E-cigarettes Induce Dysregulation of Autophagy Leading to Endothelial Dysfunction in Pulmonary Arterial Hypertension.

Given the increasing popularity of electronic cigarettes (e-cigs), it is imperative to evaluate the potential health risks of e-cigs, especially in users with preexisting health concerns such as pulmonary arterial hypertension (PAH). The aim of the present study was to investigate whether differential susceptibility exists between healthy and patients with PAH to e-cig exposure and the molecular mechanisms contributing to it. Patient-specific induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from healthy individuals and patients with PAH were used to investigate whether e-cig contributes to the pathophysiology of PAH and affects EC homeostasis in PAH. Our results showed that PAH iPSC-ECs showed a greater amount of damage than healthy iPSC-ECs upon e-cig exposure. Transcriptomic analyses revealed that differential expression of Akt3 may be responsible for increased autophagic flux impairment in PAH iPSC-ECs, which underlies increased susceptibility upon e-cig exposure. Moreover, knockdown of Akt3 in healthy iPSC-ECs significantly induced autophagic flux impairment and endothelial dysfunction, which further increased with e-cig treatment, thus mimicking the PAH cell phenotype after e-cig exposure. In addition, functional disruption of mTORC2 by knocking down Rictor in PAH iPSC-ECs caused autophagic flux impairment, which was mediated by downregulation of Akt3. Finally, pharmacological induction of autophagy via direct inhibition of mTORC1 and indirect activation of mTORC2 with rapamycin reverses e-cig-induced decreased Akt3 expression, endothelial dysfunction, autophagic flux impairment, and decreased cell viability, and migration in PAH iPSC-ECs. Taken together, these data suggest a potential link between autophagy and Akt3-mediated increased susceptibility to e-cig in PAH.

Polymer Coatings Affect Transport and Remobilization of Colloidal Activated Carbon in Saturated Sand Columns: Implications for In Situ Groundwater Remediation.

Colloidal activated carbon (CAC) is an emerging technology for the in situ remediation of groundwater impacted by per- and polyfluoroalkyl substances (PFAS). In assessing the long-term effectiveness of a CAC barrier, it is crucial to evaluate the potential of emplaced CAC particles to be remobilized and migrate away from the sorptive barrier. We examine the effect of two polymer stabilizers, carboxymethyl cellulose (CMC) and polydiallyldimethylammonium chloride (PolyDM), on CAC deposition and remobilization in saturated sand columns. CMC-modified CAC showed high mobility in a wide ionic strength (IS) range from 0.1 to 100 mM, which is favorable for CAC delivery at a sufficient scale. Interestingly, the mobility of PolyDM-modified CAC was high at low IS (0.1 mM) but greatly reduced at high IS (100 mM). Notably, significant remobilization (release) of deposited CMC-CAC particles occurred upon the introduction of solution with low IS following deposition at high IS. In contrast, PolyDM-CAC did not undergo any remobilization following deposition due to its favorable interactions with the quartz sand. We further elucidated the CAC deposition and remobilization behaviors by analyzing colloid-collector interactions through the application of Derjaguin-Landau-Verwey-Overbeek theory, and the inclusion of a discrete representation of charge heterogeneity on the quartz sand surface. The classical colloid filtration theory was also employed to estimate the travel distance of CAC in saturated columns. Our results underscore the roles of polymer coatings and solution chemistry in CAC transport, providing valuable guidelines for the design of in situ CAC remediation with maximized delivery efficiency and barrier longevity.

Impact of clinical pharmacist services on physicians' guideline compliance and prognosis of patients for venous thromboembolism prophylaxis in ICU.

BACKGROUND: Whether the clinical pharmacist services (CPS) improve ICU physicians' compliance with venous thromboembolism (VTE) prophylaxis guidelines remains unclear, and the impact of CPS on VTE incidence and mortality in ICU patients should also be investigated. MATERIALS AND METHODS: ICU patients were assigned to a CPS group or a control group according to the medical arrangements of the day of patient admission, without any intervention. The impact of CPS on guideline compliance, VTE incidence, and mortality was assessed. RESULTS: A total of 338 patients were included. With CPS, ICU physicians' compliance with VTE prophylaxis guideline was improved by 7 - 25% (p < 0.001). The incidences of VTE (9 vs. 17%, p = 0.037) and bleeding events (5 vs. 11%, p = 0.042) were both lower in the CPS group than in the control group. Multivariate Cox regression model showed that CPS was an independent risk factor for VTE events (HR = 0.438, 95% CI = 0.224 - 0.857, p = 0.016) and 14-day mortality (HR = 0.416, 95%CI = 0.25 - 0.692, p = 0.001). CONCLUSION: CPS could significantly improve ICU physician compliance with VTE prophylaxis guidelines and reduce the incidence of VTE events and mortality in ICU patients. A clinical pharmacist should be involved in the daily management of ICU patients as an important member of the clinical team.

