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ObjectivesWe previously reported microvascular leakage resulting from fibrinogen-γ chain C-terminal products (γC) occurred via a RhoA-dependent mechanism. The objective of this study was to further elucidate the signaling mechanism by which γC induces endothelial hyperpermeability. Since it is known that γC binds and activates endothelial αvβ3, a transmembrane integrin receptor involved in intracellular signaling mediated by the tyrosine kinases FAK and Src, we hypothesized that γC alters endothelial barrier function by activating the FAK-Src pathway leading to junction dissociation and RhoA driven cytoskeletal stress-fiber formation.Methods and resultsUsing intravital microscopy of rat mesenteric microvessels, we show increased extravasation of plasma protein (albumin) resulting from γC administration. In addition, capillary fluid filtration coefficient (Kfc) indicated γC-induced elevated lung vascular permeability. Furthermore, γC decreased transendothelial barrier resistance in a time-dependent and dose-related fashion in cultured rat lung microvascular endothelial cells (RLMVECs), accompanied by increased FAK/Src phosphorylation detection by western blot. Experiments with pharmacological inhibition or gene silencing of FAK showed significantly reduced γC-induced albumin and fluid leakage across microvessels, stress-fiber formation, VE-cadherin tyrosine phosphorylation, and improved γC-induced endothelial barrier dysfunction, indicating the involvement of FAK in γC mediated hyperpermeability. Comparable results were found when Src was targeted in a similar manner, however inhibition of FAK prevented Src activation, suggesting that FAK is upstream of Src in γC-mediated hyperpermeability. In addition, γC-induced cytoskeletal stress-fiber formation was attenuated during inhibition or silencing of these tyrosine kinases, concomitantly with RhoA inhibition.ConclusionThe FAK-Src pathway contributes to γC-induced microvascular barrier dysfunction, junction protein phosphorylation and disorganization in a manner that involves RhoA and stress-fiber formation.

This study aimed to investigate the efficacy, safety, and prognostic factors of drug-eluting beads transarterial chemoembolization (DEB-TACE) in treating Chinese patients with liver cancer. A total of 367 liver cancer patients from 24 medical centers were consecutively enrolled in this multiple-center, prospective cohort study, including 275 hepatocellular carcinoma (HCC) cases, 37 intrahepatic cholangiocarcinoma (ICC) cases, and 55 secondary liver cancer cases. All the patients received CalliSpheres® DEB-TACE treatment. Treatment response, overall survival (OS), change of liver function, and adverse events (AEs) were assessed. DEB-TACE treatment achieved 19.9% complete response (CR) and 79.6% objective response rate (ORR), with mean OS of 384 days [95% confidence interval (CI): 375–393 days]. CR and ORR were both higher in HCC patients compared with primary ICC patients and secondary liver cancer patients, while no difference was discovered in OS. Portal vein invasion was an independent risk factor for CR, while portal vein invasion, previous conventional TACE (cTACE) treatment, and abnormal blood creatinine (BCr) were independent risk factors for ORR. In addition, largest nodule size ≥5.0 cm, abnormal albumin (ALB), and abnormal total bilirubin (TBIL) independently correlated with unfavorable OS. Most liver function indexes were recovered to baseline levels at 1–3 months after DEB-TACE. Common AEs were pain, fever, vomiting, and nausea; most of them were at mild grade. CalliSpheres® DEB-TACE is efficient and well tolerated in Chinese liver cancer patients. Portal vein invasion, previous cTACE treatment, largest nodule size, abnormal BCr, ALB, and TBIL correlate with worse prognosis independently.

Idiopathic renal hypouricemia is a rare hereditary condition. Type 2 renal hyperuricemia (RHUC2) is caused by a mutation in the SLC2A9 gene, which encodes a high-capacity glucose and urate transporter, glucose transporter (GLUT)9. RHUC2 predisposes to exercise-induced acute renal failure (EIARF) and nephrolithiasis, which is caused by a defect in renal tubular urate transport and is characterized by increased clearance of renal uric acid. In the present study a case of a 35-year-old Chinese man with EIARF is reported. The patient had isolated renal hypouricemia, with a serum uric acid level of 21 µmol/l and a fractional excretion of uric acid of 200%. The mutational analysis revealed a homozygous mutation (c.857G>A in exon 8) in the SLC2A9 gene. The patient's family members carried the same mutation, but were heterozygous and clinically asymptomatic. In conclusion, to the best of our knowledge, this is the first report of a RHUC2 patient with a GLUT9 mutation, p.W286X, which may be a pathogenic mutation of RHUC2. Further investigation into the functional role of GLUT9 in this novel SLC2A9 mutation is required.

The purpose of this study was to investigate the efficacy and safety of drug-eluting beads transarterial chemoembolization (DEB-TACE) treatment in Chinese hepatocellular carcinoma (HCC) patients and the prognostic factors for treatment response as well as survival. A total of 275 HCC patients were included in this prospective study. Treatment response was assessed by modified Response Evaluation Criteria in Solid Tumors (mRECIST), and progression-free survival (PFS) as well as overall survival (OS) were determined. Liver function and adverse events (AEs) were assessed before and after DEB-TACE operation. Complete response (CR), partial response (PR), and objective response rate (ORR) were 22.9%, 60.7%, and 83.6%, respectively. The mean PFS was 362 (95% CI: 34.9–375) days, the 6-month PFS rate was 89.4 ± 2.1%, while the mean OS was 380 (95% CI: 370–389) days, and the 6-month OS rate was 94.4 ± 1.7%. Multivariate logistic regression revealed that portal vein invasion (p = 0.011) was an independent predictor of worse clinical response. Portal vein invasion (p = 0.040), previous cTACE treatment (p = 0.030), as well as abnormal serum creatinine level (BCr) (p = 0.017) were independent factors that predicted worse ORR. In terms of survival, higher Barcelona Clinic Liver Cancer (BCLC) stage (p = 0.029) predicted for worse PFS, and abnormal albumin (ALB) (p = 0.011) and total serum bilirubin (TBIL) (p = 0.009) predicted for worse OS. The number of patients with abnormal albumin, total protein (TP), TBIL, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) were augmented at 1 week posttreatment and were similar at 1–3 months compared with baseline. The most common AEs were pain, fever, nausea, and vomiting, and no severe AEs were observed in this study. DEB-TACE was effective and tolerable in treating Chinese HCC patients, and portal vein invasion, previous cTACE treatment, abnormal BCr, ALB, and TBIL appear to be important factors that predict worse clinical outcome.

