Impact of 2D-3D Heterointerface on Remote Epitaxial Interaction through Graphene.

Remote epitaxy has drawn attention as it offers epitaxy of functional materials that can be released from the substrates with atomic precision, thus enabling production and heterointegration of flexible, transferrable, and stackable freestanding single-crystalline membranes. In addition, the remote interaction of atoms and adatoms through two-dimensional (2D) materials in remote epitaxy allows investigation and utilization of electrical/chemical/physical coupling of bulk (3D) materials via 2D materials (3D-2D-3D coupling). Here, we unveil the respective roles and impacts of the substrate material, graphene, substrate-graphene interface, and epitaxial material for electrostatic coupling of these materials, which governs cohesive ordering and can lead to single-crystal epitaxy in the overlying film. We show that simply coating a graphene layer on wafers does not guarantee successful implementation of remote epitaxy, since atomically precise control of the graphene-coated interface is required, and provides key considerations for maximizing the remote electrostatic interaction between the substrate and adatoms. This was enabled by exploring various material systems and processing conditions, and we demonstrate that the rules of remote epitaxy vary significantly depending on the ionicity of material systems as well as the graphene-substrate interface and the epitaxy environment. The general rule of thumb discovered here enables expanding 3D material libraries that can be stacked in freestanding form.

Heterogeneous integration of single-crystalline complex-oxide membranes.

Complex-oxide materials exhibit a vast range of functional properties desirable for next-generation electronic, spintronic, magnetoelectric, neuromorphic, and energy conversion storage devices1-4. Their physical functionalities can be coupled by stacking layers of such materials to create heterostructures and can be further boosted by applying strain5-7. The predominant method for heterogeneous integration and application of strain has been through heteroepitaxy, which drastically limits the possible material combinations and the ability to integrate complex oxides with mature semiconductor technologies. Moreover, key physical properties of complex-oxide thin films, such as piezoelectricity and magnetostriction, are severely reduced by the substrate clamping effect. Here we demonstrate a universal mechanical exfoliation method of producing freestanding single-crystalline membranes made from a wide range of complex-oxide materials including perovskite, spinel and garnet crystal structures with varying crystallographic orientations. In addition, we create artificial heterostructures and hybridize their physical properties by directly stacking such freestanding membranes with different crystal structures and orientations, which is not possible using conventional methods. Our results establish a platform for stacking and coupling three-dimensional structures, akin to two-dimensional material-based heterostructures, for enhancing device functionalities8,9.

IL-37 Attenuates Lung Fibrosis by Inducing Autophagy and Regulating TGF-ß1 Production in Mice.

Idiopathic pulmonary fibrosis (IPF) is a progressive and destructive lung disease with a poor prognosis resulting in a high mortality rate. IL-37 is an anti-inflammatory cytokine that inhibits innate and adaptive immunity by downregulating proinflammatory mediators and pathways. However, the exact role of IL-37 in lung fibrosis is unclear. In this study, we found that the IL-37 protein was expressed in alveolar epithelial cells (AECs) and alveolar macrophages in healthy controls but significantly reduced in patients with IPF. IL-37 significantly inhibited oxidative stress-induced primary mouse AEC death in a dose-dependent manner, and knockdown of IL-37 significantly potentiated human lung cancer-derived AEC (A549 cells) death. IL-37 attenuated constitutive mRNA and protein expression of fibronectin and collagen I in primary human lung fibroblasts. IL-37 inhibited TGF-ß1-induced lung fibroblast proliferation and downregulated the TGF-ß1 signaling pathway. Moreover, IL-37 enhanced beclin-1-dependent autophagy and autophagy modulators in IPF fibroblasts. IL-37 significantly decreased inflammation and collagen deposition in bleomycin-exposed mouse lungs, which was reversed by treatment with the autophagy inhibitor 3-methyladenine. Our findings suggested that a decrease in IL-37 may be involved in the progression of IPF and that IL-37 inhibited TGF-ß1 signaling and enhancement of autophagy in IPF fibroblasts. Given its antifibrotic activity, IL-37 could be a therapeutic target in fibrotic lung diseases, including IPF.

Prognostic value of baseline carcinoembryonic antigen and cytokeratin 19 fragment levels in advanced non-small cell lung cancer.

