Controlling aggregation-induced emission by supramolecular interactions and colloidal stability in ionic emitters for light-emitting electrochemical cells.

Chromophores face applicability limitations due to their natural tendency to aggregate, with a subsequent deactivation of their emission features. Hence, there has been a fast development of aggregation induced emission (AIE) emitters, in which non-radiative motional deactivation is inhibited. However, a fine control of their colloidal properties governing the emitting performance is fundamental for their application in thin film optoelectronics. In addition, ion-based lighting devices, such as light emitting electrochemical cells (LECs), requires the design of ionic AIE emitters, whose structure allows (i) an easy ion polarizability to assist charge injection and (ii) a reversible electrochemical behavior. To date, these fundamental questions have not been addressed. Herein, the hydrophilic/hydrophobic balance of a family of cationic tetraphenyl ethene (TPE) derivatives is finely tuned by chemical design. The hydrophilic yet repulsive effect of pyridinium-based cationic moieties is balanced with hydrophobic variables (long alkyl chains or counterion chemistry), leading to (i) a control between monomeric/aggregate state ruling photoluminescence, (ii) redox behavior, and (iii) enhanced ion conductivity in thin films. This resulted in a LEC enhancement with the first ionic AIE emitters, reaching values of 0.19 lm W-1 at ca. 50 cd m-2. Overall, this design rule will be key to advance ionic active species for optoelectronics.

A Conformationally Stable π-Expanded X-Type Double Helicene Comprising Dihydropyracylene Units with Multistage Redox Behavior.

A π-expanded X-type double [5]helicene comprising dihydropyracylene moieties was synthesized from commercially available acenaphthene. X-ray crystallographic analysis revealed the unique highly twisted structure of the compound resulting in the occurrence of two enantiomers which were separated by chiral HPLC, owing to their high conformational stability. The compound shows strongly bathochromically shifted UV/vis absorption and emission bands with small Stokes shift and considerable photoluminescence quantum yield and circular polarized luminescence response. The electrochemical studies revealed five facilitated reversible redox events, including three reductions and two oxidations, thus qualifying the compound as chiral multistage redox amphoter. The experimental findings are in line with the computational studies based on density functional theory pointing towards increased spatial extension of the frontier molecular orbitals over the polycyclic framework and a considerably narrowed HOMO-LUMO gap.

Elexacaftor/tezacaftor/ivacaftor corrects monocyte microbicidal deficiency in cystic fibrosis.

BACKGROUND: Cystic fibrosis (CF), which is caused by mutations in the CF transmembrane conductance regulator (CFTR), is characterised by chronic bacterial lung infection and inflammation. In CF, monocytes and monocyte-derived macrophages have been shown to display defective phagocytosis and antimicrobial activity against relevant lung pathogens, including Pseudomonas aeruginosa. Thus, we addressed the effect of CFTR triple modulator therapy (elexacaftor/tezacaftor/ivacaftor (ETI)) on the activity of CF monocytes against P. aeruginosa. METHODS: Monocytes from people with CF (PWCF) before and after 1 and 6 months of ETI therapy were isolated from blood and infected with P. aeruginosa to assess phagocytic activity and intracellular bacterial killing. The oxidative burst and interleukin-6 secretion were also determined. Monocytes from healthy controls were also included. RESULTS: Longitudinal analysis of the clinical parameters confirmed an improvement of lung function and lung microbiology by ETI. Both the phagocytic and microbicidal deficiencies of CF monocytes also improved significantly, although not completely. Furthermore, we measured an exuberant oxidative burst in CF monocytes before therapy, which was reduced considerably by ETI. This led to an improvement of reactive oxygen species-dependent bactericidal activity. Inflammatory response to bacterial stimuli was also lowered compared with pre-therapy. CONCLUSIONS: PWCF on ETI therapy, in a real-life setting, in addition to clinical recovery, showed significant improvement in monocyte activity against P. aeruginosa, which may have contributed to the overall effect of ETI on pulmonary disease. This also suggests that CF monocyte dysfunctions may be specifically targeted to ameliorate lung function in CF.

