Targeting ETosis by miR-155 inhibition mitigates mixed granulocytic asthmatic lung inflammation

Asthma is phenotypically heterogeneous with several distinctive pathological mechanistic pathways. Previous studies indicate that neutrophilic asthma has a poor response to standard asthma treatments comprising inhaled corticosteroids. Therefore, it is important to identify critical factors that contribute to increased numbers of neutrophils in asthma patients whose symptoms are poorly controlled by conventional therapy. Leukocytes release chromatin fibers, referred to as extracellular traps (ETs) consisting of double-stranded (ds) DNA, histones, and granule contents. Excessive components of ETs contribute to the pathophysiology of asthma; however, it is unclear how ETs drive asthma phenotypes and whether they could be a potential therapeutic target. We employed a mouse model of severe asthma that recapitulates the intricate immune responses of neutrophilic and eosinophilic airway inflammation identified in patients with severe asthma. We used both a pharmacologic approach using miR-155 inhibitor-laden exosomes and genetic approaches using miR-155 knockout mice. Our data show that ETs are present in the bronchoalveolar lavage fluid of patients with mild asthma subjected to experimental subsegmental bronchoprovocation to an allergen and a severe asthma mouse model, which resembles the complex immune responses identified in severe human asthma. Furthermore, we show that miR-155 contributes to the extracellular release of dsDNA, which exacerbates allergic lung inflammation, and the inhibition of miR-155 results in therapeutic benefit in severe asthma mice. Our findings show that targeting dsDNA release represents an attractive therapeutic target for mitigating neutrophilic asthma phenotype, which is clinically refractory to standard care

Cigarette smoke-induced autophagy is regulated by SIRT1-PARP-1-dependent mechanism: implication in pathogenesis of COPD

Autophagy is a fundamental cellular process that eliminates long-lived proteins and damaged organelles through lysosomal degradation pathway. Cigarette smoke (CS)-mediated oxidative stress induces cytotoxic responses in lung cells. However, the role of autophagy and its mechanism in CS-mediated cytotoxic responses is not known. We hypothesized that NAD(+)-dependent deacetylase, sirtuin 1 (SIRT1) plays an important role in regulating autophagy in response to CS. CS exposure resulted in induction of autophagy in lung epithelial cells, fibroblasts and macrophages. Pretreatment of cells with SIRT1 activator resveratrol attenuated CS-induced autophagy whereas the SIRT1 inhibitor, sirtinol, augmented CS-induced autophagy. Elevated levels of autophagy were induced by CS in the lungs of SIRT1 deficient mice. Inhibition of poly(ADP-ribose)-polymerase-1 (PARP-1) attenuated CS-induced autophagy via SIRT1 activation. These data suggest that the SIRT1-PARP-1 axis plays a critical role in the regulation of CS-induced autophagy and have important implications in understanding the mechanisms of CS-induced cell death and senescence

Mechanical Properties of Polyetheretherketone Composites with Surface-Modified Hydroxyapatite Nanofibers and Carbon Fibers

Though carbon fiber (CF)-reinforced polyetheretherketone (PEEK) has gained attention as an alternative to metallic orthopedic implant materials by virtue of its good biocompatibility and favorable mechanical properties, its applications are limited due to its bioinertness and hydrophobicity. Hydroxyapatite (HA) incorporated to address the issue has appeared to lower the mechanical strength, often severely, due to the aggregation of HA in the composites. This study aimed to develop a PEEK composite with HA and CF whose mechanical properties are comparable to those of human cortical bone. We synthesized and incorporated HA nanofibers (HANF) to improve the mechanical properties of the composite to take advantage of the high aspect ratio and bridging effect of the fibers. In addition, the HANF and CF were modified with a silane coupling agent to enhance their interfacial adhesion with the PEEK matrix. The results showed that incorporating the modified HANF (m-HANF) and the modified CF (m-CF) effectively improved the mechanical properties compared to those of neat PEEK and composites with unmodified fillers. Mechanical properties comparable to those of the cortical bone were observed in PEEK/m-HANF/m-CF composites of various compositions. The improved dispersion of the HANF and enhanced interfacial adhesion of m-HANF and m-CF with the PEEK matrix were also observed in the X-ray tomography microscope system (XRM) and scanning electron microscopy (SEM) results. This unique PEEK/m-HANF/m-CF composite can yield an effective design strategy for developing high-performance PEEK biocomposites.N