Tumor Necrosis Factor Superfamily 14 (LIGHT) Restricts Neovascularization by Decreasing Circulating Endothelial Progenitor Cells and Function.

Tumor necrosis factor superfamily 14 (TNFSF14) is also known as the LT-related inducible ligand (LIGHT). It can bind to the herpesvirus invasion mediator and lymphotoxin-ß receptor to perform its biological activity. LIGHT has multiple physiological functions, including strengthening the synthesis of nitric oxide, reactive oxygen species, and cytokines. LIGHT also stimulates angiogenesis in tumors and induces the synthesis of high endothelial venules; degrades the extracellular matrix in thoracic aortic dissection, and induces the expression of interleukin-8, cyclooxygenase-2, and cell adhesion molecules in endothelial cells. While LIGHT induces tissue inflammation, its effects on angiogenesis after tissue ischemia are unclear. Thus, we analyzed these effects in the current study. In this study, the animal model of hind limb ischemia surgery in C57BL/6 mice was performed. Doppler ultrasound, immunohistochemical staining, and Western blotting were employed to analyze the situation of angiogenesis. In addition, human endothelial progenitor cells (EPCs) were used for in vitro studies to analyze the possible mechanisms. The results in the animal study showed that LIGHT injection inhibited angiogenesis in ischemic limbs. For the in vitro studies, LIGHT inhibited the expression of integrins and E-selectin; decreased migration and tube formation capabilities, mitochondrial respiration, and succinate dehydrogenase activity; and promoted senescence in EPCs. Western blotting revealed that the impairment of EPC function by LIGHT may be due to its effects on the proper functioning of the intracellular Akt signaling pathway, endothelial nitrite oxide synthase (eNOS), and mitochondrial respiration. In conclusion, LIGHT inhibits angiogenesis after tissue ischemia. This may be related to the clamped EPC function.

Multidimensional item response theory models for testlet-based doubly bounded data.

A testlet-based visual analogue scale (VAS) is a doubly bounded scaling approach (e.g., from 0% to 100% or from 0 to 1) composed of multiple adjectives, nouns, or sentences (statements/items) within testlets for measuring individuals' attitudes, opinions, or career interests. While testlet-based VASs have many advantages over Likert scales, such as reducing response style effects, the development of proper statistical models for analyzing testlet-based VAS data lags behind. This paper proposes a novel beta copula model and a competing logit-normal model based on the item response theory framework, assessed by Bayesian parameter estimation, model comparison, and goodness-of-fit statistics. An empirical career interest dataset based on a testlet-based VAS design was analyzed using the proposed models. Simulation studies were conducted to assess the two models' parameter recovery. The results show that the beta copula model had superior fit in the empirical data analysis, and also exhibited good parameter recovery in the simulation studies, suggesting that it is a promising statistical approach to testlet-based doubly bounded responses.

Pharmacokinetic/Pharmacodynamic Target Attainment of Different Antifungal Agents in De-escalation Treatment in Critically Ill Patients: a Step toward Dose Optimization Using Monte Carlo Simulation.