Supramolecular Chalcogen-Bonded Semiconducting Nanoribbons at Work in Lighting Devices.

This work describes the design and synthesis of a π-conjugated telluro[3,2-ß][1]-tellurophene-based synthon that, embodying pyridyl and haloaryl chalcogen-bonding acceptors, self-assembles into nanoribbons through chalcogen bonds. The ribbons π-stack in a multi-layered architecture both in single crystals and thin films. Theoretical studies of the electronic states of chalcogen-bonded material showed the presence of a local charge density between Te and N atoms. OTFT-based charge transport measurements showed hole-transport properties for this material. Its integration as a p-type semiconductor in multi-layered CuI -based light-emitting electrochemical cells (LECs) led to a 10-fold increase in stability (38 h vs. 3 h) compared to single-layered devices. Finally, using the reference tellurotellurophene congener bearing a C-H group instead of the pyridyl N atom, a herringbone solid-state assembly is formed without charge transport features, resulting in LECs with poor stabilities (<1 h).

Multivariate Analysis Identifying [Cu(N

White light-emitting electrochemical cells (LECs) comprising only [Cu(N^N)(P^P)]+ have not been reported yet, as all the attempts toward blue-emitting complexes failed. Multivariate analysis, based on prior-art [Cu(N^N)(P^P)]+ -based thin-film lighting (>90 papers) and refined with computational calculations, identifies the best blue-emitting [Cu(N^N)(P^P)]+ design for LECs, that is, N^N: 2-(4-(tert-butyl)phenyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyridine and P^P: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene, to achieve predicted thin-film emission at 490 nm and device performance of 3.8 cd A-1 @170 cd m-2 . Validation comes from synthesis, X-ray structure, thin-film spectroscopic/microscopy/electrochemical characterization, and device optimization, realizing the first [Cu(N^N)(P^P)]+ -based blue-LEC with 3.6 cd A-1 @180 cd m-2 . This represents a record performance compared to the state-of-the-art tricoordinate Cu(I)-complexes blue-LECs (0.17 cd A-1 @20 cd m-2 ). Versatility is confirmed with the synthesis of the analogous complex with 2-(4-(tert-butyl)phenyl)-6-(3,5-dimethyl-1H-pyrazol-1-yl)pyrazine (N^N), showing a close prediction/experiment match: λ = 590/580 nm; efficiency = 0.55/0.60 cd A-1 @30 cd m-2 . Finally, experimental design is applied to fabricate the best white multicomponent host:guest LEC, reducing the number of trial-error attempts toward the first white all-[Cu(N^N)(P^P)]+ -LECs with 0.6 cd A-1 @30 cd m-2 . This corresponds to approximately ten-fold enhancement compared to previous LECs (<0.05 cd A-1 @<12 cd m-2 ). Hence, this work sets in the first multivariate approach to design emitters/active layers, accomplishing first-class [Cu(N^N)(P^P)]+ -based blue/white LECs that were previously elusive.

Anti-Inflammatory Potential of Cow, Donkey and Goat Milk Extracellular Vesicles as Revealed by Metabolomic Profile.

In recent years, extracellular vesicles (EVs), cell-derived micro and nano-sized structures enclosed in a double-layer membrane, have been in the spotlight for their high potential in diagnostic and therapeutic applications. Indeed, they act as signal mediators between cells and/or tissues through different mechanisms involving their complex cargo and exert a number of biological effects depending upon EVs subtype and cell source. Being produced by almost all cell types, they are found in every biological fluid including milk. Milk EVs (MEVs) can enter the intestinal cells by endocytosis and protect their labile cargos against harsh conditions in the intestinal tract. In this study, we performed a metabolomic analysis of MEVs, from three different species (i.e., bovine, goat and donkey) by mass spectroscopy (MS) coupled with Ultrahigh-performance liquid chromatography (UHPLC). Metabolites, both common or specific of a species, were identified and enriched metabolic pathways were investigated, with the final aim to evaluate their anti-inflammatory and immunomodulatory properties in view of prospective applications as a nutraceutical in inflammatory conditions. In particular, metabolites transported by MEVs are involved in common pathways among the three species. These metabolites, such as arginine, asparagine, glutathione and lysine, show immunomodulating effects. Moreover, MEVs in goat milk showed a greater number of enriched metabolic pathways as compared to the other kinds of milk.

ent-Beyerane Diterpenes as a Key Platform for the Development of ArnT-Mediated Colistin Resistance Inhibitors.