BACKGROUND: Serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) levels are prognostic predictors in non-small cell lung cancer (NSCLC). However, even in patients with the same stage of cancer, the serum levels of those markers often vary. OBJECTIVE: We investigated the association between the initial biomarker levels and prognosis. METHODS: We retrospectively reviewed 445 patients with advanced NSCLC and their baseline serum CEA and CYFRA 21-1 levels. Patients were divided into four groups according to the initial levels of those markers: the NN, HN, NH, and HH group. Kaplan-Meier survival analysis with Log-rank test and Cox proportional hazards regression analysis were performed. RESULTS: The 5-year overall survival (OS) rate in the HN group was the highest (32.2%). Multivariate analyses indicated that the HN group (HR 0.520, 95% CI 0.309-0.878, P= 0.014), female sex (HR 0.685, 95% CI 0.498-0.944, P= 0.021), serum CRP level (HR 1.057, 95% CI 1.034-1.080, P< 0.001), chemotherapy (HR 0.324, 95% CI 0.228-0.460, P< 0.001), and chemotherapy/radiotherapy (HR 0.266, 95% CI 0.171-0.414, P< 0.001) were independent prognostic factors for overall survival. CONCLUSIONS: In advanced NSCLC, patients with baseline high serum CEA but low CYFRA 21-1 level have a significant longer overall survival regardless of clinical stage.

Involvement of Alveolar Epithelial Cell Necroptosis in Idiopathic Pulmonary Fibrosis Pathogenesis.

Alveolar epithelial cell (AEC) injury leading to cell death is involved in the process of fibrosis development during idiopathic pulmonary fibrosis (IPF). Among regulated/programmed cell death, the excessive apoptosis of AECs has been widely implicated in IPF pathogenesis. Necroptosis is a type of regulated/programmed necrosis. A multiprotein complex composed of receptor-interacting protein kinase (RIPK)-1 and -3 plays a key regulatory role in initiating necroptosis. Although necroptosis participates in disease pathogeneses through the release of damage-associated molecular patterns, its association with IPF progression remains elusive. In this study, we attempted to illuminate the involvement of RIPK3-regulated necroptosis in IPF pathogenesis. IPF lung tissues were used to detect necroptosis, and the role of RIPK3 was determined using cell culturing models of AECs. Lung fibrosis models of bleomycin (BLM) treatment were also used. RIPK3 expression levels were increased in IPF lungs, and both apoptosis and necroptosis were detected mainly in AECs. Necrostatin-1 and RIPK3 knockout experiments in AECs revealed the participation of necroptosis in BLM and hydrogen peroxide-induced cell death. BLM treatment induced RIPK3 expression in AECs and increased high-mobility group box 1 and IL-1ß levels in mouse lungs. The efficient attenuation of BLM-induced lung inflammation and fibrosis was determined in RIPK3 knockout mice and by necrostatin-1 with a concomitant reduction in high-mobility group box 1 and IL-1ß. RIPK3-regulated necroptosis in AECs is involved in the mechanism of lung fibrosis development through the release of damage-associated molecular patterns as part of the pathogenic sequence of IPF.

Annexin A1 in plasma from patients with bronchial asthma: its association with lung function.

BACKGROUND: Annexin-A1 (ANXA1) is a glucocorticoid-induced protein with multiple actions in the regulation of inflammatory cell activation. The anti-inflammatory protein ANXA1 and its N-formyl peptide receptor 2 (FPR2) have protective effects on organ fibrosis. However, the exact role of ANXA1 in asthma remains to be determined. The aim of this study was to identify the role of ANXA1 in bronchial asthma. METHODS: In mice sensitized and challenged with ovalbumin (OVA-OVA mice) and mice sensitized with saline and challenged with air (control mice), we investigated the potential links between ANXA1 levels and bronchial asthma using ELISA, immunoblotting, and immunohistochemical staining. Moreover, we also determined ANXA1 levels in blood from 50 asthmatic patients (stable and exacerbated states). RESULTS: ANXA1 protein levels in lung tissue and bronchoalveolar lavage fluid were significantly higher in OVA-OVA mice compared with control mice. FPR2 protein levels in lung tissue were significantly higher in OVA-OVA mice compared with control mice. Plasma ANXA1 levels were increased in asthmatic patients compared with healthy controls. Plasma ANXA1 levels were significantly lower in exacerbated patients compared with stable patients with bronchial asthma (p < 0.05). The plasma ANXA1 levels in controlled asthmatic patients were correlated with forced expiratory volume in 1 s (FEV1) (r = - 0.191, p = 0.033) and FEV1/forced vital capacity (FVC) (r = -0.202, p = 0.024). CONCLUSION: These results suggest that ANXA1 may be a potential marker and therapeutic target for asthma.

