Lipid nanoparticles for antisense oligonucleotide gene interference into brain border-associated macrophages.

A colloidal synthesis' proof-of-concept based on the Bligh-Dyer emulsion inversion method was designed for integrating into lipid nanoparticles (LNPs) cell-permeating DNA antisense oligonucleotides (ASOs), also known as GapmeRs (GRs), for mRNA interference. The GR@LNPs were formulated to target brain border-associated macrophages (BAMs) as a central nervous system (CNS) therapy platform for silencing neuroinflammation-related genes. We specifically aim at inhibiting the expression of the gene encoding for lipocalin-type prostaglandin D synthase (L-PGDS), an anti-inflammatory enzyme expressed in BAMs, whose level of expression is altered in neuropsychopathologies such as depression and schizophrenia. The GR@LNPs are expected to demonstrate a bio-orthogonal genetic activity reacting with L-PGDS gene transcripts inside the living system without interfering with other genetic or biochemical circuitries. To facilitate selective BAM phagocytosis and avoid subsidiary absorption by other cells, they were functionalized with a mannosylated lipid as a specific MAN ligand for the mannose receptor presented by the macrophage surface. The GR@LNPs showed a high GR-packing density in a compact multilamellar configuration as structurally characterized by light scattering, zeta potential, and transmission electronic microscopy. As a preliminary biological evaluation of the mannosylated GR@LNP nanovectors into specifically targeted BAMs, we detected in vivo gene interference after brain delivery by intracerebroventricular injection (ICV) in Wistar rats subjected to gene therapy protocol. The results pave the way towards novel gene therapy platforms for advanced treatment of neuroinflammation-related pathologies with ASO@LNP nanovectors.

Moulding hydrodynamic 2D-crystals upon parametric Faraday waves in shear-functionalized water surfaces.

Faraday waves, or surface waves oscillating at half of the natural frequency when a liquid is vertically vibrated, are archetypes of ordering transitions on liquid surfaces. Although unbounded Faraday waves patterns sustained upon bulk frictional stresses have been reported in highly viscous fluids, the role of surface rigidity has not been investigated so far. Here, we demonstrate that dynamically frozen Faraday waves-that we call 2D-hydrodynamic crystals-do appear as ordered patterns of nonlinear gravity-capillary modes in water surfaces functionalized with soluble (bio)surfactants endowing in-plane shear stiffness. The phase coherence in conjunction with the increased surface rigidity bears the Faraday waves ordering transition, upon which the hydrodynamic crystals were reversibly molded under parametric control of their degree of order, unit cell size and symmetry. The hydrodynamic crystals here discovered could be exploited in touchless strategies of soft matter and biological scaffolding ameliorated under external control of Faraday waves coherence.

Lipid-peptide bioconjugation through pyridyl disulfide reaction chemistry and its application in cell targeting and drug delivery.

BACKGROUND: The design of efficient drug delivery vectors requires versatile formulations able to simultaneously direct a multitude of molecular targets and to bypass the endosomal recycling pathway of cells. Liposomal-based vectors need the decoration of the lipid surface with specific peptides to fulfill the functional requirements. The unspecific binding of peptides to the lipid surface is often accompanied with uncontrolled formulations and thus preventing the molecular mechanisms of a successful therapy. RESULTS: We present a simple synthesis pathway to anchor cysteine-terminal peptides to thiol-reactive lipids for adequate and quantitative liposomal formulations. As a proof of concept, we have synthesized two different lipopeptides based on (a) the truncated Fibroblast Growth Factor (tbFGF) for cell targeting and (b) the pH sensitive and fusogenic GALA peptide for endosomal scape. CONCLUSIONS: The incorporation of these two lipopeptides in the liposomal formulation improves the fibroblast cell targeting and promotes the direct delivery of cargo molecules to the cytoplasm of the cell.