In a previous study, we demonstrated the role of polydatin (PD) in protecting against multiple organ dysfunction in sepsis. The aim of this study is to investigate whether PD protects against lipopolysaccharide (LPS)-induced endothelial barrier disruption through SIRT3 activation and to disclose the underlying mechanisms. Wild-type mice were injected with LPS and Evans Blue assay was performed to evaluate vascular permeability. Primary human umbilical vein endothelial cells (HUVECs) were stimulated with LPS. Endothelial permeability was evaluated by transendothelial electrical resistance (TER) and FITC-dextran leakage. SIRT3 activity was determined by a Deacetylase Fluorometric kit, and protein expression level of SIRT3 was detected by western blotting. Mitochondrial function was evaluated by determination of ROS level, mitochondrial membrane potential and mPTP opening. In endotoxemic mice, PD pretreatment attenuated vascular leakage in multiple organs while SIRT3 inhibition with 3-TYP reversed the effects of PD. PD treatment in late sepsis also exhibited barrier protective effects. In HUVECs, PD alleviated LPS-induced F-actin rearrangement, cadherin-catenin complex dissociation and endothelial hyperpermeability, whereas 3-TYP or SIRT3 siRNA attenuated the protective effects of PD. PD enhanced SIRT3 deacetylase activity, and attenuated LPS-induced decrease in SIRT3 expression as well. Furthermore, gain-of-function and loss-of-function strategies also confirmed the role of SIRT3 in enhancing endothelial barrier integrity. It was further ascertained that PD enhanced SIRT3-mediated deacetylation of SOD2 and cyclophilin D (CypD), thus suppressing mitochondrial dysfunction and subsequent endothelial barrier dysfunction. In addition, it was revealed that RAGE was involved in LPS-regulated SIRT3 signaling. Our results suggest that polydatin protects against LPS-induced endothelial barrier disruption dependent on SIRT3 and can be applied as a potential therapy for sepsis.

This study aims to examine microcirculation and systemic hemodynamic disturbances in severe heat stroke (HS). A total of 147 rats were divided into HS group (HS), pretreated with superoxide dismutase (SOD+HS) group, and pretreated with normal saline (NS+HS) group. Heat stress was induced by incubating the animals in certain temperatures. Blood flow and vascular reactivity were monitored dynamically with intravital microscopy. Pulmonary permeability was reflected by wet-to-dry weight ratio, the concentration of Evans Blue (EB), and histopathology of lung. The results showed that heat stress could induce blood flow rate reduced, and SOD exhibited better protective role in blood flow rate. The arteriolar reactivity threshold to norepinephrine was markedly reduced at core temperature of 41°C, but no significant decrease occurred in SOD+HS group. Water content and EB concentration in lung tissue in HS group were increased along with temperature rise. SOD treatment could attenuate those changes. The pathological lung injury caused by heat stress was also milder in SOD+HS group than that in other two groups. Mean arterial pressure decreased at early stages of heat stress, but there was no decrease in SOD+HS group. There was a significant body weight loss during heat stress in all groups. Survival time in SOD+HS group was longer than that in other two groups. These results suggest that microcirculation disturbance occurs not only at the early stage but also before systemic hemodynamic disorder, monitoring microcirculation following HS is of prognostic value, and intervention with antioxidative agents may have certain protecting effects in severe HS.

Previous researches found that apigenin exerted antidepressant-like effects in rodents. However, it is unclear whether the neurotrophic system is involved in the antidepressant-like effects of apigenin. Our present study aimed to explore the neurotrophic related mechanism of apigenin in depressive-like mice induced by chronic corticosterone treatment. Mice were repeatedly injected with corticosterone (40 mg/kg) subcutaneously (s.c) once daily for consecutive 21 days. Apigenin (20 and 40 mg/kg) and fluoxetine (20 mg/kg) were administered 30 min prior to the corticosterone injection. The behavioral tests indicated that apigenin reversed the reduction of sucrose preference and the elevation of immobility time in mice induced by chronic corticosterone treatment. In addition, the increase in serum corticosterone levels and the decrease in hippocampal brain-derived neurotrophic factor (BDNF) levels in corticosterone-treated mice were also ameliorated by apigenin administration. Taken together, our findings intensively confirmed the antidepressant-like effects of apigenin and indicated that the antidepressant-like mechanism of apigenin was mediated, at least partly by up-regulation of BDNF levels in the hippocampus.

This article uses the Apriori algorithm in the analysis of college English teaching quality, and uses this algorithm to analyze the learning situation of 1133 students. From the various elements including the college English teaching period, prerequisites and learning environment, the research shows that The main factors that have the greatest impact on learning are learning motivation, teaching methods and teaching modes. Finally, the experimental analysis shows that the Apriori algorithm used in this article can quantify the impact of different teaching factors on students’ learning quality, and also provide a basis for subsequent research on the quality of college English teaching.

This study aimed to investigate the efficacy and safety of drug-eluting beads (DEB) transarterial chemoembolization (TACE) treatment in Chinese intrahepatic cholangiocarcinoma (ICC) patients.37 ICC patients underwent DEB-TACE treatment in CTILC study (registered on clinicaltrials.gov with registry No. NCT03317483) were included in this present study. Treatment response was assessed according to modified Response Evaluation Criteria in Solid Tumors (mRECIST). Overall survival (OS) was calculated from the time of DEB-TACE operation until the date of death from any causes. Liver function change and adverse events (AEs) were recorded during and after DEB-TACE operation.3 (8.1%) patients achieved complete response (CR) and 22 (59.5%) patients achieved partial response (PR), with objective response rate (ORR) of 67.6%. After DEB-TACE treatment, mean OS was 376 days (95%CI: 341-412 days). Multivariate logistic regression analysis revealed that Bilobar disease (P = .040, OR: 0.105, 95% CI: 0.012-0.898) and portal vein invasion (P = .038, OR: 0.104, 95% CI: 0.012-0.881) could independently predict less possibility of ORR. Patients with ALB abnormal, TP abnormal, ALT abnormal and AST abnormal were increased at 1-week post DEB-TACE treatment (P = .034, P = .001, P .050). Besides, most of the AEs were mild including pain, fever, vomiting, and nausea in this study.DEB-TACE was effective and well tolerated in treating ICC patients, and bilobar disease as well as portal vein invasion were independently correlated with less probability of ORR achievement.

Background N6-methyladenosine (m6A) modification holds an important position in tumorigenesis and metastasis because it can change gene expression and even function in multiple levels including RNA splicing, stability, translocation and translation. In present study, we aim to conducted comprehensive investigation on m6A RNA methylation regulators and m6A-related genes in pancreatic cancer and their association with survival time. Methods Based on Univariate Cox regression analysis, protein-protein interaction analysis, LASSO Cox regression, a risk prognostic model, STRING, Spearman and consensus clustering analysis, data from The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC) database was used to analyze 15 m6A RNA methylation regulators that were widely reported and 1,393 m6A-related genes in m6Avar. Results We found that 283 candidate m6A RNA methylation-related genes and 4 m6A RNA methylation regulatory factors, including RNA binding motif protein 15 (RBM15), methyltransferase like 14 (METTL14), fat mass and obesity-associated protein (FTO), and α-ketoglutarate-dependent dioxygenase AlkB homolog 5 (ALKBH5), differed significantly among different stages of the American Joint Committee on Cancer (AJCC) staging system. Protein-protein interaction analysis indicated epidermal growth factor receptor (EGFR), plectin-1 (PLEC), BLM RecQ like helicase (BLM), and polo like kinase 1 (PLK1) were closely related to other genes and could be considered as hub genes in the network. The results of LASSO Cox regression and the risk prognostic model indicated that AJCC stage, stage T and N, KRAS mutation status and x8q23.3 CNV fragment mutation differed significantly between the high-risk and the low-risk subgroups. The AUCs of 1 to 5 years after surgery were all more than 0.7 and increased year by year. Finally, we found KRAS mutation status and AJCC stage differed significantly among these groups after TCGA samples divided into subgroups with k=7. Moreover, we identified four m6A RNA methylation related genes expressed significantly differently among these seven subgroups, including collagen type VII alpha 1 chain (COL7A1), branched chain amino acid transaminase 1 (BCAT1), zinc finger protein 596 (ZNF596), and PLK1. Conclusions Our study systematically analyzed the m6A RNA methylation related genes, including expression, protein-protein interaction, potential function, and prognostic value and provides important clues to further research on the function of RNA m6A methylation and its related genes in pancreatic cancer.

