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Influence of process variables in a continuous treatment of non-sterile hospital wastewater by Trametes versicolor and novel method for inoculum production

Mir-Tutusaus, J.A., Caminal, G., Sarrà, M.

 Journal of Environmental Management, 212, pp. 415-423, 2018

 Micropollutants such as pharmaceutical active compounds, present at high concentration in hospital wastewater (HWW), pose both environmental and human health challenges. Fungal reactors can effectively remove such contaminants and produce non-toxic effluents, but their ability to operate for a long period of time is yet to be demonstrated in real hospital wastewater. Several process variables need to be studied beforehand. Here, variables: pellet size, aeration and carbon-to-nitrogen ratio are studied in continuous operations with real HWW. Moreover, a novel strategy for inoculum production that could reduce economical and operational costs is proposed and tested. Optimum pellet size was found to be 2?mm and an aeration of 0.8?L?min-1 was needed to maintain fungal viability. The carbon-to-nitrogen ratio of 7.5 was selected and the pellet production time was reduced from 6 to 3 days. The novel low-cost inoculum preparation produced pellets with the same characteristics as the traditionally prepared ones.


Shedding light on metabotropic glutamate receptors using optogenetics and photopharmacology

Goudet, C., Rovira, X., Llebaria, A.

 Current Opinion in Pharmacology, 38, pp. 8-15, 2018

 Metabotropic glutamate receptors (mGluRs) are a family of G protein-coupled receptors activated by glutamate, the main excitatory neurotransmitter of the mammalian central nervous system. These receptors are considered as potential therapeutic targets in many neurological diseases but a better understanding of their complex molecular dynamics and of their role in the normal and pathological functioning of the brain is still required. Manipulating mGluRs with high spatial and temporal precision holds great promise for deciphering their physiological and pathological functions. This article reviews several recently developed optogenetic and photopharmacological solutions for the optical control of mGluRs and their applications, from the study of the molecular dynamics of receptor activation to the study of their roles in vivo.


Nucleophile Promiscuity of Engineered Class II Pyruvate Aldolase YfaU from E. Coli

Karel Hernández, Jesúls Joglar, Jordi Bujons, Teodor Parella, and Pere Clapés

 Angew.Chem.Int.Ed., 2018

 Pyruvate-dependent aldolases exhibit a stringent selectivity for pyruvate, limiting application of their synthetic potential, which is a drawback shared with other existing aldolases. Structure-guided rational protein engineering rendered a 2-keto-3-deoxy-l-rhamnonate aldolase variant, fused with a maltose-binding protein (MBP-YfaU W23V/L216A), capable of efficiently converting larger pyruvate analogues, for example, those with linear and branched aliphatic chains, in aldol addition reactions. Combination of these nucleophiles with N-Cbz-alaninal (Cbz=benzyloxycarbonyl) and N-Cbz-prolinal electrophiles gave access to chiral building blocks, for example, derivatives of (2S,3S,4R)-4-amino-3-hydroxy-2-methylpentanoic acid (68?%, d.r. 90:10) and the enantiomer of dolaproine (33?%, d.r. 94:6) as well as a collection of unprecedented a-amino acid derivatives of the proline and pyrrolizidine type. Conversions varied between 6–93?% and diastereomeric ratios from 50:50 to 95:5 depending on the nucleophilic and electrophilic components.


SOD3 improves the tumor response to chemotherapy by stabilizing endothelial HIF-2a

Emilia Mira, Lorena Carmona-Rodríguez, Beatriz Pérez-Villamil, Josefina Casas,María Jesús Fernández-Aceñero, Diego Martínez-Rey, Paula Martín-González, Ignacio Heras-Murillo, Mateo Paz-Cabezas, Manuel Tardáguila, Tim D. Oury, Silvia Martín-Puig, Rosa Ana Lacalle, Gemma Fabriás, Eduardo Díaz-Rubio and Santos Mañes


 One drawback of chemotherapy is poor drug delivery to tumor cells, due in part to hyperpermeability of the tumor vasculature. Extracellular superoxide dismutase (SOD3) is an antioxidant enzyme usually repressed in the tumor milieu. Here we show that specific SOD3 re-expression in tumor-associated endothelial cells (ECs) increases doxorubicin (Doxo) delivery into and chemotherapeutic effect on tumors. Enhanced SOD3 activity fostered perivascular nitric oxide accumulation and reduced vessel leakage by inducing vascular endothelial cadherin (VEC) transcription. SOD3 reduced HIF prolyl hydroxylase domain protein activity, which increased hypoxia-inducible factor-2a (HIF-2a) stability and enhanced its binding to a specific VEC promoter region. EC-specific HIF-2a ablation prevented both the SOD3-mediated increase in VEC transcription and the enhanced Doxo effect. SOD3, VEC, and HIF-2a levels correlated positively in primary colorectal cancers, which suggests a similar interconnection of these proteins in human malignancy.


