNBC conditioned medium and found that JAG1 promoted the exosome secretion from 231 cells via ALIX-RAB11A/RAB35. In addition, we also found that the exosomes from JAG1 overexpressed TNBC cells contained more long non-coding RNA (lncRNA) MALAT1, and MALAT1 promoted angiogenesis of HUVEC by targeting miR-140-5p. Finally, the angiogenesis-promoting effect of JAG1 in TNBC was further investigated by matrix gel assay. In conclusion, we reveal that JAG1 has a pro-invasion effect on TNBC and is involved in microenvironment angiogenesis by promoting exosome secretion and the MALAT1-miR-140-5p-JAG1/VEGFA pathway.

Ammonium-nitrate mixtures dominated by NH4+-N promote the growth of pecan (Carya illinoinensis) through enhanced N uptake and assimilation.

Nitrogen (N) limits plant productivity, and its uptake and assimilation may be regulated by N sources, N assimilating enzymes, and N assimilation genes. Mastering the regulatory mechanisms of N uptake and assimilation is a key way to improve plant nitrogen use efficiency (NUE). However, it is poorly known how these factors interact to influence the growth process of pecans. In this study, the growth, nutrient uptake and N assimilation characteristics of pecan were analyzed by aeroponic cultivation at varying NH4 +/NO3 - ratios (0/0, 0/100,25/75, 50/50, 75/25,100/0 as CK, T1, T2, T3, T4, and T5). The results showed that T4 and T5 treatments optimally promoted the growth, nutrient uptake and N assimilating enzyme activities of pecan, which significantly increased aboveground biomass, average relative growth rate (RGR), root area, root activity, free amino acid (FAA) and total organic carbon (TOC) concentrations, nitrate reductase (NR), nitrite reductase (NiR), glutamine synthetase (GS), glutamate synthase (Fd-GOGAT and NADH-GOGAT), and glutamate dehydrogenase (GDH) activities. According to the qRT-PCR results, most of the N assimilation genes were expressed at higher levels in leaves and were mainly significantly up-regulated under T1 and T4 treatments. Correlation analysis showed that a correlation between N assimilating enzymes and N assimilating genes did not necessarily exist. The results of partial least squares path model (PLS-PM) analysis indicated that N assimilation genes could affect the growth of pecan by regulating N assimilation enzymes and nutrients. In summary, we suggested that the NH4 +/NO3 - ratio of 75:25 was more beneficial to improve the growth and NUE of pecan. Meanwhile, we believe that the determination of plant N assimilation capacity should be the result of a comprehensive analysis of N concentration, N assimilation enzymes and related genes.

Parental detection of neonatal jaundice using a low-cost colour card: a multicentre prospective study.

BACKGROUND: Since most infants are usually discharged before age 48-72 hours, peak bilirubin levels will almost always occur after discharge. Parents may be the first to observe the onset of jaundice after discharge, but visual assessment is unreliable. The jaundice colour card (JCard) is a low-cost icterometer designed for the assessment of neonatal jaundice. The objective of this study was to evaluate parental use of JCard to detect jaundice in neonates. METHODS: We conducted a multicentre, prospective, observational cohort study in nine sites across China. A total of 1161 newborns ≥35 weeks of gestation were enrolled in the study. Measurements of total serum bilirubin (TSB) levels were based on clinical indications. The JCard measurements by parents and paediatricians were compared with the TSB. RESULTS: JCard values of parents and paediatricians were correlated with TSB (r=0.754 and 0.788, respectively). The parents' and paediatricians' JCard values 9 had sensitivities of 95.2% vs 97.6% and specificities of 84.5% vs 71.7% for identifying neonates with TSB ≥153.9 µmol/L. The parents' and paediatricians' JCard values 15 had sensitivities of 79.9% vs 89.0% and specificities of 66.7% vs 64.9% for identifying neonates with TSB ≥256.5 µmol/L. Areas under the receiver operating characteristic curves of parents for identifying TSB ≥119.7, ≥153.9, ≥205.2, and ≥256.5 µmol/L were 0.967, 0.960, 0.915, and 0.813, respectively, and those of paediatricians were 0.966, 0.961, 0.926 and 0.840, respectively. The intraclass correlation coefficient was 0.933 between parents and paediatricians. CONCLUSION: The JCard can be used to classify different levels of bilirubin, but it is less accurate with high bilirubin levels. The JCard diagnostic performance of parents was slightly lower than that of paediatricians.

