Metal coordination and peripheral substitution modulate the activity of cyclic tetrapyrroles on αS aggregation: A structural and cell-based study.

The discovery of aggregation inhibitors and the elucidation of their mechanism of action are key in the quest to mitigate the toxic consequences of amyloid formation. We have previously characterized the antiamyloidogenic mechanism of action of sodium phtalocyanine tetrasulfonate ([Na4(H2PcTS)]) on α-Synuclein (αS), demonstrating that specific aromatic interactions are fundamental for the inhibition of amyloid assembly. Here we studied the influence that metal preferential affinity and peripheral substituents may have on the activity of tetrapyrrolic compounds on αS aggregation. For the first time, our laboratory has extended the studies in the field of the bioinorganic chemistry and biophysics to cellular biology, using a well-established cell-based model to study αS aggregation. The interaction scenario described in our work revealed that both N- and C-terminal regions of αS represent binding interfaces for the studied compounds, a behavior that is mainly driven by the presence of negatively or positively charged substituents located at the periphery of the macrocycle. Binding modes of the tetrapyrrole ligands to αS are determined by the planarity and hydrophobicity of the aromatic ring system in the tetrapyrrolic molecule and/or the preferential affinity of the metal ion conjugated at the center of the macrocyclic ring. The different capability of phthalocyanines and meso-tetra (N-methyl-4-pyridyl) porphine tetrachloride ([H2PrTPCl4]) to modulate αS aggregation in vitro was reproduced in cell-based models of αS aggregation, demonstrating unequivocally that the modulation exerted by these compounds on amyloid assembly is a direct consequence of their interaction with the target protein

Influence of Chemical Enhancers and Iontophoresis on the In Vitro Transdermal Permeation of Propranolol: Evaluation by Dermatopharmacokinetics

[EN] The aims of this study were to assess, in vitro, the possibility of administering propranolol transdermally and to evaluate the usefulness of the dermatopharmacokinetic (DPK) method in assessing the transport of drugs through stratum corneum, using propranolol as a model compound. Four chemical enhancers (decenoic and oleic acid, laurocapram, and R-(+)-limonene) and iontophoresis at two current densities, 0.25 and 0.5 mA/cm(2) were tested. R-(+)-limonene, and iontophoresis at 0.5 mA/cm(2) were proven to be the most efficient in increasing propranolol transdermal flux, both doubled the original propranolol transdermal flux. Iontophoresis was demonstrated to be superior than the chemical enhancer because it allowed faster delivery of the drug. The DPK method was sufficiently sensitive to detect subtle vehicle-induced effects on the skin permeation of propranolol. The shorter duration of these experiments and their ability to provide mechanistic information about partition between vehicle and skin and diffusivity through skin place them as practical and potentially insightful approach to quantify and, ultimately, optimize topical bioavailability.This research was funded by Ministerio de Ciencia e Innovación (AP2007-03456) and the Universidad CEU Cardenal Herrera.Calatayud-Pascual, M.; Sebastian-Morelló, M.; Balaguer-Fernandez, C.; Delgado-Charro, M.; Lopez-Castellano, A.; Merino Sanjuán, V. (2018). Influence of Chemical Enhancers and Iontophoresis on the In Vitro Transdermal Permeation of Propranolol: Evaluation by Dermatopharmacokinetics. Pharmaceutics. 10(4):1-15. https://doi.org/10.3390/pharmaceutics10040265S11510

Inhibiting the Plasmodium eIF2α Kinase PK4 Prevents Artemisinin-Induced Latency

Artemisinin and its derivatives (ARTs) are frontline antimalarial drugs. However, ART monotherapy is associated with a high frequency of recrudescent infection, resulting in treatment failure. A subset of parasites is thought to undergo ART-induced latency, but the mechanisms remain unknown. Here, we report that ART treatment results in phosphorylation of the parasite eukaryotic initiation factor-2α (eIF2α), leading to repression of general translation and latency induction. Enhanced phosphorylated eIF2α correlates with high rates of recrudescence following ART, and inhibiting eIF2α dephosphorylation renders parasites less sensitive to ART treatment. ART-induced eIF2α phosphorylation is mediated by the Plasmodium eIF2α kinase, PK4. Overexpression of a PK4 dominant-negative or pharmacological inhibition of PK4 blocks parasites from entering latency and abolishes recrudescence after ART treatment of infected mice. These results show that translational control underlies ART-induced latency and that interference with this stress response may resolve the clinical problem of recrudescent infection

Resolving galaxies in time and space: II: Uncertainties in the spectral synthesis of datacubes

