Smooth, Chemically Altered Nucleating Platform for Abrupt Performance Enhancement of Ultrathin Cu-Layer-Based Transparent Electrodes.

Rapid advances in flexible optoelectronic devices necessitate the concomitant development of high-performance, cost-efficient, and flexible transparent conductive electrodes (TCEs). This Letter reports an abrupt enhancement in the optoelectronic characteristics of ultrathin Cu-layer-based TCEs via Ar+-mediated modulation of the chemical and physical states of a ZnO support surface. This approach strongly regulates the growth mode for the subsequently deposited Cu layer, in addition to marked alteration to the ZnO/Cu interface states, resulting in exceptional TCE performance in the form of ZnO/Cu/ZnO TCEs. The resultant Haacke figure of merit (T10/Rs) of 0.063 Ω-1, 53% greater than that of the unaltered, otherwise identical structure, corresponds to a record-high value for Cu-layer-based TCEs. Moreover, the enhanced TCE performance in this approach is shown to be highly sustainable under severe simultaneous loadings of electrical, thermal, and mechanical stresses.

Simultaneous Enhancement in Visible Transparency and Electrical Conductivity via the Physicochemical Alterations of Ultrathin-Silver-Film-Based Transparent Electrodes.

A methodology for the simultaneous modulation of the chemical and physical states of an amorphous TiOx layer surface and its impact on the subsequent deposition of a polycrystalline Ag layer are presented. The smoothened TiOx layer surface comprising chemically altered, oxygen-deficient states serves as a nucleating platform for Ag deposition, facilitating a marked increase (∼75%) in the nucleation number density, which strongly enhances the wettability of ultrathin Ag layers. The physically smoothened TiOx/Ag interface further reduces the optical and electrical losses. When the proposed methodology is applied to TiOx/Ag/ZnO transparent conductive electrodes (TCEs), exceptional TCE properties are yielded owing to the simultaneous improvement in visible transparency and electrical conductivity; specifically, a record-high 0.22 Ω-1 Haacke figure of merit is realized. TCEs are prepared on flexible substrates to verify their applicability as stand-alone flexible transparent heaters and as integrated heaters within electrochromic devices to enhance color-switching reactions.

Strategy for Fabricating Ultrathin Au Film Electrodes with Ultralow Optoelectrical Losses and High Stability.

A vital objective in the wetting of Au deposited on chemically heterogeneous oxides is to synthesize a completely continuous, highly crystalline, ultrathin-layered geometry with minimized electrical and optical losses. However, no effective solution has been proposed for synthesizing an ideal Au-layered structure. This study presents evidence for the effectiveness of atomic oxygen-mediated growth of such an ideal Au layer by improving Au wetting on ZnO substrates with a substantial reduction in free energy. The unexpected outcome of the atomic oxygen-mediated Au growth can be attributed to the unconventional segregation and incorporation of atomic oxygen along the outermost boundaries of Au nanostructures evolving in the clustering and layering stages. Moreover, the experimental and numerical investigations revealed the spontaneous migration of atomic oxygen from an interstitial oxygen surplus ZnO bulk to the Au-ZnO interface, as well as the segregation (float-out) of the atomic oxygen toward the top Au surfaces. Thus, the implementation of a 4-nm-thick, two-dimensional, quasi-single-crystalline Au layer with a nearly complete crystalline realignment at a mild temperature (570 K) enabled exceptional optoelectrical performance with record-low resistivity (<7.5 × 10-8 Ω·m) and minimal optical loss (∼3.5%) at a wavelength of 700 nm.

Wip1 regulates Smad4 phosphorylation and inhibits TGF-ß signaling.

The tumor suppressor Smad4, a key mediator of the TGF-ß/BMP pathways, is essential for development and tissue homeostasis. Phosphorylation of Smad4 in its linker region catalyzed by the mitogen-activated protein kinase (MAPK) plays a pivotal role in regulating its transcriptional activity and stability. In contrast, roles of Smad4 dephosphorylation as a control mechanism of TGF-ß/BMP signaling and the phosphatases responsible for its dephosphorylation remain so far elusive. Here, we identify Wip1 as a Smad4 phosphatase. Wip1 selectively binds and dephosphorylates Smad4 at Thr277, a key MAPK phosphorylation site, thereby regulating its nuclear accumulation and half-life. In Xenopus embryos, Wip1 limits mesoderm formation and favors neural induction by inhibiting TGF-ß/BMP signals. Wip1 restrains TGF-ß-induced growth arrest, migration, and invasion in human cells and enhances the tumorigenicity of cancer cells by repressing the antimitogenic activity of Smad4. We propose that Wip1-dependent dephosphorylation of Smad4 is critical for the regulation of TGF-ß signaling.

