Local strain heterogeneity and elastic relaxation dynamics associated with relaxor behavior in the single-crystal perovskite Pb(I n1/2 N b1/2) O3-PbZr O3-Pb(M g1/3 N b2/3) O3-PbTi O3

© 2017 American Physical Society. Recently, Pb(In1/2Nb1/2)O3-PbZrO3-Pb(Mg1/3Nb2/3)O3-PbTiO3 (PIN-PZ-PMN-PT) relaxor single crystals were demonstrated to possess improved temperature-insensitive properties, which would be desirable for high-power device applications. The relaxor character associated with the development of local random fields (RFs) and a high rhombohedral-tetragonal (R-T) ferroelectric transition temperature (TR-T > 120°C) would be critical for the excellent properties. A significant effect of the chemical substitution of In3+ and Zr4+ in PMN-PT to give PIN-PZ-PMN-PT is the development of local strain heterogeneity, which acts to suppress the development of macroscopic shear strains without suppressing the development of local ferroelectric moments and contribute substantially to the RFs in PIN-PZ-PMN-PT. Measurements of elastic and anelastic properties by resonant ultrasound spectroscopy show that PIN-PZ-PMN-PT crystal has a quite different form of elastic anomaly due to Vogel-Fulcher freezing, rather than the a discrete cubic-T transition seen in a single crystal of PMN-28PT. It also has high acoustic loss of the relaxor phase down to TR-T. Analysis of piezoresponse force microscopy phase images at different temperatures provides a quantitative insight into the extent to which the RFs influence the microdomain structure and the short-range order correlation length (ξ)

Synthesis and anticancer activity of Pt(0)-olefin complexes bearing 1,3,5-triaza-7-phosphaadamantane and N-heterocyclic carbene ligands

A series of Pt(0)-η2-olefin complexes bearing 1,3,5-triaza-7-phosphaadamantane (PTA) or N-heterocyclic carbenes are prepared following different synthetic strategies depending on the nature of coordinated alkene and spectator ligands. These new platinum(0) derivatives have been tested in vitro as anticancer agents toward three different tumor (human ovarian cancer A2780 and A2780cis and K562 myelogenous leukemia) and one non-tumor (Hacat keratinocytes) cell lines, proving to be in several cases highly and selectively cytotoxic against ovarian cancer cells. Furthermore, this antiproliferative effect is associated with the activation of an apoptosis process. In particular, complexes equipped with PTA as spectator ligand give comparable IC50 values on A2780 (cisplatin sensitive) and A2780cis (cisplatin resistant) cell lines, indirectly proving that these new Pt(0) substrates act with a mechanism of action conceivably different from cisplatin. This hypothesis is also confirmed by the fact that our compounds, in contrast to cisplatin, are not able to promote erythroid-differentiation activity on the K562 myelogenous leukemia cell line

Changing the game of time resolved X-ray diffraction on the mechanochemistry playground by downsizing

Time resolved in situ (TRIS) monitoring has revolutionised the study of mechanochemical transformations but has been limited by available data quality. Here we report how a combination of miniaturised grinding jars together with innovations in X-ray powder diffraction data collection and state-of-the-art analysis strategies transform the power of TRIS synchrotron mechanochemical experiments. Accurate phase compositions, comparable to those obtained by ex situ measurements, can be obtained with small sample loadings. Moreover, microstructural parameters (crystal size and microstrain) can be also determined with high confidence. This strategy applies to all chemistries, is readily implemented, and yields high-quality diffraction data even using a low energy synchrotron source. This offers a direct avenue towards the mechanochemical investigation of reactions comprising scarce, expensive, or toxic compounds. Our strategy is applied to model systems, including inorganic, metal-organic, and organic mechanosyntheses, resolves previously misinterpreted mechanisms in mechanochemical syntheses, and promises broad, new directions for mechanochemical research