Nivel de actividad física en la población adulta del Paraguay. Prevalencia y factores asociados / Level of physical activity among adult population in Paraguay. Prevalence and associates factors

Introducción: Los niveles de actividad física determinan las condiciones de salud y enfermedad de las poblaciones. El estudio pretende determinar la prevalencia de los niveles de actividad física (AF) en la población adulta en el Paraguay e identificar los factores asociados a la inactividad física. Métodos: Estudio transversal tipo encuesta poblacional con representatividad nacional, incluyó personas con edades de 15 a 74 años. El muestreo fue probabilístico, trietápico sin reemplazo. STEPSwise fue la metodología y encuesta aplicada durante junio-setiembre 2011. Se consideraron los niveles de actividad física según el cuestionario Mundial sobre Actividad Física. Los valores de AF fueron estimados en MET. Los valores determinados se distribuyeron según las variables sociodemográficas y clínicas. Por regresión logística se estimó asociación entre las variables, en odd ratios con intervalos de confianza del 95%. Resultados: Se incluyeron 2536 participantes. Resultaron inactivos el 27,2% de la población, 20,1% y 31,3% hombres y mujeres, respectivamente. Los grupos que mostraron una mayor prevalencia de inactividad física con diferencias estadísticamente significativas fueron las mujeres, el grupo de edad superior a 55 años, vivir en área urbana, contar con un mayor nivel de estudios, así como un mayor nivel de ingresos. El sobrepeso y la obesidad se asociaron a una mayor prevalencia de inactividad física, principalmente en los varones. Conclusiones: El estudio además de la prevalencia de AF, aporta datos que serán de gran utilidad como línea de referencia para la vigilancia de los factores de riesgos de las enfermedades crónicas no transmisibles. Además contribuye a identificar los subgrupos prioritarios para intervenciones en salud pública.

Introduction: Physical activity levels determine health conditions and diseases in whole populations. The study attempts to determine the prevalence of physical activity (PA) levels in Paraguay and to identify factors associated with physical inactivity. Methods: A cross-sectional population-type survey with national representatively, included people aged between 15 and 74 years old. Sampling was probabilistic, tri-stage without replacement. STEPSwise was the methodology and survey applied during June-September 2011. The levels of physical activity were considered according to the Global Physical Activity Questionnaire (GPAQ). The PA values were estimated in MET. The determined values were distributed according to sociodemographic and clinical variables. Logistic regression was made for estimate the association between the variables in odd ratios with 95% confidence intervals. Results: 2536 participants were included. 27,2% of the population was inactive, 20,1% and 31,3% men and women, respectively. The groups that showed a higher prevalence of PA with statistically significant differences were: women, the age group over 55 years old, living in the urban area, having a higher level of studies and a higher level of income. Overweight and obesity were associated with a higher prevalence of physical inactivity, mainly in males. Conclusions: The study is the first to present the prevalence and differences of levels of global physical activity in Paraguay and related factors. This first step of surveillance of chronic diseases is very useful to provide a baseline for new interventions in public health.

Control of long-distance cell-to-cell communication and autophagosome transfer in squamous cell carcinoma via tunneling nanotubes.

Tunneling nanotubes (TnTs) are thin channels that temporally connect nearby cells allowing the cell-to-cell trafficking of biomolecules and organelles. The presence or absence of TnTs in human neoplasms and the mechanisms of TnT assembly remains largely unexplored. In this study, we have identified TnTs in tumor cells derived from squamous cell carcinomas (SCC) cultured under bi-dimensional and tri-dimensional conditions and also in human SCC tissues. Our study demonstrates that TnTs are not specific of epithelial or mesenchymal phenotypes and allow the trafficking of endosomal/lysosomal vesicles, mitochondria, and autophagosomes between both types of cells. We have identified focal adhesion kinase (FAK) as a key molecule required for TnT assembly via a mechanism involving the MMP-2 metalloprotease. We have also found that the FAK inhibitor PF-562271, which is currently in clinical development for cancer treatment, impairs TnT formation. Finally, FAK-deficient cells transfer lysosomes/autophagosomes to FAK-proficient cells via TnTs which may represent a novel mechanism to adapt to the stress elicited by impaired FAK signaling. Collectively, our results strongly suggest a link between FAK, MMP-2, and TnT, and unveil new vulnerabilities that can be exploited to efficiently eradicate cancer cells.

Synthesis of new quinazolin-2,4-diones as anti-Leishmania mexicana agents.

The quinazolin-2,4-dione moiety is found in many compounds with important biological activities making it a target for its synthesis. In this work, a one-pot three-step synthesis of new quinazolin-2,4-diones from phthalic anhydrides and their activity against Leishmania mexicana are described. The new quinazolin-2,4-diones were isolated with yields in the range of 32-70 %. All compounds displayed lower cytotoxicity in RAW 264.7 macrophage over miltefosine. Compound 6,7-dichloro-3-phenylquinazoline-2,4(1H,3H)-dione (6e) displayed an attractive profile which includes anti-Leishmania mexicana activity ([Formula: see text] [Formula: see text]M), much lower cytotoxic activity ([Formula: see text] [Formula: see text]M) and a high selective index ([Formula: see text]) proving to be superior to miltefosine.