Gold Nanocube–Nanosphere Dimers: Preparation, Plasmon Coupling, and Surface-Enhanced Raman Scattering

We explore plasmon coupling and surface-enhanced Raman scattering (SERS) from nanogaps defined by different surface shapes. To this end, we assemble heterodimers where gold nanocubes (AuNCs, edge length 84 nm) are linked to gold nanospheres (AuNSs, diameter 55 nm) through their vertices or edges via 1,8-octanedithiol (C8DT). Regioselective disintegration of trimethylammonium bilayers on the vertices and edges of AuNCs using acetonitrile permits the formation of AuNC–AuNS dimers in high yield. Strong plasmonic interactions between the AuNCs and AuNSs produce the longitudinal plasmon coupling band at 790 nm, significantly red-shifted from the surface plasmon resonance band of the isolated AuNCs (λ = 581 nm) or AuNSs (λ = 534 nm). Localized electric fields confined to the nanogaps between the AuNCs and AuNSs also generate a strong SERS signal. We observe the Raman spectrum for C8DT from the AuNC–AuNS dimers with a 1 × 10¹⁰ enhancement factor (EF), which is much larger than that for nanoassemblies consisting of only AuNSs, such as core–satellites (EF = ∼10⁸) and clusters (EF = ∼10⁷). Comparison with finite difference time domain simulations reveals the nature of the plasmon coupling and the local field enhancement in the AuNC–AuNS dimers

Effect of Nanogap Curvature on SERS: A Finite-Difference Time-Domain Study

Surface-enhanced Raman scattering (SERS) is one of the most important plasmonic effects, offering a wide range of applications. Strong SERS arises from narrow nanogaps between nanoparticles. The SERS enhancement factor (EF) depends on many parameters that define the nanogap, such as the gap distance, gap geometry, and size and material of the constituent nanoparticles. In this study, we focus on the effect of the curvature of the nanogap on SERS. We perform finite-difference time-domain (FDTD) simulations for Au nanocube–nanosphere dimers, where nanocubes are attached to nanospheres on their vertices with various radii of curvature. The calculations reveal that the induced electric field becomes more localized around the vertex of the nanocube in the nanogap with the decrease in the curvature radius. The EF also drastically increases when the corner of the cube in the dimer sharpens. The EF of the nanocube–nanosphere dimer at ∼10¹³ is far greater than that of nanosphere dimers or nanorod–nanosphere dimers. Through systematic changes of the variables that may affect the SERS EF, we find that in addition to the sharp local structure, a sizable volume is required to obtain the maximum EF. The curvature effect is the dominant contributor to the highest SERS EF for the nanocube–nanosphere dimers, overwhelming radiation damping or plasmon damping by the interband transition. This study identifies the governing factors for SERS and provides a design principle for the best SERS substrates

Mechanical Properties and Bioactivity of Poly(Lactic Acid) Composites Containing Poly(Glycolic Acid) Fiber and Hydroxyapatite Particles

To enhance the mechanical strength and bioactivity of poly(lactic acid) (PLA) to the level that can be used as a material for spinal implants, poly(glycolic acid) (PGA) fibers and hydroxyapatite (HA) were introduced as fillers to PLA composites. To improve the poor interface between HA and PLA, HA was grafted by PLA to form HA-g-PLA through coupling reactions, and mixed with PLA. The size of the HA particles in the PLA matrix was observed to be reduced from several micrometers to sub-micrometer by grafting PLA onto HA. The tensile and flexural strength of PLA/HA-g-PLA composites were increased compared with those of PLA/HA, apparently due to the better dispersion of HA and stronger interfacial adhesion between the HA and PLA matrix. We also examined the effects of the length and frequency of grafted PLA chains on the tensile strength of the composites. By the addition of unidirectionally aligned PGA fibers, the flexural strength of the composites was greatly improved to a level comparable with human compact bone. In the bioactivity tests, the growth of apatite on the surface was fastest and most uniform in the PLA/PGA fiber/HA-g-PLA composite