Objective Endothelial hyperpermeability is a hallmark of acute lung injury in response to sepsis. The imbalance between adherence junction (AJ) mediated cell-cell adherence forces and stress fiber driven contractile forces contributes to increased endothelial permeability. Here, we spotlight the effects of β-catenin Y654 andY142 phosphorylation on HMGB1-mediated endothelial barrier leakage. Approach and results Our results showed that phospho-deficiencies at both β-catenin Y654and Y142ameliorated pulmonary vascular dysfunction in male C57 mice receiving a cecal ligation and puncture operation. In vitro analysis indicated that high mobility group box-1 protein (HMGB1) triggered β-catenin Y654 and Y142 phosphorylation, causing β-catenin translocation and adherence junction (AJ) disruptions as well as cytoskeleton rearrangement. In addition,β-catenin Y654 dephosphorylation attenuated HMGB1-mediated dissociation of VE-cadherin/β-catenin and, hence, partially prevented endothelial hyperpermeability. β-catenin Y142 dephosphorylation abolished HMGB1-induced uncoupling of β-catenin and α-catenin, suppressed cytoskeletal reassembly and, hence, alleviated endothelial hyperpermeability. Further investigation demonstrated that RAGE and Src were required forβ-catenin Y654 phosphorylation in response to HMGB1, while FAK was responsible for HMGB1-triggered β-catenin Y142 phosphorylation. Conclusions In sum, this study revealed the role of β-catenin Y654 and Y142 phosphorylation in HMGB1-mediated endothelial hyperpermeability through dysregulation between adherence and contractile forces. This result advances understanding of the mechanisms underlying pulmonary vascular hyperpermeability in sepsis.

Advanced glycation end products (AGEs), produced by the non-enzymatic glycation of proteins and lipids under hyperglycemia or oxidative stress conditions, has been implicated to be pivotal in the development of diabetic vascular complications, including diabetic retinopathy. We previously demonstrated that Src kinase played a causative role in AGE-induced hyper-permeability and barrier dysfunction in human umbilical vein endothelial cells (HUVECs). While the increase of vascular permeability is the early event of angiogenesis, the effect of Src in AGE-induced angiogenesis and the mechanism has not been completely revealed. Here, we investigated the impact of Src on AGE-induced HUVECs proliferation, migration, and tubulogenesis. Inhibition of Src with inhibitor PP2 or siRNA decreased AGE-induced migration and tubulogenesis of HUVECs. The inactivation of Src with pcDNA3/flag-SrcK298M also restrained AGE-induced HUVECs proliferation, migration, and tube formation, while the activation of Src with pcDNA3/flag-SrcY530F enhanced HUVECs angiogenesis alone and exacerbated AGE-induced angiogenesis. AGE-enhanced HUVECs angiogenesis in vitro was accompanied with the phosphorylation of ERK in HUVECs. The inhibition of ERK with its inhibitor PD98059 decreased AGE-induced HUVECs angiogenesis. Furthermore, the inhibition and silencing of Src suppressed the AGE-induced ERK activation. And the silencing of AGEs receptor (RAGE) inhibited the AGE-induced ERK activation and angiogenesis as well. In conclusions, this study demonstrated that Src plays a pivotal role in AGE-promoted HUVECs angiogenesis by phosphorylating ERK, and very likely through RAGE-Src-ERK pathway.

Recent studies have shown that activation of liver X receptors (LXRs) attenuates the development of atherosclerosis, not only by regulating lipid metabolism but also by suppressing inflammatory signaling. Sphingosine 1-phosphate receptor 2 (S1PR2), an important inflammatory gene product, plays a role in the development of various inflammatory diseases. It was proposed that S1PR2 might be regulated by LXR-α. In the present study, the effect of LXR-α on tumor necrosis factor-α (TNF-α)-induced S1PR2 expression in human umbilical vein endothelial cells (HUVECs) was investigated and the underlying mechanism was explored. The results demonstrated that TNF-α led to an increase in S1PR2 expression and triggered a downregulation of LXR-α expression in HUVECs as well. Downregulation of LXR-α with specific small interfering RNA (siRNA) remarkably enhanced the primary as well as TNF-α-induced expression of S1PR2 in HUVECs. Activation of LXR-α by agonist GW3965 inhibited both primary and TNF-α-induced S1PR2 expression. GW3965 also attenuated S1PR2-induced endothelial barrier dysfunction. The data further showed that TNF-α induced a significant decrease in miR-130a-3p expression. Overexpression of miR-130a-3p with mimic product reduced S1PR2 protein expression, and inhibition of miR-130a-3p by specific inhibitor resulted in an increase in S1PR2 protein expression. Furthermore, activation of LXRs with agonist enhanced the expression of miR-130a-3p, and knockdown of LXR-α by siRNA suppressed miR-130a-3p expression. These results suggest that LXR-α might downregulate S1PR2 expression via miR-130a-3p in quiescent HUVECs. Stimulation of TNF-α attenuates the activity of LXR-α and results in enhanced S1PR2 expression.

Two large landslides, Dehenglong and Suozi, blocked the upper Yellow River from Longyang Gorge to Liujia Gorge on the Qinghai-Tibetan Plateau. This research is significant because no relevant chronologies for this landslide-dammed lake had been reported. Twelve OSL samples were collected from the lacustrine sediments of the landslide-dammed lake deposited on both banks of the upper Yellow River. Samples yielded similar ages of ca. 80 ka. The Dehenglong landslide and Suozi landslide are thus inferred to be triggered by ca. 80 ka tectonic movements.