Colistin is a last-resort antibiotic for the treatment of multidrug resistant Gram-negative bacterial infections. Recently, a natural ent-beyerene diterpene was identified as a promising inhibitor of the enzyme responsible for colistin resistance mediated by lipid A aminoarabinosylation in Gram-negative bacteria, namely, ArnT (undecaprenyl phosphate-alpha-4-amino-4-deoxy-l-arabinose arabinosyl transferase). Here, semisynthetic analogues of hit were designed, synthetized, and tested against colistin-resistant Pseudomonas aeruginosa strains including clinical isolates to exploit the versatility of the diterpene scaffold. Microbiological assays coupled with molecular modeling indicated that for a more efficient colistin adjuvant activity, likely resulting from inhibition of the ArnT activity by the selected compounds and therefore from their interaction with the catalytic site of ArnT, an ent-beyerane scaffold is required along with an oxalate-like group at C-18/C-19 or a sugar residue at C-19 to resemble L-Ara4N. The ent-beyerane skeleton is identified for the first time as a privileged scaffold for further cost-effective development of valuable colistin resistance inhibitors.

A novel colistin adjuvant identified by virtual screening for ArnT inhibitors.

BACKGROUND: Colistin is a last-resort treatment option for many MDR Gram-negative bacteria. The covalent addition of l-aminoarabinose to the lipid A moiety of LPS is the main colistin resistance mechanism in the human pathogen Pseudomonas aeruginosa. OBJECTIVES: Identification (by in silico screening of a chemical library) of potential inhibitors of ArnT, which catalyses the last committed step of lipid A aminoarabinosylation, and their validation in vitro as colistin adjuvants. METHODS: The available ArnT crystal structure was used for a docking-based virtual screening of an in-house library of natural products. The resulting putative ArnT inhibitors were tested in growth inhibition assays using a reference colistin-resistant P. aeruginosa strain. The most promising compound was further characterized for its range of activity, specificity and cytotoxicity. Additionally, the effect of the compound on lipid A aminoarabinosylation was verified by MS analyses of lipid A. RESULTS: A putative ArnT inhibitor (BBN149) was discovered by molecular docking and demonstrated to specifically potentiate colistin activity in colistin-resistant P. aeruginosa isolates, without relevant effect on colistin-susceptible strains. BBN149 also showed adjuvant activity against colistin-resistant Klebsiella pneumoniae and low toxicity to bronchial epithelial cells. Lipid A aminoarabinosylation was reduced in BBN149-treated cells, although only partially. CONCLUSIONS: This study demonstrates that in silico screening targeting ArnT can successfully identify inhibitors of colistin resistance and provides a promising lead compound for the development of colistin adjuvants for the treatment of MDR bacterial infections.

Escaping the Phagocytic Oxidative Burst: The Role of SODB in the Survival of Pseudomonas aeruginosa Within Macrophages.