Statistical Indoor Exclusion Zone Analysis by Investigating Electromagnetic Fields inside a Nuclear Power Plant

This article investigates a statistical indoor exclusion zone (EZ) that can be efficiently applied to a nuclear power plant (NPP) by examining electromagnetic fields inside the actual NPP. To obtain the statistical indoor EZ, the indoor environment of the Korea Institute of Nuclear Safety (KINS) simulator room is modeled using the Wireless InSite commercial electromagnetic simulation software. The indoor space around the transmitting antenna is classified as multiple observation regions, and the EZ boundaries of each region are independently defined within each separate observation region. The EZ boundaries are then obtained using a margined regression model, which makes it possible to determine a reasonable boundary of the statistical indoor EZ. To validate the statistical indoor EZ, the received power inside the KINS simulator room is then measured, which agrees well with the simulated results. The results demonstrate that the proposed statistical indoor EZ can be properly obtained not only from the simulation data but also from the measurement data

Bridging the Nanogap with Light: Continuous Tuning of Plasmon Coupling between Gold Nanoparticles

The control of nanogaps lies at the heart of plasmonics for nanoassemblies. The plasmon coupling sensitively depends on the size and the shape of the nanogaps between nanoparticles, permitting fine-tuning of the resonance wavelength and near-field enhancement at the gap. Previously reported methods of molecular or lithographic control of the gap distance are limited to producing discrete values and encounter difficulty in achieving subnanometer gap distances. For these reasons, the study of the plasmon coupling for varying degrees of interaction remains a challenge. Here, we report that by using light, the interparticle distance for gold nanoparticle (AuNP) dimers can be continuously tuned from a few nanometers to negative values (<i>i.e.</i>, merged particles). Accordingly, the plasmon coupling between the AuNPs transitions from the classical electromagnetic regime to the contact regime <i>via</i> the nonlocal and quantum regimes in the subnanometer gap region. We find that photooxidative desorption of alkanedithiol linkers induced by UV irradiation causes the two AuNPs in a dimer to approach each other and eventually merge. Light-driven control of the interparticle distance offers a novel means of exploring the fundamental nature of plasmon coupling as well as the possibility of fabricating nanoassemblies with any desired gap distance in a spatially controlled manner

Association between Peak Expiratory Flow Rate and Exposure Level to Indoor PM2.5 in Asthmatic Children, Using Data from the Escort Intervention Study

Various studies have indicated that particulate matter &lt;2.5 &mu;m (PM2.5) could cause adverse health effects on pulmonary functions in susceptible groups, especially asthmatic children. Although the impact of ambient PM2.5 on children&rsquo;s lower respiratory health has been well-established, information regarding the associations between indoor PM2.5 levels and respiratory symptoms in asthmatic children is relatively limited. This randomized, crossover intervention study was conducted among 26 asthmatic children&rsquo;s homes located in Incheon metropolitan city, Korea. We aimed to evaluate the effects of indoor PM2.5 on children&rsquo;s peak expiratory flow rate (PEFR), with a daily intervention of air purifiers with filter on, compared with those groups with filter off. Children aged between 6&ndash;12 years diagnosed with asthma were enrolled and randomly allocated into two groups. During a crossover intervention period of seven weeks, we observed that, in the filter-on group, indoor PM2.5 levels significantly decreased by up to 43%. (p &lt; 0.001). We also found that the daily or weekly unit (1 &mu;g/m3) increase in indoor PM2.5 levels could significantly decrease PEFR by 0.2% (95% confidence interval (CI) = 0.1 to 0.5) or PEFR by 1.2% (95% CI = 0.1 to 2.7) in asthmatic children, respectively. The use of in-home air filtration could be considered as an intervention strategy for indoor air quality control in asthmatic children&rsquo;s homes