PtdIns4P exchange at endoplasmic reticulum-autolysosome contacts is essential for autophagy and neuronal homeostasis.

Inter-organelle contacts enable crosstalk among organelles, facilitating the exchange of materials and coordination of cellular events. In this study, we demonstrated that, upon starvation, autolysosomes recruit Pi4KIIα (Phosphatidylinositol 4-kinase II α) to generate phosphatidylinositol-4-phosphate (PtdIns4P) on their surface and establish endoplasmic reticulum (ER)-autolysosome contacts through PtdIns4P binding proteins Osbp (Oxysterol binding protein) and cert (ceramide transfer protein). We found that the Sac1 (Sac1 phosphatase), Osbp, and cert proteins are required for the reduction of PtdIns4P on autolysosomes. Loss of any of these proteins leads to defective macroautophagy/autophagy and neurodegeneration. Osbp, cert, and Sac1 are required for ER-Golgi contacts in fed cells. Our data establishes a new mode of organelle contact formation - the ER-Golgi contact machinery can be reused by ER-autolysosome contacts by re-locating PtdIns4P from the Golgi apparatus to autolysosomes when faced with starvation.Abbreviations: Atg1: Autophagy-related 1; Atg8: Autophagy-related 8; Atg9: Autophagy-related 9; Atg12: Autophagy-related 12; cert: ceramide transfer protein; Cp1/CathL: cysteine proteinase-1; CTL: control; ER: endoplasmic reticulum; ERMCS: ER-mitochondria contact site; fwd: four wheel drive; GM130: Golgi matrix protein 130 kD; Osbp: Oxysterol binding protein; PG: phagophore; PtdIns4K: phosphatidylinositol 4-kinase; Pi4KIIα: Phosphatidylinositol 4-kinase II α; Pi4KIIIα: Phosphatidylinositol 4-kinase III α; PtdIns4P: phosphatidylinositol-4-phosphate; PR: photoreceptor cell; RT: room temperature; Sac1: Sac1 phosphatase; Stv: starvation; Syx17: Syntaxin 17; TEM: transmission electron microscopy; VAP: VAMP-associated protein.

Zinc promotes cell proliferation via regulating metal-regulatory transcription factor 1 expression and transcriptional activity in pulmonary arterial hypertension.

Metal responsive transcription factor 1 (MTF-1) is a zinc-dependent transcription factor involved in the development of pulmonary arterial hypertension (PAH), which is a life-threatening disease characterized by elevated pulmonary artery pressure and pulmonary vascular remodeling. However, little is known about the role and regulatory signaling of MTF-1 in PAH. This study aimed to investigate the effect and mechanism of MTF-1 on the proliferation of pulmonary arterial smooth muscle cells (PASMCs). Several techniques including intracellular-free zinc detected by fluorescent indicator-fluozinc-3-AM, western blot, luciferase reporter, and cell proliferation assay were conducted to perform a comprehensive analysis of MTF-1 in proliferation of PASMCs in PAH. Increased cytosolic zinc was shown in monocrotaline (MCT)-PASMCs and ZnSO4-treated PASMCs, which led to overexpression and overactivation of MTF-1, followed by the up-regulation of placental growth factor (PlGF). Elevated MTF-1 and PlGF were observed in western blot, and high transcriptional activity of MTF-1 was confirmed by luciferase reporter in ZnSO4-treated cells. Further investigation of cell proliferation revealed a favorable impact of zinc ions on PASMCs proliferation, with the deletion of Mtf-1/Plgf attenuating ZnSO4-induced proliferation. Flow cytometry analysis showed that blockade of PKC signaling inhibited the cell cycle of MCT-PASMCs and ZnSO4-treated PASMCs. The Zinc/PKC/MTF-1/PlGF pathway is involved in the up-regulatory effect on the PASMCs proliferation in the process of PAH. This study provided novel insight into zinc homeostasis in the pathogenesis of PAHs, and the regulation of MTF-1 might be a potential target for therapeutic intervention in PAH.