Differences in pharmacokinetics/pharmacodynamics (PK/PD) target attainment are rarely considered when antifungals are switched in critically ill patients. This study intends to explore whether the antifungal de-escalation treatment strategy and the new intermittent dosing strategy of echinocandins in critically ill patients are able to achieve the corresponding PK/PD targets. The published population PK models of antifungals in critically ill patients and a public data set from the MIMIC-III database (n = 662) were employed to evaluate PK/PD target attainment of different dosing regimens of antifungals. Cumulative fraction of response (CFR) was calculated for each dosing regimen. Most guideline-recommended dosing regimens of fluconazole and voriconazole could achieve target exposure as de-escalation treatment in critically ill patients. For initial echinocandin treatment, achievement of the target exposure decreased as body weight increased, and the intermittent dosing strategy had a slightly higher CFR value in most simulations compared to conventional dosing strategy. For Candida albicans and Candida glabrata infection, caspofungin at the lowest dose achieved a CFR of >90%, while micafungin or anidulafungin required almost the highest doses simulated in this study to achieve the same effect. None of the echinocandins other than 150 mg every 24 h (q24h) or 200 mg q48h of caspofungin achieved the target CFR for Candida parapsilosis infection. These findings support the guideline-recommended dose of triazoles for antifungal de-escalation treatment and confirm the insufficient dosage of echinocandins in critically ill patients, indicating that a dosing regimen based on body weight or intermittent dosing of echinocandins may be required.

Suppressing Phase Segregation in Wide Bandgap Perovskites for Monolithic Perovskite/Organic Tandem Solar Cells with Reduced Voltage Loss.

Wide bandgap (WBG) perovskites through tuning iodine/bromine ratios are capable of merging with narrow bandgap organic bulk heterojunctions to construct tandem solar cells to overcome the Shockley-Queisser limitation. However, WBG perovskites readily suffer from light-induced halide ion migration, leading to detrimental phase segregation and hence severe open-circuit voltage (VOC ) loss. Here, to solve this issue, lead thiocyanate (Pb(SCN)2 ) and 2-thiopheneethylammonium chloride (TEACl) are synergistically employed to passivate and stabilize WBG perovskites with 1.79 eV bandgap. It is demonstrated that the synergetic employment of Pb(SCN)2 and TEACl suppresses light-induced phase segregation, passivates WBG perovskite defects, and reduces non-radiative recombination, hence alleviating VOC loss. As a result, optimized WBG perovskite solar cells (PSCs) are obtained with an impressive VOC of 1.26 V and power conversion efficiency (PCE) over 17.0%. Furthermore, the interconnection layer is optimized to minimize the VOC loss and construct two-terminal perovskite/organic tandem solar cells with a narrow bandgap organic blend bulk heterojunction of PM6:Y6 and achieve a champion PCE of 22.29% with a high VOC of 2.072 V. In addition, these tandem solar cells maintain 81% of their initial efficiency after 1000 h continuous tracking at the maximum power point (MPP) under 100 mW cm-2 white light illumination.

Evaluation of work resumption strategies after COVID-19 reopening in the Chinese city of Shenzhen: a mathematical modeling study.

OBJECTIVES: As China is facing a potential second wave of the epidemic, we reviewed and evaluated the intervention measures implemented in a major metropolitan city, Shenzhen, during the early phase of Wuhan lockdown. STUDY DESIGN: Based on the classic SEITR model and combined with population mobility, a compartmental model was constructed to simulate the transmission of COVID-19 and disease progression in the Shenzhen population. METHODS: Based on published epidemiological data on COVID-19 and population mobility data from Baidu Qianxi, we constructed a compartmental model to evaluate the impact of work and traffic resumption on the epidemic in Shenzhen in various scenarios. RESULTS: Imported cases account for most (58.6%) of the early reported cases in Shenzhen. We demonstrated that with strict inflow population control and a high level of mask usage after work resumption, various resumptions resulted in only an insignificant difference in the number of cumulative infections. Shenzhen may experience this second wave of infections approximately two weeks after the traffic resumption if the incidence risk in Hubei is high at the moment of resumption. CONCLUSION: Regardless of the work resumption strategy adopted in Shenzhen, the risk of a resurgence of COVID-19 after its reopening was limited. The strict control of imported cases and extensive use of facial masks play a key role in COVID-19 prevention.

Theoretical Calculation Guided Design of Single-Atom Catalysts toward Fast Kinetic and Long-Life Li-S Batteries.

Lithium-sulfur (Li-S) batteries are promising next-generation energy storage technologies due to their high theoretical energy density, environmental friendliness, and low cost. However, low conductivity of sulfur species, dissolution of polysulfides, poor conversion from sulfur reduction, and lithium sulfide (Li2S) oxidation reactions during discharge-charge processes hinder their practical applications. Herein, under the guidance of density functional theory calculations, we have successfully synthesized large-scale single atom vanadium catalysts seeded on graphene to achieve high sulfur content (80 wt % sulfur), fast kinetic (a capacity of 645 mAh g-1 at 3 C rate), and long-life Li-S batteries. Both forward (sulfur reduction) and reverse reactions (Li2S oxidation) are significantly improved by the single atom catalysts. This finding is confirmed by experimental results and consistent with theoretical calculations. The ability of single metal atoms to effectively trap the dissolved lithium polysulfides (LiPSs) and catalytically convert the LiPSs/Li2S during cycling significantly improved sulfur utilization, rate capability, and cycling life. Our work demonstrates an efficient design pathway for single atom catalysts and provides solutions for the development of high energy/power density Li-S batteries.