Ferric and ferrous ion plays critical roles in bioprocesses, their influences in many fields have not been fully explored due to the lack of methods for quantification of ferric and ferrous ions in biological system or complex matrix. In this study, an M13 bacteriophage (phage) was engineered for use as a sensor for ferric and ferrous ions via the display of a tyrosine residue on the P8 coat protein. The interaction between the specific phenol group of tyrosine and Fe(3+) / Fe(2+) was used as the sensor. Transmission electron microscopy showed aggregation of the tyrosine-displaying phages after incubation with Fe(3+) and Fe(2+). The aggregated phages infected the host bacterium inefficiently. This phenomenon could be utilized for detection of ferric and ferrous ions. For ferric ions, a calibration curve ranging from 200 nmol/L to 8 μmol/L with a detection limit of 58 nmol/L was acquired. For ferrous ions, a calibration curve ranging from 800 nmol/L to 8 μmol/L with a detection limit of 641.7 nmol/L was acquired. The assay was specific for Fe(3+) and Fe(2+) when tested against Ni(2+), Pb(2+), Zn(2+), Mn(2+), Co(2+), Ca(2+), Cu(2+), Cr(3+), Ba(2+), and K(+). The tyrosine displaying phage to Fe(3+) and Fe(2+) interaction would have plenty of room in application to biomaterials and bionanotechnology. [Image: see text]

We have previously reported that advanced glycation end products activated Rho-associated protein kinase and p38 mitogen–activated protein kinase, causing endothelial hyperpermeability. However, the mechanisms involved were not fully clarified. Here, we explored the role of myosin light chain kinase in advanced glycation end product–induced endothelial hyperpermeability. Myosin light chain phosphorylation significantly increased by advanced glycation end products in endothelial cells in a time- and dose-dependent manner, indicating that myosin light chain phosphorylation is involved in the advanced glycation end product pathway. Advanced glycation end products also induced myosin phosphatase–targeting subunit 1 phosphorylation, and small interfering RNA knockdown of the receptor for advanced glycation end products, or blocking myosin light chain kinase with its inhibitor, ML-7, or small interfering RNA abated advanced glycation end product–induced myosin light chain phosphorylation. Advanced glycation end product–induced F-actin rearrangement and endothelial hyperpermeability were also diminished by inhibition of receptor for advanced glycation end product or myosin light chain kinase signalling. Moreover, inhibiting myosin light chain kinase with ML-7 or blocking receptor for advanced glycation end product with its neutralizing antibody attenuated advanced glycation end product–induced microvascular hyperpermeability. Our findings suggest a novel role for myosin light chain and myosin light chain kinase in advanced glycation end product–induced endothelial hyperpermeability.

Amorphous monodisperse spheres of amino-functionalized zirconia (ZrO 2 ) were prepared by the co-condensation of zirconium tetrabutoxide as the precursor of ZrO 2 in the presence of aminopropyltriethoxy silane (APS) as the source of terminal amino groups. The resultant amino functional groups possess lone-pair electrons that can be coordinated with Ag seed colloid to immobilize the Ag seeds on the surface of ZrO 2 . Ag seeds tethered on the surface of the amino-functionalized ZrO 2 served as nucleation sites for the growth of Ag nanoshell overlayer via the reduction of AgNO 3 by polyvinylpyrrolidone (PVP), thereby affording core–shell structure ZrO 2 @Ag composite. The microstructure and chemical state of the as-prepared ZrO 2 @Ag composite were characterized by X-ray diffraction, transmission electron microscopy and X-ray photoelectron spectroscopy, and its catalytic activity towards the hydrogenation reduction of Rhodamine B (RhB) and 4-nitrophenol (4-NP), two of common organic dye, was evaluated by ultraviolet–visible spectrophotometry. The results indicate that the uniformly distributed Ag nanoparticles with average size of 10 nm are strongly attached to ZrO 2 surface. Besides, the as-prepared ZrO 2 @Ag composite exhibits excellent catalytic performance for the hydrogenation reduction of RhB and 4-NP.

To prevent and avoid magnetic loss caused by magnetite core phase transitions involved in high-temperature crystallization of sol-gel TiO2, a direct and feasible low-temperature crystallization technique was developed to deposit anatase TiO2 nanoparticle shell on Fe3O4 sphere cores. To promote the photocatalytic efficiency of the obtained core-shell Fe3O4@TiO2 magnetic photocatalyst, uniformly distributed Au nanoparticles (NPs) were successfully immobilized on the core-shell Fe3O4@TiO2 spheres via a seed-mediated growth procedure. The 3 nm Au colloid absorbed on Fe3O4@TiO2 served as a nucleation site for the growth of Au NPs overlayer. The morphology, structure, composition and magnetism of the resulting composites were characterized, and their photocatalytic activities were also evaluated. In comparison to Fe3O4@TiO2, Fe3O4@TiO2-Au exhibited higher photocatalytic activity for organic degradation under UV irradiation. This enhanced mechanism may have resulted from efficient charge separation of photogenerated electrons and holes due to the Au NPs attached on the TiO2. In addition, the composites possessed superparamagnetic properties with a high saturation magnetization of 44.6 emu g−1 and could be easily separated and recycled by a magnet.

Monodispersed Cu2O spherical colloids with diameter of about 300 nm were prepared by a facile additive-assisted complex-precursor solution method. Core-shell structure Cu2O/Au composites, constructed by spherical Cu2O core and Au nanoparticles shell, were obtained via galvanic replacement method. The morphology, microstructure and optical properties of the Cu2O/Au composites were characterized by X-ray diffraction, transmission electron microscopy, X-ray photoelectron spectra and ultraviolet-visible absorption. The results showed that Au NPs with an average size of 12 nm were uniformly distributed on the surface of the Cu2O spheres with size about 300 nm. Cu2O/Au composites exhibit high catalytic activity toward 4-NP reduction at room temperature.

Monodisperse Cu2O colloidal spheres were produced by a sol–gel reaction. The Cu2O@Ag composite spheres with core–shell structure were prepared by photodeposition route. The size and shape as well as the optical properties of the composites were characterized with transmission electron microscopy (TEM) and UV–vis spectroscopy. The results showed that the average particle size of Cu2O among the composites was about 150 nm, and the average particle size of Ag nanoparticles (NPs) was around 8 nm. Ag NPs were relatively monodisperse and presented spherical shape, and their deposition on the Cu2O surface was uniform. Formation of metallic Ag NPs on the surface of Cu2O spheres was also confirmed by X-ray diffraction (XRD) and X-ray photoelectron spectroscopy (XPS). The antibacterial activity of the as-synthesized Cu2O spheres and Cu2O@Ag composites was also investigated. Owing to the synergistic action between Cu2O and Ag NPs, the Cu2O@Ag composites exhibit more excellent antibacterial activity compared to the pristine Cu2O.

Photocatalytic reduction is a facile and effective route to deposit Ag nanoparticles (NPs) on TiO2. Nevertheless, it is difficult to produce Ag NPs that have small particle size and uniform distribution on TiO2 to form core–shell structure TiO2@Ag composites by straightforward photodeposition. In this study, monodisperse TiO2 spheres composed of anatase nanocrystals were directly employed as templates to deposit small and homogeneously dispersed Ag NPs by modified photodeposition procedure. To prove the feasibility of the innovative method, we evaluated the catalytic performance and bactericidal efficacy of the as-prepared samples based on the characterizations, since there is strong dependence between size and dispersion of Ag NPs and catalytic performance and inhibition of bacterial growth, where smaller and more highly dispersed Ag NPs displayed better antimicrobial and catalytic properties. The results indicate that the modified photodeposition route can effectively prevent TiO2 spheres themselves from aggregating and Ag NPs from rapid overgrowing on the TiO2 surface in the deposition process. The superior bactericidal and catalytic properties of the TiO2@Ag composites are largely attributed to the small and highly dispersed Ag NPs on TiO2 spheres.