Deposition of Ni nanoparticles onto porous supports using supercritical CO2: effect of the precursor and reduction methodology.

The deposition of Ni nanoparticles into porous supports is very important in catalysis. In this paper, we explore the use of supercritical CO(2) (scCO(2)) as a green solvent to deposit Ni nanoparticles on mesoporous SiO2 SBA-15 and a carbon xerogel. The good transport properties of scCO(2) allowed the efficient penetration of metal precursors dissolved in scCO(2) within the pores of the support without damaging its structure. Nickel hexafluoroacetylacetonate hydrate, nickel acetylacetonate, bis(cyclopentadienyl)nickel, Ni(NO(3))2⋅6H(2)O and NiCl(2)⋅6H(2)O were tried as precursors. Different methodologies were used: impregnation in scCO(2) and reduction in H(2)/N(2) at 400°C and low pressure, reactive deposition using H(2) at 200-250°C in scCO(2) and reactive deposition using ethanol at 150-200°C in scCO(2). The effect of precursor and methodology on the nickel particle size and the material homogeneity (on the different substrates) was analysed. This technology offers many opportunities in the preparation of metal-nanostructured materials.

Mass-transport Control on the Discharge Mechanism in Li-O2 Batteries Using Carbon Cathodes with Varied Porosity.

By comparing carbon electrodes with varying porosity in Li-O2 cells, we show that the effect of electrolyte stirring at a given current density can result in a change from 2D to 3D growth of discharged deposits. The change of morphology is evident using electron microscopy and by analyzing electrode pore size distribution with respect to discharge capacity. As a consequence, carbon electrodes with different textural properties exhibit different capacity enhancements in stirred-electrolyte cells. We demonstrate that mass transport can directly control the discharge mechanism, similar to the electrolyte composition and current density, which have already been recognized as determining factors.

Conventional unidirectional laser action enhanced by dye confined in nanoparticle scatters.

The synthesis, structural characterization, and lasing properties of new dye-sensitized organic scattering gain medium based on Rhodamine 6G (Rh6G) confined in polymeric nanoparticles are reported. We have demonstrated coherent laser action from amplifying random media using dye confined into polymeric nanoparticles as scattering centers and gain media. Lasing efficiency and photostability were significantly enhanced by nonresonant feedback of the emission by multiple scattering.

Effect of supercritical CO2 in modified polystyrene 3D latex arrays.

The effect of supercritical CO(2) (scCO(2)) in 3D latex arrays formed by monodispersed particles of polystyrene (PS), PS cross-linked with divinylbenzene (PS-DVB), and PS block copolymers with 2-hydroxyethyl methacrylate (PS-HEMA), methacrylic acid (PS-MA), acrylic acid (PS-AA), itaconic acid (PS-IA), and a mixture of methacrylic and itaconic acid (PS-IA-MA) has been studied. Sorption of CO(2) into the polymer particles leads to a decrease in the glass transition temperature of the polymer and the swelling of the particles and induces their coalescence. 3D-latex arrays of the former compositions were treated in scCO(2) at temperatures and pressures ranging from 40 to 80 degrees C and from 85 to 197 bar, respectively. The effect of CO(2) on the polymeric template was assessed by scanning electron microscopy and N(2) adsorption analysis. Bare PS and PS-HEMA particles sintered readily in scCO(2) at 40 degrees C and 85 bar. On the other hand, particles containing carboxylic acid groups on their surface (PS-MA, PS-AA, PS-IA, and PS-IA-MA) were, at the same temperature and pressure, more resistant to the CO(2) treatment. For a given polymer composition, the sorption of CO(2) inside the polymer particles, the swelling, and the degree of coalescence depend on the pressure, temperature, and time of the CO(2) treatment. Analysis of the pore size distributions from the N(2) adsorption data has allowed us to quantify the degree of coalescence of the particles in the matrix. By careful control of the experimental variables, the coalescence of the 3D latex array could be finely tuned using CO(2).

Synthesis of ordered macroporous SiO2 in supercritical CO2 using 3D-latex array templates.

Ordered macroporous SiO(2) membranes were produced by the decomposition of silicon alkoxides in supercritical carbon dioxide (scCO(2)) using 3D-latex arrays as templates.