Thermophilic Solid-State Anaerobic Digestion of Corn Straw, Cattle Manure, and Vegetable Waste: Effect of Temperature, Total Solid Content, and C/N Ratio.

Thermophilic solid-state anaerobic digestion (SS-AD) of agricultural wastes, i.e., corn straw, cattle manure, and vegetable waste, was carried out in this study. The effects of temperature (40-60°C), initial solid content (ISC, 17.5-32.5%), and C/N ratio (15-32 : 1) on biogas production were evaluated using a Box-Behnken experimental design (BBD) combined with response surface methodology (RSM). The results showed that optimization of process parameters is important to promote the SS-AD performance. All the factors, including interactive terms (except the ISC), were significant in the quadratic model for biogas production with SS-AD. Among the three operation parameters, the C/N ratio had the largest effect on biogas production, followed by temperature, and a maximum biogas yield of 241.4 mL gVS-1 could be achieved at 47.3°C, ISC = 24.81%, and C/N = 22.35. After 20 d of SS-AD, the microbial community structure under different conditions was characterized by high-throughput sequencing, showing that Firmicutes, Bacteroidetes, Chloroflexi, Synergistetes, and Proteobacteria dominated the bacterial community, and that Firmicutes had a competitive advantage over Bacteroidetes at elevated temperatures. The biogas production values and relative abundance of OPB54 and Bacteroidia after 20 d of SS-AD can be fitted well using a quadratic model, implying that OPB54 and Bacteroidia play important roles in the methanogenic metabolism for agricultural waste thermophilic SS-AD.

Effects of Solid Precipitation and Surface Corrosion on the Adhesion Strengths of Sintered Hydrate Deposits on Pipe Walls.

A hydrate directly growing and sintering on a pipe wall is an important hydrate deposition case that has been relatively unexplored. In the present study, the adhesion strengths of a sintered cyclopentane (CyC5) hydrate deposit under different solid precipitation and surface corrosion conditions were measured and discussed. It was found that the hydrate adhesion strengths increased by 1.2-1.5× when the soaking time of the carbon steel substrate in a 5 wt % NaCl solution increased from 24 to 72 h, which reduced the water wetting angle from 112 ± 3.5° to 94 ± 3.3°. The wax coating reduced the strength of CyC5 hydrate adhesion by up to nearly 20-fold by reversing the substrate wettability and affecting the hydrate morphology. The measurements performed on scales indicate that calcium carbonate scales strengthen the adhesion strength because of the decrease in the water wetting angle. In addition, honeycomb holes on the surface reduce amplification. Furthermore, settling quartz sand on the wall reduced the adhesion strengths by decreasing the effective sintering area of the hydrate on the underlying base. Finer sand and higher concentrations led to lower strengths. On the basis of the verified linear correlation between the hydrate adhesion strength and the adhesion work of droplets on different substrates and the influence of water conversion during deposition, both an equation and a key constant parameter were obtained to predict the sintered hydrate deposit adhesion strengths on substrates.

Experimental Investigation on Microscopic Force Measurement of Foam and Heavy Oil.

This paper combined experiments with a theoretical model to simulate the behavior between a foam and heavy oil during contact pressing, separation, and adsorption. We discuss the changes in the elasticity and adsorption forces during the pressing and adsorption of the two fluids. The influence of the changes in temperature and pressure, the concentration of the sodium dodecyl sulfate surfactant, the heavy oil viscosity, and the addition of partially hydrolyzed polyacrylamide and hydrophobic SiO2 nanoparticles was studied. The results showed that the overall increase in the elasticity and adsorption forces between the foam at 1 wt % surfactant and heavy oil was more than 2 times greater than those of the foam with 0.2 wt % surfactant. The increase in viscosity of heavy oil also increased various forces. The overall improvement in the adsorption force between fluids caused by nanoparticles during separation and adsorption stages reached 1.8 times, which was better than that obtained using the polymer (1.65 times). However, the polymer showed a 1.4 times higher elastic force during the fluid pressing stage than the nanoparticles and about 4 times higher than the control foam, and the increase in temperature greatly weakened the effect of the force, while the change in pressure did not cause much impact. An analytical model was built based on fluid mechanics, and the calculation results were consistent with the experimental data with an error of about 5-12%, suggesting that this model provides a good reference value.