Role of S100A9 in the development of neutrophilic inflammation in asthmatics and in a murine model.

S100A9 is an endogenous danger signal that promotes and exacerbates the neutrophilic inflammatory response. To investigate the role of S100A9 in neutrophilic asthma, S100A9 levels were measured in sputum from 101 steroid-naïve asthmatics using an ELISA kit and the levels were significantly correlated with percentages of neutrophils in sputum. Intranasal administration of recombinant S100A9 markedly increased neutrophil numbers at 8h and 24h later with concomitant elevation of IL-1ß, IL-17, and IFN-γ levels. Treatment with an anti-S100A9 antibody restored the increased numbers of neutrophils and the increased airway resistance in OVA/CFA mice toward the levels of sham-treated mice. Concomitantly, the S100A9 and neutrophil elastase double positive cells were markedly reduced with attenuation of IL-1ß, IL-17, and IFN-γ levels by the treatment with the anti-S100A9 antibody. Our data support a role of S100A9 to initiate and amplify the neutrophilic inflammation in asthma, possibly via inducing IL-1ß, IL-17 and IFN-γ.

Neutrophilic inflammation in asthma: mechanisms and therapeutic considerations.

INTRODUCTION: Neutrophilic airway inflammation represents a pathologically distinct form of asthma and frequently appears in symptomatic adulthood asthmatics. However, clinical impacts and mechanisms of the neutrophilic inflammation have not been thoroughly evaluated up to date. Areas covered: Currently, distinct clinical manifestations, triggers, and molecular mechanisms of the neutrophilic inflammation (namely Toll-like receptor, Th1, Th17, inflammasome) are under investigation in asthma. Furthermore, possible role of the neutrophilic inflammation is being investigated in respect to the airway remodeling. We searched the related literatures published during the past 10 years on the website of Pub Med under the title of asthma and neutrophilic inflammation in human. Expert commentary: Epidemiologic and experimental studies have revealed that the neutrophilic airway inflammation is induced by a wide variety of stimuli including ozone, particulate matters, cigarette smoke, occupational irritants, endotoxins, microbial infection and colonization, and aeroallergens. These triggers provoke diverse immune and inflammatory responses leading to progressive and sometimes irreversible airway obstruction. Clinically, neutrophilic airway inflammation is frequently associated with severe asthma and poor response to glucocorticoid therapy, indicating the need for other treatment strategies. Accordingly, therapeutics will be targeted against the main mediators behind the underlying molecular mechanisms of the neutrophilic inflammation.

Circulating IL-33 level is associated with the progression of lung cancer.

OBJECTIVES: Interleukin (IL)-33 protects against infection and inflammation; however, few studies have explored the relevance of IL-33 in lung cancer patients. We evaluated relation of plasma IL-33 levels with development and progression of lung cancer. MATERIALS AND METHODS: A total of 160 patients with lung cancer and 160 controls with normal lungs were enrolled. Plasma IL-33 levels were measured using a specific sandwich ELISA; these levels were followed-up in 18 patients who underwent surgery and in 14 patients treated with chemotherapy. Malignant lesions and normal lung tissues from 10 cancer patients were subjected to immunohistochemical staining for IL-33. RESULTS: IL-33 levels were significantly lower in cancer patients than normal controls (0.08 vs. 0.38 ng/mL, p=0.005). Among cancer patients, IL-33 decreased in a stage-dependent manner from 0.76 ng/mL in stage I patients to 0.25 ng/mL in those with stage II, 0.08 ng/mL in those with stage III, and 0.08 ng/mL in those with stage IV (p=0.002). The levels were higher at stage I (p=0.041) and markedly lower at stages III and IV than those of controls (p=0.005 and p=0.001, respectively). A similar pattern was observed when IL-33 levels were analyzed by T stage; the levels were 0.39 ng/mL at T1/T2 vs. 0.08 ng/mL at T3/T4 (p=0.001). However, no difference was noted when stage N1 levels were compared with N2 and N3 levels (p=0.058), or between stage M0 and M1 levels (p=0.147). IL-33 levels gradually decreased after surgical resection of malignant lesions (from 1.075 to 0.756 ng/mL, p=0.006), but were unchanged after chemotherapy (0.705 vs. 0.829 ng/mL, p=0.875). On immunohistochemical staining, bronchial epithelial and vascular endothelial cells of normal lung tissues mainly expressed IL-33. CONCLUSIONS: Plasma IL-33 levels are associated inversely with progression of lung cancer. The observed decreases may be attributed to lung volume reduction containing bronchial epithelium and vascular endothelium as the sources of IL-33.