A method is described for the matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF)-based determination of benzo[a]pyrene (BaP) by using the metal-organic framework MIL-101(Fe) as a matrix. Following optimization of the experimental parameters, the method has a detection limit as low as 0.1 μg·L-1, which makes it more sensitive than previous methods for BaP analysis, and its analysis time is only 1 min. Its applicability was evaluated by analyzing sesame oil, linseed oil, camellia seed oil, and olive oil spiked with BaP at three levels (10, 1, and 0.5 μg·kg-1), and the recovery range was found to range from 80.0 to 114.8% with relative standard deviations (RSDs) between 3.9 and 13.7%. Graphical abstract The metal-organic framework MIL-101(Fe) was applied as a new matrix to the quantitative detection of benzo[a]pyrene (BaP) by matrix assisted laser desorption/ionization time-of-flight (MALDI-TOF).

Background The association between body mass index (BMI) and clinical outcomes of gastric cancer were still under debate. The aim of the present study was to investigate the impact of BMI on intraoperative conditions, postoperative complications and prognosis of gastric cancer. Methods From October 2008 to March 2015, 1210 gastric cancer patients treated with D2 gastrectomy were enrolled in the present study. Patients were divided into three groups: low BMI group (BMI 0.05). High BMI was associated with increased blood loss and operation time, and deceased number of retrieved lymph nodes (all P 0.05). Conclusions BMI was inversely associated with tumor size, tumor depth, LNM and tumor stage. High BMI was associated with increased blood loss and operation time, and deceased number of retrieved lymph nodes. Low BMI was associated with decreased rate of postoperative fever and decreased survival.

Irrigation is vital to agriculture and economic development, especially in arid areas. It is essential to study the characteristics of water infiltration with respect to understanding of water balance information and to provide scientific theory for rationally utilizing water resource. In this study, a HYDRUS-1D model was established to simulate the process of soil water infiltration after a field infiltration experiment conducted in Yaoba Oasis, and the measured water content data were used to calibrate and validate the model. Results showed that average correlation coefficients of simulation results were up to 0.9, and relative error and root mean square error were 6.11% and 0.015 cm3 cm−3, indicating that the HYDRUS model has a higher degree of accuracy and could be used to simulate the procedure of soil water infiltration in Yaoba Oasis. During 2015 season, consumption of evaporation and transpiration was 429 and 386 mm, respectively, and transpiration was only 67% of potential transpiration, which caused that the yield of corn was affected by water stress. Contrarily, due to high sand content and inappropriate irrigation regime, the amount of invalid leakage waste was up to 581 mm, accounted for 40.9% of the total infiltration. The simulation of different irrigation regimes found that increasing the irrigation times and controlling the single irrigation amount properly could both save water resource and improve root water uptake amount.

It was previously reported that low‑dose sphingosine‑1‑phosphate (S1P) enhanced endothelial barrier integrity, whereas high‑dose S1P induced endothelial monolayer hyperpermeability responses. A number of studies have revealed the underlying molecular mechanisms of the physiological‑dose of S1P on barrier‑protective effect. However, little work has been performed to determine the effect of S1P‑induced endothelial barrier responses. In the present study, the role of moesin phosphorylation in excessive S1P‑induced endothelial hyperpermeability was investigated by western blotting, fluorescence staining and transendothelial electrical resistance detection. It was revealed that S1P induced moesin phosphorylation in a time‑ and concentration‑dependent manner. In addition, it was confirmed that high‑dose S1P‑induced moesin phosphorylation occurred via S1P receptor 2 (S1PR2). Moesin phosphorylation was required for S1P‑induced F‑actin rearrangement and endothelial barrier disruption. The results suggested that the S1PR2‑moesin axis is involved in high‑dose S1P‑induced endothelial barrier responses. The results of the present study may provide novel therapeutic targets for endothelial injury‑associated vascular disorders.

Trichosanthin (TCS), isolated from the root tuber of Trichosantheskirilowii, a well-known traditional Chinese medicinal plant, belonging to the Cucurbitaceae family, was found to exhibit numerous biological and pharmacological activities including anti-inflammatory. However, the effects of TCS on arterial injury induced neointimal hyperplasia and inflammatory cell infiltration remains poorly understood. The aim of study was to examine the effectiveness of TCS on arterial injury-mediated inflammatory processes and underlying mechanisms. A balloon-injured carotid artery induced injury in vivo in rats was established as a model of vascular injury. After 1 day TCS at 20, 40, or 80 mg/kg/day was administered intraperitoneally, daily for 14 days. Subsequently, the carotid artery was excised and taken for immunohistochemical staining. Data showed that TCS significantly dose-dependently reduced balloon injury-induced neointima formation in the carotid artery model rat, accompanied by markedly decreased positive expression percentage proliferating cell nuclear antigen (PCNA). In the in vitro study vascular smooth muscle cells (VSMC) were cultured, proliferation stimulated with platelet-derived growth factor-BB (PDGF-BB) (20 ng/ml) and TCS at 1, 2, or 4 μM added. Data demonstrated that TCS inhibited proliferation and cell cycle progression of VSMC induced by PDGF-BB. Further, TCS significantly lowered mRNA expression of cyclinD1, cyclinE1, and c-fos, and protein expression levels of Akt1, Akt2, and mitogen-activated protein kinase MAPK (ERK1) signaling pathway mediated by PDGF-BB. These findings indicate that TCS inhibits vascular neointimal hyperplasia induced by vascular injury in rats by suppression of VSMC proliferation and migration, which may involve inhibition of Akt/MAPK/ERK signal pathway.

Background/Aims: Disruption of endothelial barrier integrity in response to advanced glycation end products (AEGs) stimulation contributes to vasculopathy associated with diabetes mellitus. Mammalian diaphanous-related formin (mDia1) has been reported to bind to the cytoplasmic domain of the receptor for advanced glycation end products (RAGE), which induces a series of cellular processes. This study directly evaluated the participation of mDia1 in AGE-induced hyperpermeability and revealed the precise intracellular signal transductions of this pathological process. Methods: Human umbilical vein endothelial cells (HUVECs) were used in the in vitro studies. Trans-endothelial electric resistance and permeability coefficient for dextran (Pd) were measured to analyze cell permeability. Western blotting, immunofluorescence staining and flow cytometry assay were performed to investigate the underlying mechanism. Dextran flux across the mesentery in mice was monitored to investigate in vivo microvascular permeability. Results: we found that AGEs evoked Nox4 membrane translocation, reactive oxygen species production, phosphorylation of Src and VE-cadherin, dissociation of adherens junctions and eventual endothelial hyperpermeability through RAGE-mDia1 binding. Cells overexpressing mDia1 by recombinant adenovirus infection showed stronger cellular responses induced by AGEs. Down-regulation of mDia1 by infection with an adenovirus encoding siRNA or blockade of RAGE-mDia1 binding by transfection with RAGE mutant plasmids into HUVECs abolished these AGE-induced effects. Furthermore, knockdown of mDia1 using an adenovirus or genetical knockout of RAGE in C57 mice rescued AGE-evoked microvascular hyperpermeability. Conclusion: Our study revealed that mDia1 plays a critical role in AGE-induced microvascular hyperpermeability through binding to RAGE.