Particulate matters increase epithelial-mesenchymal transition and lung fibrosis through the ETS-1/NF-κB-dependent pathway in lung epithelial cells.

BACKGROUND: Particulate matters (PMs) in ambient air pollution are closely related to the incidence of respiratory diseases and decreased lung function. Our previous report demonstrated that PMs-induced oxidative stress increased the expression of proinflammatory intracellular adhesion molecule-1 (ICAM-1) through the IL-6/AKT/STAT3/NF-κB pathway in A549 cells. However, the role of O-PMs in epithelial-mesenchymal transition (EMT) development and pulmonary fibrosis and the related mechanisms have not been determined. The aim of this study was to investigate the effects of O-PMs on the pathogenesis of EMT and pulmonary fibrosis as well as the expression of ETS-1 and NF-κB p65, in vitro and in vivo. RESULTS: O-PMs treatment induced EMT development, fibronectin expression, and cell migration. O-PMs affected the expression of the EMT-related transcription factors NF-κB p65 and ETS-1. Interference with NF-κB p65 significantly decreased O-PMs-induced fibronectin expression. In addition, O-PMs affected the expression of fibronectin, E-cadherin, and vimentin through modulating ETS-1 expression. ATN-161, an antagonist of integrin α5ß1, decreased the expression of fibronectin and ETS-1 and EMT development. EMT development and the expression of fibronectin and ETS-1 were increased in the lung tissue of mice after exposure to PMs for 7 and 14 days. There was a significant correlation between fibronectin and ETS-1 expression in human pulmonary fibrosis tissue. CONCLUSION: O-PMs can induce EMT and fibronectin expression through the activation of transcription factors ETS-1 and NF-κB in A549 cells. PMs can induce EMT development and the expression of fibronectin and ETS-1 in mouse lung tissues. These findings suggest that the ETS-1 pathway could be a novel and alternative mechanism for EMT development and pulmonary fibrosis.

PM2.5-induced oxidative stress increases intercellular adhesion molecule-1 expression in lung epithelial cells through the IL-6/AKT/STAT3/NF-κB-dependent pathway.

BACKGROUND: Epidemiological studies have shown that ambient air pollution is closely associated with increased respiratory inflammation and decreased lung function. Particulate matters (PMs) are major components of air pollution that damages lung cells. However, the mechanisms remain to be elucidated. This study examines the effects of PMs on intercellular adhesion molecule-1 (ICAM-1) expression and the related mechanisms in vitro and in vivo. RESULT: The cytotoxicity, reactive oxygen species (ROS) generation, and monocyte adherence to A549 cells were more severely affected by treatment with O-PMs (organic solvent-extractable fraction of SRM1649b) than with W-PMs (water-soluble fraction of SRM1649b). We observed a significant increase in ICAM-1 expression by O-PMs, but not W-PMs. O-PMs also induced the phosphorylation of AKT, p65, and STAT3. Pretreating A549 cells with N-acetyl cysteine (NAC), an antioxidant, attenuated O-PMs-induced ROS generation, the phosphorylation of the mentioned kinases, and the expression of ICAM-1. Furthermore, an AKT inhibitor (LY294002), NF-κB inhibitor (BAY11-7082), and STAT3 inhibitor (Stattic) significantly down-regulated O-PMs-induced ICAM-1 expression as well as the adhesion of U937 cells to epithelial cells. Interleukin-6 (IL-6) was the most significantly changed cytokine in O-PMs-treated A549 cells according to the analysis of the cytokine antibody array. The IL-6 receptor inhibitor tocilizumab (TCZ) and small interfering RNA for IL-6 significantly reduced ICAM-1 secretion and expression as well as the reduction of the AKT, p65, and STAT3 phosphorylation in O-PMs-treated A549 cells. In addition, the intratracheal instillation of PMs significantly increased the levels of the ICAM-1 and IL-6 in lung tissues and plasma in WT mice, but not in IL-6 knockout mice. Pre-administration of NAC attenuated those PMs-induced adverse effects in WT mice. Furthermore, patients with chronic obstructive pulmonary disease (COPD) had higher plasma levels of ICAM-1 and IL-6 compared to healthy subjects. CONCLUSION: These results suggest that PMs increase ICAM-1 expression in pulmonary epithelial cells in vitro and in vivo through the IL-6/AKT/STAT3/NF-κB signaling pathway.