Structural effects in UO2 thin films irradiated with fission-energy Xe ions

Uranium dioxide thin films have been successfully grown on LSAT (Al10La3O51Sr14Ta7) substrates by reactive magnetron sputtering. Irradiation by 92 MeV 129Xe23+ ions to simulate fission damage that occurs within nuclear fuels caused microstructural and crystallographic changes. Initially flat and continuous thin films were produced by magnetron sputtering with a root mean square roughness of 0.35 nm determined by AFM. After irradiation, this roughness increased to 60–70 nm, with the films developing discrete microstructural features: small grains (∼3 μm), along with larger circular (up to 40 μm) and linear formations with non-uniform composition according to the SEM, AFM and EDX results. The irradiation caused significant restructuring of the UO2 films that was manifested in significant film-substrate mixing, observed through EDX analysis. Diffusion of Al from the substrate into the film in unirradiated samples was also observed

Structural effects in UO2 thin films irradiated with U ions

This work presents the results of a detailed structural characterisation of irradiated and unirradiated single crystal thin films of UO2. Thin films of UO2 were produced by reactive magnetron sputtering onto (0 0 1), (1 1 0) and (1 1 1) single crystal yttria-stabilised zirconia (YSZ) substrates. Half of the samples were irradiated with 110 MeV 238U31+ ions to fluences of 5 × 1010, 5 × 1011 and 5 × 1012 ions/cm2 to induce radiation damage, with the remainder kept for reference measurements. It was observed that as-produced UO2 films adopted the crystallographic orientation of their YSZ substrates. The irradiation fluences used in this study however, were not sufficient to cause any permanent change in the crystalline nature of UO2. It has been demonstrated that the effect of epitaxial re-crystallisation of the induced radiation damage can be quantified in terms of kernel average misorientation (KAM) and different crystallographic orientations of UO2 respond differently to ion irradiation

Revisiting Host-Pathogen Interactions in Cystic Fibrosis Lungs in the Era of CFTR Modulators

Cystic fibrosis transmembrane conductance regulator (CFTR) modulators, a new series of therapeutics that correct and potentiate some classes of mutations of the CFTR, have provided a great therapeutic advantage to people with cystic fibrosis (pwCF). The main hindrances of the present CFTR modulators are related to their limitations in reducing chronic lung bacterial infection and inflammation, the main causes of pulmonary tissue damage and progressive respiratory insufficiency, particularly in adults with CF. Here, the most debated issues of the pulmonary bacterial infection and inflammatory processes in pwCF are revisited. Special attention is given to the mechanisms favoring the bacterial infection of pwCF, the progressive adaptation of Pseudomonas aeruginosa and its interplay with Staphylococcus aureus, the cross-talk among bacteria, the bronchial epithelial cells and the phagocytes of the host immune defenses. The most recent findings of the effect of CFTR modulators on bacterial infection and the inflammatory process are also presented to provide critical hints towards the identification of relevant therapeutic targets to overcome the respiratory pathology of pwCF

A peptide-nucleic acid targeting miR-335-5p enhances expression of cystic fibrosis transmembrane conductance regulator (CFTR) gene with the possible involvement of the CFTR scaffolding protein NHERF1

(1) Background: Up-regulation of the Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) might be of great relevance for the development of therapeutic protocols for cystic fibrosis (CF). MicroRNAs are deeply involved in the regulation of CFTR and scaffolding proteins (such as NHERF1, NHERF2 and Ezrin). (2) Methods: Content of miRNAs and mRNAs was analyzed by RT-qPCR, while the CFTR and NHERF1 production was analyzed by Western blotting. (3) Results: The results here described show that the CFTR scaffolding protein NHERF1 can be upregulated in bronchial epithelial Calu-3 cells by a peptide-nucleic acid (PNA) targeting miR-335-5p, predicted to bind to the 3′-UTR sequence of the NHERF1 mRNA. Treatment of Calu-3 cells with this PNA (R8-PNA-a335) causes also up-regulation of CFTR. (4) Conclusions: We propose miR-335-5p targeting as a strategy to increase CFTR. While the efficiency of PNA-based targeting of miR-3355p should be verified as a therapeutic strategy in CF caused by stop-codon mutation of the CFTR gene, this approach might give appreciable results in CF cells carrying other mutations impairing the processing or stability of CFTR protein, supporting its application in personalized therapy for precision medicine