Reactive oxygen species (ROS) are small oxygen-derived molecules that are used to control infections by phagocytic cells. In macrophages, the oxidative burst produced by the NOX2 NADPH-oxidase is essential to eradicate engulfed pathogens by both oxidative and non-oxidative killing. Indeed, while the superoxide anion ( O2- ) produced by NOX2, and the other ROS derived from its transformation, can directly target pathogens, ROS also contribute to activation of non-oxidative microbicidal effectors. The response of pathogens to the phagocytic oxidative burst includes the expression of different enzymes that target ROS to reduce their toxicity. Superoxide dismutases (SODs) are the primary scavengers of O2- , which is transformed into H2O2. In the Gram-negative Salmonella typhimurium, periplasmic SODCI has a major role in bacterial resistance to NOX-mediated oxidative stress. In Pseudomonas aeruginosa, the two periplasmic SODs, SODB, and SODM, appear to contribute to bacterial virulence in small-animal models. Furthermore, NOX2 oxidative stress is essential to restrict P. aeruginosa survival in macrophages early after infection. Here, we focused on the role of P. aeruginosa SODs in the counteracting of the lethal effects of the macrophage oxidative burst. Through this study of the survival of sod mutants in macrophages and the measurement of ROS in infected macrophages, we have identified a dual, antagonistic, role for SODB in P. aeruginosa survival. Indeed, the survival of the sodB mutants, but not of the sodM mutants, was greater than that of the wild-type (WT) bacteria early after infection, and sodB-infected macrophages showed higher levels of O2- and lower levels of H2O2. This suggests that SODB contributes to the production of lethal doses of H2O2 within the phagosome. However, later on following infection, the sodB mutants survived less that the WT bacteria, which highlights the pro-survival role of SODB. We have explained this defensive role through an investigation of the activation of autophagy, which was greater in the sodB-infected macrophages.

MiR-146a is over-expressed and controls IL-6 production in cystic fibrosis macrophages.

Cystic fibrosis (CF) is an inherited disease that is characterised by susceptibility to bacterial infections and chronic lung inflammation. Recently, it was suggested that macrophages contribute to impaired host defence and excessive inflammatory responses in CF. Indeed, dysfunction attributed to CF macrophages includes decreased bacterial killing and exaggerated inflammatory responses. However, the mechanisms behind such defects have only been partially defined. MicroRNAs (miRNAs) have emerged as key regulators of several macrophage functions, including their activation, differentiation and polarisation. The goal of this study was to investigate whether miRNA dysregulation underlies the functional abnormalities of CF macrophages. MiRNA profiling of macrophages was performed, with 22 miRNAs identified as differentially expressed between CF and non-CF individuals. Among these, miR-146a was associated with significant enrichment of validated target genes involved in responses to microorganisms and inflammation. As miR-146a dysregulation has been reported in several human inflammatory diseases, we analysed the impact of increased miR-146a expression on inflammatory responses of CF macrophages. These data show that inhibition of miR-146a in lipopolysaccharide-stimulated CF macrophages results in increased interleukin-6 production, which suggests that miR-146a overexpression in CF is functional, to restrict inflammatory responses.

Assembly and Functional Analysis of an S/MAR Based Episome with the Cystic Fibrosis Transmembrane Conductance Regulator Gene.

Improving the efficacy of gene therapy vectors is still an important goal toward the development of safe and efficient gene therapy treatments. S/MAR (scaffold/matrix attached region)-based vectors are maintained extra-chromosomally in numerous cell types, which is similar to viral-based vectors. Additionally, when established as an episome, they show a very high mitotic stability. In the present study we tested the idea that addition of an S/MAR element to a CFTR (cystic fibrosis transmembrane conductance regulator) expression vector, may allow the establishment of a CFTR episome in bronchial epithelial cells. Starting from the observation that the S/MAR vector pEPI-EGFP (enhanced green fluorescence protein) is maintained as an episome in human bronchial epithelial cells, we assembled the CFTR vector pBQ-S/MAR. This vector, transfected in bronchial epithelial cells with mutated CFTR, supported long term wt CFTR expression and activity, which in turn positively impacted on the assembly of tight junctions in polarized epithelial cells. Additionally, the recovery of intact pBQ-S/MAR, but not the parental vector lacking the S/MAR element, from transfected cells after extensive proliferation, strongly suggested that pBQ-S/MAR was established as an episome. These results add a new element, the S/MAR, that can be considered to improve the persistence and safety of gene therapy vectors for cystic fibrosis pulmonary disease.