Curcumin accelerates cutaneous wound healing via multiple biological actions: The involvement of TNF-α, MMP-9, α-SMA, and collagen.

Curcumin, a constituent of the turmeric plant, has antitumor, anti-inflammatory, and antioxidative effects, but its effects on wound healing are unclear. We created back wounds in 72 mice and treated them with or without topical curcumin (0.2 mg/mL) in Pluronic F127 gel (20%) daily for 3, 5, 7, 9, and 12 days. Healing in wounds was evaluated from gross appearance, microscopically by haematoxylin and eosin staining, by immunohistochemistry for tumour necrosis factor alpha and alpha smooth muscle actin, and by polymerase chain reaction amplification of mRNA expression levels. Treatment caused fast wound closure with well-formed granulation tissue dominated by collagen deposition and regenerating epithelium. Curcumin increased the levels of tumour necrosis factor alpha mRNA and protein in the early phase of healing, which then decreased significantly. However, these levels remained high in controls. Levels of collagen were significantly higher in curcumin-treated wounds. Immunohistochemical staining for alpha smooth muscle actin was increased in curcumin-treated mice on days 7 and 12. Curcumin treatment significantly suppressed matrix metallopeptidase-9 and stimulated alpha smooth muscle levels in tumour necrosis factor alpha-treated fibroblasts via nuclear factor kappa B signalling. Thus, topical curcumin accelerated wound healing in mice by regulating the levels of various cytokines.

Portable wireless neurofeedback system of EEG alpha rhythm enhances memory.

BACKGROUND: Effect of neurofeedback training (NFT) on enhancement of cognitive function or amelioration of clinical symptoms is inconclusive. The trainability of brain rhythm using a neurofeedback system is uncertainty because various experimental designs are used in previous studies. The current study aimed to develop a portable wireless NFT system for alpha rhythm and to validate effect of the NFT system on memory with a sham-controlled group. METHODS: The proposed system contained an EEG signal analysis device and a smartphone with wireless Bluetooth low-energy technology. Instantaneous 1-s EEG power and contiguous 5-min EEG power throughout the training were developed as feedback information. The training performance and its progression were kept to boost usability of our device. Participants were blinded and randomly assigned into either the control group receiving random 4-Hz power or Alpha group receiving 8-12-Hz power. Working memory and episodic memory were assessed by the backward digital span task and word-pair task, respectively. RESULTS: The portable neurofeedback system had advantages of a tiny size and long-term recording and demonstrated trainability of alpha rhythm in terms of significant increase of power and duration of 8-12 Hz. Moreover, accuracies of the backward digital span task and word-pair task showed significant enhancement in the Alpha group after training compared to the control group. CONCLUSIONS: Our tiny portable device demonstrated success trainability of alpha rhythm and enhanced two kinds of memories. The present study suggest that the portable neurofeedback system provides an alternative intervention for memory enhancement.

Cytoplasmic aryl hydrocarbon receptor regulates glycogen synthase kinase 3 beta, accelerates vimentin degradation, and suppresses epithelial-mesenchymal transition in non-small cell lung cancer cells.