Apolipoprotein A1 Inhibits TGF-ß1-Induced Epithelial-to-Mesenchymal Transition of Alveolar Epithelial Cells.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease characterized by the accumulation of excessive fibroblasts and myofibroblasts in the extracellular matrix. The transforming growth factor ß1 (TGF-ß1)-induced epithelial-to-mesenchymal transition (EMT) is thought to be a possible source of fibroblasts/myofibroblasts in IPF lungs. We have previously reported that apolipoprotein A1 (ApoA1) has anti-fibrotic activity in experimental lung fibrosis. In this study, we determine whether ApoA1 modulates TGF-ß1-induced EMT in experimental lung fibrosis and clarify its mechanism of action. METHODS: The A549 alveolar epithelial cell line was treated with TGF-ß1 with or without ApoA1. Morphological changes and expression of EMT-related markers, including E-cadherin, N-cadherin, and α-smooth muscle actin were evaluated. Expressions of Smad and non-Smad mediators and TGF-ß1 receptor type 1 (TßRI) and type 2 (TßRII) were measured. The silica-induced lung fibrosis model was established using ApoA1 overexpressing transgenic mice. RESULTS: TGF-ß1-treated A549 cells were changed to the mesenchymal morphology with less E-cadherin and more N-cadherin expression. The addition of ApoA1 inhibited the TGF-ß1-induced change of the EMT phenotype. ApoA1 inhibited the TGF-ß1-induced increase in the phosphorylation of Smad2 and 3 as well as that of ERK and p38 mitogen-activated protein kinase mediators. In addition, ApoA1 reduced the TGF-ß1-induced increase in TßRI and TßRII expression. In a mouse model of silica-induced lung fibrosis, ApoA1 overexpression reduced the silica-mediated effects, which were increased N-cadherin and decreased E-cadherin expression in the alveolar epithelium. CONCLUSION: Our data demonstrate that ApoA1 inhibits TGF-ß1-induced EMT in experimental lung fibrosis.

Gene - Gene Interactions Among MCP Genes Polymorphisms in Asthma.

PURPOSE: Monocyte chemoattractant proteins (MCPs) are important cytokines that involved in cellular activation and releasing of inflammatoy mediators by basophils and eosinophils in allergic disease. Some MCP gene variants implicate in asthma and monoclonal antibody for MCP-3 blocks allergic inflammations in the patients with asthma. Detection of interactions between gene and environment or between genes for complex disease such as asthma is important. We searched for an evidence of genetic effect of single nucleotide polymorphisms (SNPs) of MCP genes as well as gene - gene interactions involved in asthma. METHODS: Four hundreds asthmatics and four hundreds normal controls were enrolled. Asthma was defined as a positive bronchodilator response or positive methacholine provocation test with compatible clinical symptoms. Seven MCP gene SNPs (2 SNPs in MCP-1, 1 in MCP-2, and 4 in MCP-3) were included. Association analyses between SNP and asthma, and the tests for gene - gene interaction were performed. RESULTS: Strong linkage disequilibria were found among 7 MCP gene polymorphisms. There was no SNP that showed a significant association with asthma among 7 SNPs of 3 MCP genes. No haplotype was associated with asthma, either. The combination of MCP1-2518G>A, MCP2+46A>C, and MCP3+563C>T was the best predictive model for asthma as compared to the control in tests for gene - gene interaction. The MCP1-2518G>A and MCP2+46A>C was the second best predictive combination and this had the highest synergistic interaction effect on the subject's status than any other combination of polymorphisms. Complete linkages were not associated with the gene - gene interactions models. CONCLUSIONS: MCP gene polymorphisms probably interact with each other; thus, these findings may help in developing a possible genetic marker to predict asthma.