Pharmacological Modulators of Sphingolipid Metabolism for the Treatment of Cystic Fibrosis Lung Inflammation

Cystic Fibrosis (CF) lung disease is characterised by progressive chronic infection and inflammation of the airways. This prolonged airway inflammatory response leads to irreversible lung damage and fibrosis which is believed to be driven by two distinct, coordinated events: a) a defective cystic fibrosis transmembrane regulator (CFTR) causes airway surface dehydration and increased mucus viscosity leading to chronic colonization with Pseudomonas aeruginosa (P.aeruginosa) (Boucher, 2007); b) mutated CFTR triggers the generation of pro-inflammatory and chemotactic cytokines orchestrated by bronchial epithelial cells, independently of infection (Rubin, 2007; Elizur et al., 2008). The chemokine IL-8, abundantly expressed at sites of chronic inflammation, seems to play a major role in driving the formation of neutrophil (PMN)-rich exudates into the lung of CF patients (Khan et al., 1995; Noah et al., 1997; DiMango et al., 1998; Puchelle et al., 2001; Joseph et al., 2005; Perez et al., 2007). Therefore, reduction of the exaggerated production of IL-8 is key therapeutic target in CF. Anti-inflammatory drugs are an attractive therapeutic tool in CF aimed to decrease the rate of decline in lung function. However, the inherent complexity of the inflammatory response combined with the obvious dependency on this response to contain infection and the side effect profiles of common anti-inflammatories, have made identifying the most suitable therapy a major priority. Consensus is growing on sphingolipids (SLs) as novel targets to cure pulmonary disorders including CF, since modulation of cellular ceramide reduces lung inflammation (Lahiri and Futerman, 2007; Uhlig and Gulbins, 2008). The results in the area of ceramide and CF pathophysiology are very interesting, although contradicting due to the animal models used and methods of ceramide detection (Wojewodka , 2011). The accumulation of ceramide has been identified as one of the key regulators of inflammation in CF airways in different CFTR-/- mouse models (Teichgraber, 2008). On the contrary, decreased ceramide levels have been shown in CFTR ko mice (Guibault, 2008). The possible explanation for this discrepancy seems to be the special diet required for CFTR ko mice, that severely affects the concentration of SLs. Other possible causes, such as genetic determinants, could influence individual levels of SLs (Hicks, 2009). In a different study, no significant difference has been found in basal ceramide levels in immortalised CF bronchial epithelial cells and lung homogenate from CFTR ko mice compared to wild type cells and mice (Yu, 2009). Very importantly, ceramide has been demonstrated to accumulate in the lower airways of CF patients and to be positively associated with neutrophilic inflammation (Brodlie, 2010), supporting the hypothesis that reduction of ceramide may be a therapeutic target for CF lung inflammation. Extending our previous study (Dechecchi, 2008), we have recently demonstrated that the iminosugar N-butyldeoxynojirimycin (miglustat), an inhibitor of the first step in glycosphingolipid (GSL) biosynthesis, reducing the P.aeruginosa induced immunoreactive ceramide expression, produces an anti-inflammatory effect in human bronchial epithelial cells in vitro and down-regulates the neutrophil chemotaxis in murine lungs in vivo (Dechecchi, 2011). These findings strengthen the notion that the metabolism of SLs can be manipulated as a therapeutic option for CF lung disease. With regard to new treatments for CF lung pathology, miglustat deserves great attention since it restores CFTR function in respiratory and pancreatic cells in vitro (Norez, 2006; Dechecchi, 2008) and in CF mice (Lubamba, 2009) and produces an anti-inflammatory effect in vitro and in vivo Dechecchi, 2011). Notably, miglustat is a FDA-approved and EMA−designated orally bioavailable orphan drug, used in Europe and USA for the treatment of Gaucher disease and other GSL storage diseases. In this chapter we review the pre-clinical evidence on the anti-inflammatory effect of miglustat in comparative effectiveness studies with the SL inhibitor amitriptyline and the glucocorticoid (GC) dexamethasone. Importance will be placed on the efficacy of each anti-inflammatory molecule to balance between the anti-inflammatory activity and possible impairment of the host defence