Aryl hydrocarbon receptor (AHR), a ligand-activated transcription factor, has been studied extensively in carcinogenesis through the genomic pathway. In recent years, AHR has also been reported to exert positive or negative effects on epithelial-mesenchymal transition (EMT), the crucial step in tumor malignant progression. However, the detailed mechanism remains controversial. Analysis of AHR-expression levels in non-small cell lung cancer cell lines and lung cancer tissues revealed an inverse correlation between AHR protein levels and tumor cell invasion and metastasis. Overexpression of wild-type AHR in H1299 cells (AHR poorly expressed, potently invasive) not only accelerated mesenchymal vimentin degradation, but also prevented cell invasion in vitro and in vivo. In the absence of AHR agonists, the overexpressed AHR protein was predominantly localized in the cytoplasm, where it interacted with vimentin and functioned as an E3 ubiquitin ligase. A 6-h incubation with the proteasome inhibitor MG-132 fully rescued vimentin from AHR-mediated proteasomal degradation. In AHR-overexpressing H1299 cells, either vimentin degradation or invasive suppression could be reversed when glycogen synthase kinase 3 beta (GSK3ß) was inactivated by CHIR-99021 treatment. In contrast, silencing of AHR in A549 cells (AHR highly expressed, weakly invasive) resulted in the downregulation of epithelial biomarkers (E-cadherin and claudin-1), augmentation of mesenchymal vimentin level, and GSK3ß Ser-9 hyper-phosphorylation, which led to enhanced invasiveness. This work demonstrates that cytoplasmic, resting AHR protein may act as an EMT suppressor via a non-genomic pathway. Depletion of cytoplasmic AHR content represents a potential switch for EMT, thereby leading to the scattering of tumor cells.

Indoxyl sulfate enhances IL-1ß-induced E-selectin expression in endothelial cells in acute kidney injury by the ROS/MAPKs/NFκB/AP-1 pathway.

Uremic toxins are considered a risk factor for cardiovascular disorders in kidney diseases, but it is not known whether, under inflammatory conditions, they affect adhesion molecule expression on endothelial cells, which may play a critical role in acute kidney injury (AKI). In the present study, in cardiovascular surgery-related AKI patients, who are known to have high plasma levels of the uremic toxin indoxyl sulfate (IS), plasma levels of IL-1ß were found to be positively correlated with plasma levels of the adhesion molecule E-selectin. In addition, high E-selectin and IL-1ß expression were seen in the kidney of ischemia/reperfusion mice in vivo. We also examined the effects of IS on E-selectin expression by IL-1ß-treated human umbilical vein endothelial cells (HUVECs) and the underlying mechanism. IS pretreatment of HUVECs significantly increased IL-1ß-induced E-selectin expression, monocyte adhesion, and the phosphorylation of mitogen-activated protein kinases (ERK, p38, and JNK) and transcription factors (NF-κB and AP-1), and phosphorylation was decreased by pretreatment with inhibitors of ERK1/2 (PD98059), p38 MAPK (SB202190), and JNK (SP600125). Furthermore, IS increased IL-1ß-induced reactive oxygen species (ROS) production and this effect was inhibited by pretreatment with N-acetylcysteine (a ROS scavenger) or apocynin (a NADPH oxidase inhibitor). Gel shift assays and ChIP-PCR demonstrated that IS enhanced E-selectin expression in IL-1-treated HUVECs by increasing NF-κB and AP-1 DNA-binding activities. Moreover, IS-enhanced E-selectin expression in IL-1ß-treated HUVECs was inhibited by Bay11-7082, a NF-κB inhibitor. Thus, IS may play an important role in the development of cardiovascular disorders in kidney diseases during inflammation by increasing endothelial expression of E-selectin.

Direct measurements of the interactions between clathrate hydrate particles and water droplets.

Clathrate hydrate particle agglomeration is often considered to be one of the key limiting factors in plug formation. The hydrate particle-water interaction can play a critical role in describing hydrate agglomeration, yet is severely underexplored. Therefore, this work investigates the interactions between water droplets and cyclopentane hydrate particles using a micromechanical force (MMF) apparatus. Specifically, the effect of contact time, temperature/subcooling, contact area, and the addition of Sorbitane monooleate (Span 80) surfactant on the water droplet-hydrate particle interaction behavior are studied. The measurements indicate that hydrate formation during the measurement would increase the water-hydrate interaction force significantly. The results also indicate that the contact time, subcooling and concentration of cyclopentane, which determine the hydrate formation rate and hydrate amount, will affect the hydrate-water interaction force. In addition, the interaction forces also increase with the water-hydrate contact area. The addition of Span 80 surfactant induces a change in the hydrate morphology and renders the interfaces stable versus unstable (leading to coalescence), and the contact force can affect the hydrate-water interaction behavior significantly. Compared with the hydrate-hydrate cohesion force (measured in cyclopentane), the hydrate-water adhesion force is an order of magnitude larger. These new measurements can help to provide new and critical insights into the hydrate agglomeration process and potential strategies to control this process.