Gene-Gene Interaction Between CCR3 and Eotaxin Genes: The Relationship With Blood Eosinophilia in Asthma.

PURPOSE: Eosinophils function as an effector cell in the development of asthma and allergic disease. Eotaxins are cytokines that promote pulmonary eosinophilia via the receptor CCR3. Single-nucleotide polymorphisms (SNPs) in CCR3 and eotaxin genes are associated with asthma. In this study, genetic interactions among SNPs of several eotaxin genes and CCR3 were assessed and their relationship with blood eosinophilia in asthma was examined. METHODS: A total of 533 asthmatics were enrolled in this study. Asthmatics with eosinophilia (>0.5×10(9)/L) were compared with those without eosinophilia (≤0.5×10(9)/L). Chi-square tests were used to compare SNP frequencies. Two different models were used to evaluate gene-gene interactions: logistic regression and generalized multifactor dimensionality reduction (GMDR). RESULTS: EOT2+304C>A (29L>I) was significantly associated with 3 of the 4 CCR3 SNPs among asthmatics with eosinophilia (P=0.037-0.009). EOT2+304C>A (29L>I) and the CCR3 SNPs were also significantly associated with blood eosinophilia in an interaction model constructed by logistic regression (P=0.0087). GMDR analysis showed that the combination of EOT2+304C>A (29L>I) and CCR3-174C>T was the best model (accuracy=0.536, P=0.005, CVC 9/10). CONCLUSIONS: The epistatic influence of CCR3 on eotaxin gene variants indicates that these variants may be candidate markers for eosinophilia in asthma.

Acute eosinophilic pneumonia related to a mesalazine suppository.

It has been well known that mesalazine can cause the interstitial lung disease, such as Bronchiolitis obliterans with organizing pneumonia (BOOP), Non-Specific Interstitial Pneumonia (NSIP), or eosinophilic pneumonia. 5-Aminosalicylic acid (5-ASA), mesalazine, and sulfasalazine are important drugs for treating inflammatory bowel disease. Topical products of these limited systemic absorption and have less frequent side effects, therefore suppository form of these drugs have been used more than systemic drug. Most cases of measalzine-induced lung toxicity develop from systemic use of the drug. A 30-year-old woman had an interstitial lung disease after using mesalazine suppository because of ulcerative colitis. The lung biopsy demonstrated eosinophilic pneumonia combined with BOOP. She was recovered after stopping of mesalazine suppository and treatment with systemic steroid.

Electronic origin of ultrafast photoinduced strain in BiFeO3.

Above-band-gap optical excitation produces interdependent structural and electronic responses in a multiferroic BiFeO(3) thin film. Time-resolved synchrotron x-ray diffraction shows that photoexcitation can induce a large out-of-plane strain, with magnitudes on the order of half of one percent following pulsed-laser excitation. The strain relaxes with the same nanosecond time dependence as the interband relaxation of excited charge carriers. The magnitude of the strain and its temporal correlation with excited carriers indicate that an electronic mechanism, rather than thermal effects, is responsible for the lattice expansion. The observed strain is consistent with a piezoelectric distortion resulting from partial screening of the depolarization field by charge carriers, an effect linked to the electronic transport of excited carriers. The nonthermal generation of strain via optical pulses promises to extend the manipulation of ferroelectricity in oxide multiferroics to subnanosecond time scales.

Air trapping is a major determinant of persistent airway obstruction in asthmatics.