In a companion paper we have presented many products derived from the application of the spectral synthesis code STARLIGHT to datacubes from the CALIFA survey, including 2D maps of stellar population properties and 1D averages in the temporal and spatial dimensions. Here we evaluate the uncertainties in these products. Uncertainties due to noise and spectral shape calibration errors and to the synthesis method are investigated by means of a suite of simulations based on 1638 CALIFA spectra for NGC 2916, with perturbations amplitudes gauged in terms of the expected errors. A separate study was conducted to assess uncertainties related to the choice of evolutionary synthesis models. We compare results obtained with the Bruzual & Charlot models, a preliminary update of them, and a combination of spectra derived from the Granada and MILES models. About 100k CALIFA spectra are used in this comparison. Noise and shape-related errors at the level expected for CALIFA propagate to 0.10-0.15 dex uncertainties in stellar masses, mean ages and metallicities. Uncertainties in A_V increase from 0.06 mag in the case of random noise to 0.16 mag for shape errors. Higher order products such as SFHs are more uncertain, but still relatively stable. Due to the large number statistics of datacubes, spatial averaging reduces uncertainties while preserving information on the history and structure of stellar populations. Radial profiles of global properties, as well as SFHs averaged over different regions are much more stable than for individual spaxels. Uncertainties related to the choice of base models are larger than those associated with data and method. Differences in mean age, mass and metallicity are ~ 0.15 to 0.25 dex, and 0.1 mag in A_V. Spectral residuals are ~ 1% on average, but with systematic features of up to 4%. The origin of these features is discussed. (Abridged)Comment: A&A, accepte

RIP2 plays a role in cardiac Ca2+ mishandling prompted by chronic kidney disease

post-print81,7 K

A Hubble Space Telescope ACS Search for Brown Dwarf Binaries in the Pleiades Open Cluster

We present the results of a high-resolution imaging survey for brown dwarf binaries in the Pleiades open cluster. The observations were carried out with the Advance Camera for Surveys onboard the Hubble Space Telescope. Our sample consists of 15 bona-fide brown dwarfs. We confirm 2 binaries and detect their orbital motion, but we did not resolve any new binary candidates in the separation range between 5.4AU and 1700AU and masses in the range 0.035--0.065~Msun. Together with the results of our previous study (Martin et al., 2003), we can derive a visual binary frequency of 13.3$^{+13.7}_{-4.3}$\% for separations greater than 7~AU masses between 0.055--0.065~M_{\sun} and mass ratios between 0.45--0.9$<q<$1.0. The other observed properties of Pleiades brown dwarf binaries (distributions of separation and mass ratio) appear to be similar to their older counterparts in the field.Comment: 29 pages, 7 figures, 6 tables, accepted for publication in Ap

Star formation histories in mergers: the spatially resolved properties of the early-stage merger luminous infrared galaxies IC 1623 and NGC 6090

The role of major mergers in galaxy evolution is investigated through a detailed characterization of the stellar populations, ionized gas properties and star formation rates (SFR) in the early-stage merger luminous infrared galaxies (LIRGs) IC 1623 W and NGC 6090, by analysing optical integral field spectroscopy and high-resolution Hubble Space Telescope imaging. The spectra were processed with the starlight full spectral fitting code, and the emission lines measured in the residual spectra. The results are compared with non-interacting control spiral galaxies from the Calar Alto Legacy Integral Field Area survey. Merger-induced star formation is extended and recent, as revealed by the young ages (50–80 Myr) and high contributions to light of young stellar populations (50–90 per cent), in agreement with merger simulations in the literature. These early-stage mergers have positive central gradients of the stellar metallicity, with an average ∼0.6 Z⊙. Compared to non-interacting spirals, they have lower central nebular metallicity, and flatter profiles, in agreement with the gas inflow scenario. We find that they are dominated by star formation, although shock excitation cannot be discarded in some regions, where high velocity dispersion is found (170–200 km s−1). The average SFR in these early-stage mergers (∼23–32 M⊙ yr−1) is enhanced with respect to main-sequence Sbc galaxies by factors of 6–9, slightly above the predictions from classical merger simulations, but still possible in about 15 per cent of major galaxy mergers, where U/LIRGs belong

Effect of sugar beet pulp fibre fractions on growth performance, fecal digestibility and digestive physiology in rabbits around weaning

The present study investigated the effect of the different fibre components of sugar beet pulp (SBP) on growth performance and some digestive traits. Four semi-synthetic diets were formulated with similar NDF (33% DM) and protein (16% DM) level. Control diet was formulated to contain the lowest level of soluble fibre (3% DM) and SBP diet the highest (9%). The soluble (pectins) and insoluble fractions of SBP were studied in other two diets (Pectin and InsSBP diets). A total of 136 weanling rabbits (25 d of age) was housed individually, randomly assigned to 4 experimental groups, and fed ad libitum with the experimental diets during 10 days after weaning. The type of diet did not affect growth rate and stomach pH. Animals fed with SBP diet showed higher DM and NDF digestibility (4 and 83%, respectively), gain:feed ratio (13%), cecal and total tract weight (13 and 9%) and ileal viscosity (148%) than rabbits fed the Control diet, but lower cecal pH (9%). Pectin diet increased ileal viscosity and decreased the weight of stomach content with respect to SBP diet. Rabbits fed InsSBP diet showed similar results to SBP diet but lower ileal viscosity and cecal pH than those fed Pectin diet. In conclusion, SBP and their soluble and insoluble fractions are well digested in young rabbits. However the soluble and insoluble fibre of SBP produce different effects in the gastrointestinal tract