Aims To investigate the association of several single nucleotide polymorphisms (SNPs) within RAGE gene and additional gene- smoking interaction with diabetic nephropathy (DN) risk in Chinese patients with type 2 diabetes mellitus (T2DM). Methods A total of 865 participants (570 males, 295 females) were selected, including 430 T2DM complicated DN patients and 435 controls (T2DM patients without DN). Generalized multifactor dimensionality reduction (GMDR) was used to screen the best interaction combination among SNPs and smoking. Logistic regression was performed to investigate impact of 4 SNPs within RAGE gene, additional gene- smoking interaction on DN risk. Results DN risk was significantly higher in carriers with the C allele of rs1800625 than those with TT genotype, adjusted OR (95%CI) =1.57 (1.16-2.17), and higher in carriers with the T allele of rs184003 than those with GG genotype, adjusted OR (95%CI) = 1.64 (1.21-2.12). GMDR model indicated a significant two-locus model (p=0.0010) involving rs1800625 and smoking, the cross-validation consistency of this two- locus model was 10/ 10, and the testing accuracy was 60.72%. We also conducted stratified analysis for the significant models in the GMDR analysis by using logistic regression. We found that current smokers with rs1800625- TC or CC genotype have the highest DN risk, compared with never- smokers with rs1800625- TT genotype, OR (95%CI) = 2.92 (1.94 -3.96), after covariates adjustment. Conclusions We found that the C allele of rs1800625 and the T allele of rs184003 within RAGE gene, interaction between rs1800625 and smoking were all associated with increased DN risk.

Background The infiltration and activation of macrophages play key roles in arterial restenosis, providing a promising strategy for the treatment of restenosis caused by intimal hyperplasia. Although miR-150 has been implicated in cardiovascular diseases, the individual effect of miR-150 on intimal hyperplasia remains unclear. Methods and results We observed that the expression of miR-150 was robustly reduced in proinflammatory M1 macrophages and reversely induced in resolving M2 macrophages. An in vitro experiment demonstrated that miR-150 deficiency promoted extensive upregulation of the expression of M1 markers but attenuated the expression of M2 macrophage markers. MiR-150 enhanced the proliferation and migration of vascular smooth muscle cells (VSMCs) when co-cultured with conditioned medium from polarized macrophages upon LPS or IL-4 stimulation. Mechanistically, the bioinformatics analysis and luciferase assay results showed that miR-150 directly targeted STAT1 and STAT1 was required for the effect of miR-150 knockout on macrophage polarization. More importantly, we showed that knockout of miR-150 accelerated neointima formation, accompanied by the activation of M1 macrophages and the inactivation of M2 macrophages. Furthermore, miR-150 deficiency in marrow-derived cell accelerated neointima formation. Conclusion Our research demonstrated that miR-150 deficiency promoted intimal hyperplasia with high ratios of M1 to M2 macrophages and subsequently increased VSMCs proliferation and migration, which were partially mediated by directly targeting to STAT1. Collectively, these results suggested that miR-150 may act as a novel therapeutic target for arterial restenosis.

New Findings What is the central question of this study? Why do different doses of sphingosine-1-phosphate (S1P) induce distinct biological effects in endothelial cells? What is the main finding and its importance? S1P at physiological concentrations preserved endothelial barrier function by binding to S1P receptor 1, then triggering Ca2+ release from endoplasmic reticulum through phosphoinositide phospholipase C and inositol triphosphate, and consequently strengthening tight junction and F-actin assembly through Rac1 activation. Excessive S1P induced endothelial malfunction by activating S1P receptor 2 and RhoA/ROCK pathway, causing F-actin and tight junction disorganisation. Extracellular Ca2+ influx was involved in this process. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid in plasma, and its plasma concentration can be adjusted through a complex metabolic process. The alterations in S1P levels and the activation of receptors collaboratively regulate distinct biological effects. This study was performed to investigate comparatively the effect of different concentrations of S1P on endothelial barrier function and to explore the roles of S1P receptors (S1PRs), Rho GTPases and calcium in S1P-induced endothelial responses. Endothelial barrier function was studied using transendothelial electric resistance and a resistance meter in human umbilical vein endothelial cells. Specific agonists or antagonists were applied to control the activation of S1P receptors and the release of calcium from different cellular compartments. The results indicated that at physiological concentrations, S1P preserved endothelial barrier function by binding with S1PR1. The activation of S1PR1 triggered the release of intracellular Ca2+ from the endoplasmic reticulum through the PI–phospholipase C and inositol trisphosphate pathways. Consequently, the Rho GTPase Rac1 was activated, strengthening the assembly of tight junction proteins and F-actin. However, excessive S1P induced endothelial barrier dysfunction by activating S1PR2 followed by the RhoA/RhoA kinase pathway, causing the disorganization of F-actin and the disassembly of the tight junction protein ZO-1. An influx of extracellular Ca2+ was involved in this process. These data suggest that physiological and excessive amounts of S1P induce different responses in human umbilical vein endothelial cells; the activation of the 1PR1–PLC–IP3R–Ca2+–Rac1 pathway governs the low-dose S1P-enhanced endothelial barrier integrity, and the activation of S1PR2–calcium influx–RhoA/ROCK dominates the high-dose S1P-induced endothelial monolayer hyperpermeability response.

In this work, monodispersed TiO 2 spheres with diameter of about 360 nm were prepared by an acetic acid assisted sol–gel method. Core–shell structure TiO 2 @Ag composites, constructed by the anatase TiO 2 sphere cores and Ag nanoparticles (NPs) shell, were obtained via Ag nanoseed mediated photochemical reduction (modified photo-deposition) and characterized using transmission electron microscopy, XRD, X-ray photoelectron spectroscope and UV–vis spectroscopy. The characterization results indicate that Ag NPs with an average size of about 10 nm are uniformly distributed on the surface of the Ag nanoseed modified TiO 2 spheres under UV radiation. For the purpose of comparison, the TiO 2 /Ag composites were also prepared by conventional photodeposition method and characterized. The catalytic performance of the as-prepared composites through different photo-deposited methods was evaluated by catalysis reduction of 4-nitrophenol. The results indicated that the catalytic efficiency of TiO 2 @Ag core–shell structures is higher than that of TiO 2 /Ag composites. This could be because TiO 2 @Ag composites have a more homogeneous distribution of Ag NPs on the TiO 2 surface as well as a better contact between the Ag NPs and TiO 2 than TiO 2 /Ag composites.

Landslides are natural hazards whose occurring time-scale is critical for management. There are a number of giant landslides in the upper Yellow River valley due to the uplift of the Qinghai-Tibetan Plateau, and corresponding rapid incision of the river. Suozi landslide is the largest landslide found in the northeastern Qinghai-Tibetan Plateau. In this study, luminescence samples were collected from the shear outlet of the landslide and lens from alluvial sections formed after the landslide movement. The dating results showed that the Suozi landslide occurred at similar to 71 +/- 6 ka, similar to the age of the Dehenglong fault nearby. The agreement between a topographic analysis and the numerical age of landslides implies that the formation of Suozi landslide is strongly correlated with the tectonic activity. (c) 2014 Elsevier Ltd and INQUA. All rights reserved.