Chronic persistent airway obstruction has been observed in moderate-to-severe asthmatics despite treatment with inhaled corticosteroids. We investigated which airway changes were associated with this obstruction. High-resolution computed tomography (HRCT) was performed at study entry and reexamined at the time of follow-up when the FEV1 reached a maximally constant level after treatment for 1 year or more with inhaled corticosteroids. Bronchial wall area and air trapping extent were compared in the recovered group (n = 18) and the persistent airway obstruction group (n = 14). Bronchial wall area and air trapping of the initial HRCT were similar between the two groups. On follow-up HRCT, air trapping was markedly decreased in the recovered group compared with that on initial HRCT (P = 0.017), whereas bronchial wall area did not change. In the persistent-airway-obstruction group, these two parameters did not change during follow-up. When follow-up HRCT was compared, air trapping was significantly greater in the persistent-airway-obstruction group than in the recovered group (P = 0.003). Difference post-bronchodilator FEV1 value between at initial and 2nd HRCT exam was correlated with difference air trapping value between at initial and 2nd HRCT exam(%) on the follow-up HRCT (P = 0.017). The presence of persistent airflow obstruction were significantly associated with the air trapping % difference between initial and 2nd time (RR = 1.70, P = 0.018). Persistence of AT could be a main contributing factor to chronic persistent airflow obstruction in asthma.

A case of propofol-induced oropharyngeal angioedema and bronchospasm.

Propofol (2,6-diisopropylphenol) is an ultrashort-acting sedative agent with sedative and amnestic effects that is used not only for anesthesia but also for sedation during minor outpatient procedures and endoscopic examinations. Rare cases of anaphylaxis following propofol administration have been reported in the medical literature. Documentation of anaphylaxis is often lacking because the cause and effect relationship is often hard to prove. Only a minority of patients get referred for allergy testing to confirm the offending drug. Here we report a 74-year-old woman who had an anaphylactic reaction with severe oropharyngeal edema and bronchospasm for a few minutes after receiving propofol during endoscopic examination. An allergy skin test was positive for both propofol and soybean. Soybean in the intralipid is one component of propofol, and we concluded that this anaphylaxis was caused by soybean.

Evaluating a thrombosed azygous vein aneurysm combined with pulmonary arterial thromboembolism by ECG-gated multidetector CT: a case report.

Azygous vein aneurysm is a rare congenital lesion that needs to be differentiated from mediastinal mass lesions. Although almost of these anomalies are asymptomatic lesions, we experienced an interesting case in which a thrombus within an azygous vein aneurysm in a 75-year-old woman caused pulmonary thromboembolism. The patient was managed by medical treatment for one month and then the thrombus within both the azygous vein aneurysm and the pulmonary arteries completely resolved.

A strong ferroelectric ferromagnet created by means of spin-lattice coupling.

Ferroelectric ferromagnets are exceedingly rare, fundamentally interesting multiferroic materials that could give rise to new technologies in which the low power and high speed of field-effect electronics are combined with the permanence and routability of voltage-controlled ferromagnetism. Furthermore, the properties of the few compounds that simultaneously exhibit these phenomena are insignificant in comparison with those of useful ferroelectrics or ferromagnets: their spontaneous polarizations or magnetizations are smaller by a factor of 1,000 or more. The same holds for magnetic- or electric-field-induced multiferroics. Owing to the weak properties of single-phase multiferroics, composite and multilayer approaches involving strain-coupled piezoelectric and magnetostrictive components are the closest to application today. Recently, however, a new route to ferroelectric ferromagnets was proposed by which magnetically ordered insulators that are neither ferroelectric nor ferromagnetic are transformed into ferroelectric ferromagnets using a single control parameter, strain. The system targeted, EuTiO(3), was predicted to exhibit strong ferromagnetism (spontaneous magnetization, approximately 7 Bohr magnetons per Eu) and strong ferroelectricity (spontaneous polarization, approximately 10 microC cm(-2)) simultaneously under large biaxial compressive strain. These values are orders of magnitude higher than those of any known ferroelectric ferromagnet and rival the best materials that are solely ferroelectric or ferromagnetic. Hindered by the absence of an appropriate substrate to provide the desired compression we turned to tensile strain. Here we show both experimentally and theoretically the emergence of a multiferroic state under biaxial tension with the unexpected benefit that even lower strains are required, thereby allowing thicker high-quality crystalline films. This realization of a strong ferromagnetic ferroelectric points the way to high-temperature manifestations of this spin-lattice coupling mechanism. Our work demonstrates that a single experimental parameter, strain, simultaneously controls multiple order parameters and is a viable alternative tuning parameter to composition for creating multiferroics.

Asthmatics without rhinitis have more fixed airway obstruction than those with concurrent rhinitis.