Role of inflammasome activation in development and exacerbation of asthma.

Human airways contact with pathogen-associated molecular patterns and danger-associated molecular patterns present in many environments. Asthmatic's airways may be more susceptible to these patterns and lead to inflammasome activation; however, the participation of inflammasome in the development and exacerbation of asthma is not fully understood and remains controversial. Asthma is a heterogeneous group composed of different airway inflammation patterns with different underlying immune mechanisms. One mechanism is neutrophilic airway inflammation based on the axis of inflammasome activation, interleukin (IL) 1ß/IL-18 production, T helper 17 activation, IL-8/IL-6 overproduction, and neutrophilic inflammation. The role of inflammasome activation has been highlighted in experimental asthma models and some evidence of inflammasome activation has been recently demonstrated in human neutrophilic asthmatic airways. In addition to caspase-1 activation, proteinase 3 and other protease from activated neutrophils directly cleave pro-IL-1ß and pro-IL-18 to IL-1ß and IL-18, which contribute to the phenotype of subsequent adaptive immune responses without inflammasome activation. Data suggests that neutrophilics in asthmatic airways may have an additional effect in initiating inflammasome activation and amplifying immune responses. Among the mediators from neutrophils, S100A9 seems to be one candidate mediator to explain the action of neutrophils in amplifying the airway inflammation in concert with inflammasome.

Elevation of S100 calcium binding protein A9 in sputum of neutrophilic inflammation in severe uncontrolled asthma.

BACKGROUND: Neutrophilic airway inflammation is frequently observed in severe uncontrolled asthma (UA) and controlled asthma (CA). However, there is no sputum biomarker to differentiate the 2 conditions. OBJECTIVE: To identify biomarkers of severe uncontrolled asthma with neutrophilic airway inflammation. METHODS: Sputum with a neutrophil content larger than 70% was pooled from 5 patients with severe UA and from 10 patients with CA. Two-dimensional electrophoresis was adopted for differential display proteomics, and candidate proteins were identified using matrix-assisted laser adsorption/ionization-time of flight mass spectrometric analysis. S100 calcium binding protein A9 (S100A9) was identified by western blot and its level was measured in sputum from asthmatics with varying disease severity, patients with chronic obstructive lung disease, and normal controls using enzyme-linked immunosorbent assay. RESULTS: Fourteen protein spots exhibited differences in relative intensity between patients with severe UA and those with CA. Matrix-assisted laser adsorption/ionization-time of flight/time of flight of these spots showed an increase in human neutrophil peptide-2, S100A9, ß-amylase, neutrophil gelatinase-associated lipocalin, 4-aminobutyrate transaminase, and cystatin SA in patients with UA compared with patients with CA. There was a decrease in the plunc precursor, complement C3 component, immunoglobulin heavy-chain variable region, glial fibrillary acidic protein isoform-1, IgM κIIIb SON, MLL-AF4 der(11) fusion protein, cytokeratin-8, and recombinant IgG4 heavy chain. S100A9 was detected at a higher level in western blots of neutrophilic sputum from patients with severe UA vs CA. S100A9 levels were significantly increased, as measured by enzyme-linked immunosorbent assay, in neutrophilic UA compared with CA, eosinophilic UA and CA, and chronic obstructive lung disease. CONCLUSION: S100A9 in sputum may be a biomarker of neutrophilic inflammation in severe UA.

Quantitative assessment of neurochemical changes in a rat model of long-term alcohol consumption as detected by in vivo and ex vivo proton nuclear magnetic resonance spectroscopy.