Endothelial cells (ECs) of thin-walled blood vessels form a barrier between blood and tissue. As a response to inflammation, the EC junctions widen and gaps form, resulting in compromised barrier functions. Although the mechanisms behind the establishment of these changes are still incompletely understood, one known reason is actomyosin-dependent actin rearrangement. Here, by using atomic force microscopy and a combination of confocal microscopy methods, we are the first to report that thermal injury induces general venular hyperpermeability and that serum from burned rats induces EC actin rearrangement, contraction, as well as tight-junction damage. Inhibition of the p38 mitogen-activated protein kinase (p38MAPK) largely ameliorates resulting vascular dysfunction by significantly reducing EC stress-fiber formation, contraction, volume changes and tight-junction damage, thereby greatly reducing the appearance of EC gaps. The findings may be of importance for the design of future pharmacotherapies aiming to ease the severe general vascular dysfunction that follows extensive burns.

Pear-shaped ZnO/Ag core–shell submicrospheres with good monodispersity were prepared via a seed-mediated particle growth procedure, where metal Ag (by reducing Ag + with Sn 2+ ) deposited on the as-prepared ZnO submicrospheres served as seeds (nucleation sites) for further growth of Ag nanoparticles. The as-prepared samples were characterized by X-ray diffraction, transmission electron microscopy, energy-dispersive X-ray spectroscopy, ultraviolet–visible and photoluminescence spectra. Structure characterization demonstrates that the ZnO/Ag composites are composed of pear-shaped wurtzite ZnO submicrosphere core and Ag nanoparticles (nanoshell). Photoluminescence indicates that Ag nanoshell can effectively inhibit the recombination of the photoinduced electrons and holes of ZnO. This is responsible for the higher photocatalytic activity of the ZnO/Ag core–shell composites. The photocatalytic performance of the prepared ZnO/Ag samples for degradation of Rhodamine B was evaluated with a comparative study. The relationship between the structure of the samples and their photocatalytic performance shows that Ag deposits can significantly enhance the photocatalytic efficiency of ZnO submicrospheres.

Foxp3 plays an essential role in conferring suppressive functionality to CD4+/Foxp3+ regulatory T cells (Tregs). Although studies showed that Foxp3 has to form cooperative complexes with NFAT to bind to target genes, it remains unclear whether NFAT is available in the nucleus of primary Tregs for Foxp3 access. It is generally believed that NFAT in resting cells resides in the cytoplasm, and its nuclear translocation depends on calcineurin (CN) activation. We report that a fraction of NFAT protein constitutively localizes in the nucleus of primary Tregs, where it selectively binds to Foxp3 target genes. Treating Tregs with CN inhibitor does not induce export of NFAT from the nucleus, indicating that its nuclear translocation is independent of CN activity. Consistently, Tregs are resistant to CN inhibitors in the presence of IL-2 and continue to proliferate in response to anti-CD3 stimulation, whereas proliferation of non-Tregs is abrogated by CN inhibitors. In addition, PMA, which activates other transcription factors required for T cell activation but not NFAT, selectively induces Treg proliferation in the absence of ionomycin. TCR interaction with self-MHC class II is not required for PMA-induced Treg proliferation. Tregs expanded by PMA or in the presence of CN inhibitors maintain Treg phenotype and functionality. These findings shed light on Treg biology, paving the way for strategies to selectively activate Tregs.

Several mitogen-activated protein kinases (MAPKs) are activated during thermal injury, and the p38 MAPK is specifically involved in endothelial cell (EC) actin and myosin rearrangement (stress-fiber formation) with ensuing cellular contraction and enhanced vessel permeability. Inhibition of p38 MAPK and extracellular signal-related kinase MAPK by their inhibitors SB203580 and PD98059, respectively, significantly reduces burn serum-induced EC stress-fiber formation, whereas SB203580 also inhibits burn serum-induced EC tight-junction damage and thereby general blood vessel hyperpermeability. The JNK MAPK inhibitor, SP600125, on the contrary, influences neither stress-fiber formation nor EC tight-junction damage. Extracellular signal-related kinase MAPK inhibition significantly decreases burn serum-induced Monocyte chemotactic protein-1 (MCP-1) release, whereas SB203580 and SP600125 have only limited such effects. Western blotting, real-time reverse transcriptase-polymerase chain reaction, and confocal laser scanning microscopy proved that SP600125 significantly inhibits burn serum-induced intercellular adhesion molecule 1 expression, whereas SB203580 depresses the expression of P selectin. In vivo studies, using the dominant negative adenoviral approach of MAPK kinase 3b and MAPK kinase 6b to block p38 MAPKs, and MKK4 and MKK7 to block JNK MAPKs, show that the latter MAPKs are involved in the regulation of P selectin and intercellular adhesion molecule 1 expression, respectively, following thermal injury. Taken together, the results suggest that several MAPKs play important, although different, roles in general EC alterations following burn injuries.

Increase in vascular permeability is the most important pathological event during the development of diabetic retinopathy. Deposition of advanced glycation end products (AGEs) plays a crucial role in the process of diabetes. This study was to investigate the role of moesin and its underlying signal transduction in retinal vascular hyper-permeability induced by AGE-modified mouse serum albumin (AGE-MSA). Female C57BL/6 mice were used to produce an AGE-treated model by intraperitoneal administration of AGE-MSA for seven consecutive days. The inner blood-retinal barrier was quantified by Evans blue leakage assay. Endothelial F-actin cytoskeleton in retinal vasculature was visualized by fluorescence probe staining. The expression and phosphorylation of moesin in retinal vessels were detected by RT-PCR and western blotting. Further studies were performed to explore the effects of Rho kinase (ROCK) and p38 MAPK pathway on the involvement of moesin in AGE-induced retinal vascular hyper-permeability response. Treatment with AGE-MSA significantly increased the permeability of the retinal microvessels and induced the disorganization of F-actin in retinal vascular endothelial cells. The threonine (T558) phosphorylation of moesin in retinal vessels was enhanced remarkably after AGE administration. The phosphorylation of moesin was attenuated by inhibitions of ROCK and p38 MAPK, while this treatment also prevented the dysfunction of inner blood-retinal barrier and the reorganization of F-actin in retinal vascular endothelial cells. These results demonstrate that moesin is involved in AGE-induced retinal vascular endothelial dysfunction and the phosphorylation of moesin is triggered via ROCK and p38 MAPK activation.