PURPOSE: Rhinitis and asthma usually occur together. There are increasing evidences that allergic rhinitis (AR) may influence the clinical course of asthma. The aim of this study is to evaluate clinical parameters and therapeutic response in patients with between asthma and asthma with AR. METHODS: Four-hundred eighty-five patients with asthma and 428 asthmatics with AR, who had lesser than 50 years old and smoked less than 10 pack-years were recruited. We compared FEV1 and FEV1/FVC following bronchodilator, atopy, IgE, emphysema on HRCT, and aspirin intolerance between two groups. Also we compared physiologic fixed airway obstruction defined using FEV1/FVC and FEV1 less than 75% following anti-asthmatic drug for 1 year. RESULTS: 46.8% (428/913) asthmatics suffered from AR. There were no differences of total IgE, body mass index, PC20, sputum eosinophils and emphysema on HRCT between two groups. The age in asthmatics was higher than that in those with AR. FEV1/FVC was lower in asthmatics than in those with AR. The prevalence of atopy was higher in asthmatics with AR than in asthmatics. Aspirin intolerance was higher in asthmatics with AR than in asthmatics (42/218 vs 13/109, P=0.001). Fixed airway obstruction were more observed in asthmatics than in those with AR (39/319 vs 28/355, P=0.001) after anti-asthmatic drug for 1 year. CONCLUSIONS: Asthmatics with AR had more atopy and aspirin intolerance than asthmatics, and asthmatics had poor response to anti-inflammatory drugs than those with concurrent rhinitis, indicating that asthmatics have more fixed airway obstruction than those with concurrent rhinitis.

The impact of smoking on clinical and therapeutic effects in asthmatics.

Smoking is associated with poor symptom control and impaired therapeutic responses in asthma. A total of 843 patients with asthma were recruited. The patients received treatment for 1 yr according to the severity of their asthma. We compared the forced expiratory volume in 1 sec (FEV1), the ratio of FEV1 to forced vital capaity (FVC), atopy, total IgE, emphysema on high-resolution computed tomography (HRCT), the number of near-fatal asthma attacks, and physiological fixed airway obstruction between the smoking and nonsmoking groups. The study population consisted of 159 (18.8%) current smokers, 157 (18.7%) ex-smokers, and 525 (62.5%) nonsmokers. Although the prevalence of atopy was not different between the smoking and nonsmoking groups, the total IgE was higher among the smokers than the nonsmokers. Compared with the nonsmoking group, the smokers had a lower FEV1 % predicted and forced expiratory flow between 25 and 75% of FVC. A greater prevalence of emphysema and a significantly higher number of asthmatic patients with fixed airway obstruction were detected in the smoking versus nonsmoking group. The 37.5% of asthmatic patients who were former or current smokers showed decreased pulmonary function and increased IgE, emphysema on HRCT, and fixed airway obstruction, indicating that smoking can modulate the clinical and therapeutic responses in asthma.

Genetic interactions model among Eotaxin gene polymorphisms in asthma.

Eotaxin family (Eotaxin 1,2 and 3) recruits and activates CCR3-bearing cells such as eosinophil, mast cells, and Th2 lymphocytes that play a major role in allergic disorders. We examined the polygenetic effects of the Eotaxin gene family in a Korean population. Gene-gene interactions were tested using a multistep approach with multifactor dimensionality reduction (MDR) method between asthmatics and normal controls. The overall best MDR model of the main effect single nucleotide polymorphisms (SNPs) included EOT2 + 1272A > G and EOT3 + 77C > T (model 1) [testing accuracy 0.597, cross-validation consistency (CVC) 10/10, P < 0.001]. The overall best MDR model of the SNPs with no main effects included EOT2 + 304C > A, EOT3 + 716A > G, and EOT3 + 1579G > A (model 2) (testing accuracy 0.616, CVC 10/10, P < 0.001). Model 3 was obtained by including the MDR variables for models 1 and 2. This new composite model predicted asthma with better accuracy than either model 1 or model 2 (testing accuracy 0.643, CVC 10/10, P < 0.001). The detection of statistical interaction models is one evidence of gene-gene interactions among Eotaxin genes, and this interaction is thought to influence the development of asthma. Although the models are limited to determining statistical interactions within a population, they may be useful for identifying groups at high risk of developing asthma.