The aim of present study was to quantitatively investigate the neurochemical profile of the frontal cortex region in a rat model of long-term alcohol consumption, by using in vivo proton magnetic resonance spectroscopy ((1)H-MRS) at 4.7 T and ex vivo(1)H high-resolution magic angle spinning (HR-MAS) technique at 11.7 T. Twenty male rats were divided into two groups and fed a liquid diet for 10 weeks. After 10 weeks, in vivo(1)H MRS spectra were acquired from the frontal cortex brain region. After in vivo(1)H MRS experiments, all animals were sacrificed and 20 frontal cortex tissue samples were harvested. All tissue examinations were performed with the 11.7 T HR-MAS spectrometer and high-resolution spectra were acquired. The in vivo and ex vivo spectra were quantified as absolute metabolite concentrations and normalized ratios of total signal-intensity (i.e., metabolitesNorm), respectively. The absolute quantifications of in vivo spectra showed significantly higher glycerophosphocholine plus phosphocholine (GPC+PCh) and lower myo-inositol (mIns) concentrations in ethanol-treated rats compared to controls. The quantifications of ex vivo spectra showed significantly higher PChNorm, ChoNorm and tChoNorm, and lower GPCNorm and mInsNorm ratio levels in ethanol-treated rats compared to controls. Our findings suggest that reduced mIns concentrations caused by the long-term alcohol consumption may lead to hypo-osmolarity syndrome and astrocyte hyponatremia. In addition, increased choline-containing compound concentrations may reflect an increased cell turnover rate of phosphatidylcholine and other phospholipids, indicating an adaptive mechanism. Therefore, these results might be utilized as key markers in chronic alcohol intoxication metabolism.

Association analysis of formyl peptide receptor 2 (FPR2) polymorphisms and aspirin exacerbated respiratory diseases.

Aspirin-exacerbated respiratory diseases (AERD) are associated with the metabolism of arachidonic acid. FPR2 (formyl peptide receptor2) is a high-affinity ligand receptor for potent anti-inflammatory lipid metabolites: lipoxins. Thus, functional alterations of the FPR2 may contribute to AERD. We investigated the relationship between single-nucleotide polymorphisms (SNPs) in the FPR2 and AERD. Asthmatics were categorized into AERD <15% decreases in forced expiratory volume in one second (FEV(1)), and/or naso-ocular reactions after oral aspirin challenge (n=170) and aspirin-tolerant asthma (ATA, n=268). In all, 11 SNPs were genotyped. FPR2 protein expressions on CD14-positive monocytes in peripheral blood were measured using flow cytometric analysis. We performed RT-PCR of the FPR2 mRNA expressed by peripheral blood mononuclear cells. Logistic regression analysis showed that the minor allele frequency of FPR2 -4209T>G (rs1769490) in intron 2 was significantly lower in the AERD group (n=170) than in the ATA group (n=268) (P=0.006, P(corr)=0.04, recessive model). The decline of FEV(1) after aspirin challenge was significantly lower in the subjects with GG homozygotes of FPR2 -4209T>G than those with the other genotypes (P=0.0002). Asthmatic homozygotes for FPR2 -4209T>G minor allele exhibited significantly higher FPR2 protein expression in CD14-positive monocytes than did those with the common allele of FPR2 -4209T>G allele (P=0.01). There was no difference in the expression of the wild form and the exon 2 deleted variant form of FPR2 gene according to the genotypes of FPR2 -4209T>G. The minor allele at FPR2 -4209T>G may have a protective role against the development of AERD, via increase of FPR2 protein expression in inflammatory cells.

Ex vivo detection for chronic ethanol consumption-induced neurochemical changes in rats.

The aim of this study was to quantitatively investigate the chronic ethanol-induced cerebral metabolic changes in various regions of the rat brain, using the proton high resolution magic angle spinning spectroscopy technique. The rats were divided into two groups (control group: N=11, ethanol-treated group: N=11) and fed with the liquid diets for 10 weeks. In each week, the mean intake volumes of liquid diet were measured. The brain tissues, including cerebellum (Cere), frontal cortex (FC), hippocampus (Hip), occipital cortex (OC) and thalamus (Thal), were harvested immediately after the end of experiments. The ex vivo proton spectra for the five brain regions were acquired with the Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence at 500-MHz NMR spectrometer. All of the spectra were processed using the LCModel software, with simulated basis-set file, and the metabolite levels were referenced to total creatine. In the ethanol liquid diet group, there were significant increases in the metabolites ratio levels, as compared to control (Cere: alanine, glutathione, and N-acetlyaspartate; FC: phosphocholine and taurine; Hip: alanine, glutamine, and N-acetylaspartate; OC: glutamine; Thal: alanine, γ-aminobutyric acid, glutamate, glycerophosphocholine, phosphocholine, taurine, and free choline). However, in the ethanol liquid diet group, the myo-inositol levels of the OC were significantly lower. The present study demonstrates how chronic ethanol consumption affects cerebral metabolites in the chronic ethanol-treated rat. Therefore, this result could be useful to pursue clinical applications for quantitative diagnosis in human alcoholism.