Advanced glycation end products (AGEs) accumulated in different pathological conditions have the potent capacity to alter cellular properties that include endothelial structural and functional regulations. The disruption of endothelial barrier integrity may contribute to AGE-induced microangiopathy and macrovasculopathy. Previous studies have shown that AGEs induced the rearrangement of actin and subsequent hyperpermeability in endothelial cells (ECs). However, the mechanisms involved in this AGE-evoked EC malfunction are not well understood. This study directly evaluated the involvement of moesin phosphorylation in AGE-induced alterations and the effects of the RhoA and p38 MAPK pathways on this process. Using immortalized human dermal microvascular ECs (HMVECs), we first confirmed that the ezrin/radixin/moesin (ERM) protein moesin is required in AGE-induced F-actin rearrangement and hyperpermeability responses in ECs by knockdown of moesin protein expression with small interfering RNA. We then detected AGE-induced moesin phosphorylation by Western blot analysis. The mechanisms involved in moesin phosphorylation were analyzed by blocking AGE receptor binding and inhibiting Rho and MAPK pathways. AGE-treated HMVECs exhibited time- and dose-dependent increases in the Thr558phosphorylation of moesin. The increased moesin phosphorylation was attenuated by preadministrations of AGE receptor antibody, Rho kinase (ROCK), or p38 inhibitor. Suppression of p38 activation via the expression of dominant negative mutants with Ad.MKK6b or Ad.p38α also decreased moesin phosphorylation. The activation of the p38 pathway by transfection of HMVECs with an adenoviral construct of dominant active MKK6b resulted in moesin phosphorylation. These results suggest a critical role of moesin phosphorylation in AGE-induced EC functional and morphological regulations. Activation of the ROCK and p38 pathways is required in moesin phosphorylation.

Prostaglandin (PG) E 2 has an established role in the regulation of vascular tone and reactivity. The present study examined the role and mechanism of microsomal PG synthase-1 (mPGES-1) in vascular response to angiotensin II (Ang II) infusion. A 7-day Ang II infusion at 0.35 mg/kg per day via osmotic minipump had no obvious effect on mean arterial blood pressure in mPGES-1 +/+ mice but induced a marked hypertensive response in mPGES-1 −/− mice, associated with a parallel increase in urinary 8-isoprostane excretion and aortic NADPH oxidase activity and mRNA expression of p47 phox , gp91 phox , and Nox1. The hypertension in mPGES-1 −/− mice was completely prevented by Tempol treatment and was fully restored on termination of the antioxidant. Apocynin induced a similar blood pressure–lowering effect as Tempol. The Ang II infusion induced mRNA expression of mPGES-1, as well as mPGES-2 and cytosolic PGE synthase in the aortas as assessed by real-time RT-PCR. Immunohistochemistry revealed remarkably enhanced immunoreactivity of mPGES-1 mostly in vascular smooth muscle cells. In cultured vascular smooth muscle cells, Ang II exerted a direct stimulatory effect on reactive oxygen species production, NADPH oxidase activity, and expression of p47 phox , gp91 phox , and Nox1 that were all inhibited by PGE 2 . The −/− mice also exhibited enhanced renal hemodynamic response to acute Ang II infusion at 150 nmol/kg per minute via a jugular vein over a period of 40 minutes. These results suggest that mPGES-1–derived PGE 2 buffers Ang II–induced vasoconstriction via inhibition of NADPH oxidase–dependent reactive oxygen species production.

Background: This study examined the possible role of atrial ectopics and short runs of atrial tachycardia in the initiation of episodes of paroxysmal atrial fibrillation (PAF). Methods: Holter recordings from patients participating in pharmacotherapy trials for the prevention of PAF were examined. Treatment comprised placebo, digoxin, disopyramide, or atenolol. The frequency of atrial ectopic beats during each 30 seconds over the 5 minutes prior to PAF and whether this was also associated with atrial tachycardia (3 or more ectopics in succession) was calculated. Results: The mean number of ectopics was 4.1 in the final minute, but patients receiving disopyramide or atenolol had significantly more ectopics than those on placebo (P > 0.05 for both). Those on digoxin had a similar number of ectopics to placebo patients. There was no relationship between heart rate at PAF onset and ectopic frequency, nor any association between the presence of one or more episodes of atrial tachycardia and ectopic frequency. Conclusion: Atrial ectopics increase in frequency prior to PAF onset, and this study suggests that antiarrhythmic therapy may increase the number of ectopics required to initiate PAF.

This paper puts forward a new depth & path-based semantic similarity method to improve the existing meaning-based approaches in HowNet. Firstly, a complete concept tree is constructed on the sememe tree according to the concept definitions in HowNet. Then an improved depth & path algorithm was put forward, in which five adjustable parameters are used to compute the depth and path of concept in concept tree. This method avoids the computation process of complicated meaning similarity and is more intuitive and efficient. The experiment shows that proposed algorithm has achieved an excellent level comparing with the existing word similarity algorithms.

Disorders of angiogenesis are related to microangiopathies during the development of diabetic vascular complications, but the effect of advanced glycation end products (AGEs) on angiogenesis and the mechanism has not been completely unveiled. We previous demonstrated that moesin belonging to the ezrin-radixin-moesin (ERM) protein family protein played a critical role in AGE-induced hyper-permeability in human umbilical vein endothelial cells (HUVECs). Here, we investigated the impact of moesin on AGE-induced HUVEC proliferation, migration, and tubulogenesis. Silencing of moesin decreased cell motility and tube formation but not cell proliferation. It also attenuated cellular F-actin reassembly. Further, phosphorylation of threonine at the 558 amino acid residue (Thr 558) in moesin suppressed AGE-induced HUVEC proliferation, migration, and tube formation, while the activating mutation of moesin at Thr 558 enhanced HUVEC angiogenesis. Further, the inhibition of either RhoA activity by adenovirus or ROCK activation with inhibitor Y27632 decreased AGE-induced moesin phosphorylation and subsequently suppressed HUVEC angiogenesis. These results indicate that the Thr 558 phosphorylation in moesin mediates endothelial angiogenesis. AGEs promoted HUVEC angiogenesis by inducing moesin phosphorylation via RhoA/ROCK pathway.

To investigate the protective effect of ulinastatin (UTI) against acute lung injury induced by heatstroke in mice.Sixty C57/BL6 mice were randomly divided into 6 groups, with 10 mice in each: control group, heatstroke group, UTI pretreatment group, saline pretreatment group, UTI post-treatment group, saline post-treatment group. The control mice were housed at a controlled room temperature of (22∓1) degrees; celsius, and the other groups were placed inside a temperature and humidity controlled chamber pre-set at 37 degrees; celsius and 60%. The two UTI groups were intraperitoneally injected with UTI at 5×10(4) U/kg 10 min before or after heat stress, and the two saline groups were given then equal amounts of saline in the same manner. The core body temperature of mice was monitored by a mercury thermometer every 30 min in the first 1.5 h during heating. The core temperature was measured, then every 15 min until it reached 42.7 degrees; celsius, which was taken as the onset of heatstroke. The animals were allowed to recover passively at ambient temperature for 6 h. The lung histopathological changes, protein concentration in BALF, lung wet/dry weight ratios, lung water content, and pulmonary microvascular permeability were assayed after 6 h of recovery at 37 degrees;celsius.Compared with the control group, the heatstroke model group and two saline groups displayed more severe lung damage and pathological morphology changes, and the lung wet/dry weight ratio, protein concentration in BALF, lung water content and pulmonary microvascular permeability were also significantly increased. These effects were significantly alleviated in UTI treated group. Pretreat ment with UTI significantly prolonged the time to Tc≥42.7 degrees; celsius but had no effect on lung injury induced by heatstroke.UTI can reduce the pulmonary edema and inflammatory exudation in acute lung injury caused by heatstroke.