Particle stimulation dephosphorylates glutathione S-transferase π1 of epithelial cells.

Environmental pollutant exposure is associated with adverse respiratory outcomes. The phosphorylation of enzymes activates or deactivates many cellular processes and is related to the development of lung diseases such as asthma and chronic obstructive pulmonary disease. However, little is known about protein phosphorylation of bronchial epithelial cells in response to airborne particulates. Herein, we screened differentially phosphorylated proteins in TiO2-treated epithelial cells and validated the change in GSTP1 protein phosphorylation. Two-dimensional electrophoresis was adopted for differential display proteomics of TiO2-treated BEAS-2B cell lysates. Phosphoproteins were screened using Pro-Q® Diamond phosphoprotein gel stain and identified by MALDI-TOF/TOF analysis. Immunoprecipitation and immunoblotting were performed for quantitative measurement of GSTP1 phosphorylation in cell lysates. Normalized relative intensities of nine phosphorylated proteins increased after TiO2 treatment, whereas those of 12 proteins decreased in the BEAS-2B cell lysates. From gene ontology and pathway analysis, proteins involved in signal transduction were commonly identified, followed by cytoskeletal proteins, proteins from oxidation and antioxidation pathways, proteins catalyzing reductions, and those involved in cellular process, transport, and modification. Immunoblotting with anti-GSTP1 antibody demonstrated no change in GSTP1 protein levels in the lysates of BEAS-2B cells after treatment with TiO2 particles; blotting with anti-phosphoserine and anti-phosphotyrosine antibodies showed dose-dependent decreases in phosphoserine and phosphotyrosine proteins. Stimulation with particulates phosphorylated and dephosphorylated several proteins in epithelial cells, and serine and tyrosine protein phosphorylation of GSTP1 decreased. These data indicate that airborne particles affect the pattern of phosphorylation of proteins involved in defense or apoptosis of respiratory epithelium.

Novel hyaluronate-atelocollagen/beta-TCP-hydroxyapatite biphasic scaffold for the repair of osteochondral defects in rabbits.

The authors devised a novel biphasic scaffold combining hyaluronic acid and atelocollagen for the chondral phase and combining hydroxyapatite (HA) and beta-tricalcium phosphate (beta-TCP) for the osseous phase. The biphasic scaffold was fabricated by placing the freeze-dried chondral phase over the HA/beta-TCP scaffold prewetted with hyaluronate/atelocollagen solution. Chondrocytes were isolated in 28 rabbits, expanded, injected inside the chondral phase of the biphasic scaffold, and then cultured in chondrogenic medium. After 2 weeks of in vitro culture, chondrocytes had evenly infiltrated inside the chondral phase and produced extracellular matrix. For in vivo study, a large osteochondral defect was made on the patellar groove of the right distal femur and managed using one of the following methods: filling with cell-biphasic scaffold composite (group I); implanting only biphasic scaffold (group II); placing the removed osteochondral fragments back into the defect (group III, positive control); leaving empty (group IV, negative control). Seven rabbits were allocated to each group. After 12 weeks, the International Cartilage Repair Society Macroscopic Score was highest in group III, followed by group I, group II, and lastly group IV. Depression of the defect was greatest in group IV. There were three rabbits (two in group I and one in group II) that were completely denuded of the chondral phase. The junction to adjacent native cartilage was distinct in rabbits of all groups. The International Cartilage Repair Society Visual Histological Score was highest in group III, followed by groups II and I, and lastly group IV. In conclusion, our results suggest that a biphasic osteochondral composite using a chondral phase consisting of hyaluronate and atelocollagen and an osseous phase consisting of HA and beta-TCP holds the promise for repair of osteochondral defects.