Wet-Chemical Etching of GaN: Underlying Mechanism of a Key Step in Blue and White LED Production

Tautz, M.; Díaz, D. D.

 ChemistrySelect 2018


 Gallium nitride (GaN) is the key material for the fabrication of blue and white light emitting diodes (LEDs). Etching of this material is applied to improve the light extraction efficiency of the product. Wet-chemical etching of GaN is commonly carried out by treatment with aqueous KOH solution at elevated temperature. Thereby, the anisotropic etching results in a highly rough surface. Hence, a remarkably higher out-coupling possibility of generated photons is feasible. On the other hand, anisotropy generally prohibits the application of a predictable and standardized etching process. In this review, both material- and process-dependent influences on the etching performance in aqueous KOH solution are classified. Herein, we critically present the factors that affect the etching rate of GaN. Moreover, the etching mechanism at the molecular level and the generation of anisotropy from the hexagonal crystal lattice are discussed. The existing gaps in the current understanding of this process maintain the field still open for further research aligned to a permanent interest of the electronic industry.


Dihydroceramide Desaturase 1 Inhibitors Reduce Amyloid-â Levels in Primary Neurons from an

Ordóñez-Gutiérrez, L., Benito-Cuesta, I., Abad, J.L., Casas, J., Fábrias, G., Wandosell, F.

Pharmaceutical Research, 35 (3), art. no. 49,

Purpose: The induction of autophagy has recently been explored as a promising therapeutic strategy to combat Alzheimer’s disease. Among many other factors, there is evidence that ceramides/dihydroceramides act as mediators of autophagy, although the exact mechanisms underlying such effects are poorly understood. Here, we describe how two dihydroceramide desaturase inhibitors (XM461 and XM462) trigger autophagy and reduce amyloid secretion by neurons. Methods: Neurons isolated from wild-type and APP/PS1 transgenic mice were exposed to the two dihydroceramide desaturase inhibitors to assess their effect on these cell’s protein and lipid profiles. Results: Both dihydroceramide desaturase inhibitors increased the autophagic vesicles in wild-type neurons, reflected as an increase in LC3-II, and this was correlated with the accumulation of dihydroceramides and dihydrosphingomyelins. Exposing APP/PS1 transgenic neurons to these inhibitors also produced a 50% reduction in amyloid secretion and/or production. The lipidomic defects triggered by these dihydroceramide desaturase inhibitors were correlated with a loss of S6K activity, witnessed by the changes in S6 phosphorylation, which strongly suggested a reduction of mTORC1 activity. Conclusions: The data obtained strongly suggest that dihydroceramide desaturase 1 activity may modulate autophagy and mTORC1 activity in neurons, inhibiting amyloid secretion and S6K activity. As such, it is tantalizing to propose that dihydroceramide desaturase 1 may be an important therapeutic target to combat amyloidosis.


Evaluation of the effect of polymorphism on G-quadruplex-ligand interaction by means of spectroscopic and chromatographic techniques

Benito, S., Ferrer, A., Benabou, S., Aviñó, A., Eritja, R., Gargallo, R.

 Spectrochimica Acta - Part A: Molecular and Biomolecular Spectroscopy, 196, 185-195, 2018

 Guanine-rich sequences may fold into highly ordered structures known as G-quadruplexes. Apart from the monomeric G-quadruplex, these sequences may form multimeric structures that are not usually considered when studying interaction with ligands. This work studies the interaction of a ligand, crystal violet, with three guanine-rich DNA sequences with the capacity to form multimeric structures. These sequences correspond to short stretches found near the promoter regions of c-kit and SMARCA4 genes. Instrumental techniques (circular dichroism, molecular fluorescence, size-exclusion chromatography and electrospray ionization mass spectrometry) and multivariate data analysis were used for this purpose. The polymorphism of G-quadruplexes was characterized prior to the interaction studies. The ligand was shown to interact preferentially with the monomeric G-quadruplex; the binding stoichiometry was 1:1 and the binding constant was in the order of 105 M−1 for all three sequences. The results highlight the importance of DNA treatment prior to interaction studies.


Covalent Strategies for Targeting Messenger and Non-Coding RNAs: An Updated Review on siRNA, miRNA and antimiR Conjugates

Grijalvo, S., Alagia, A., Jorge, A.F., Eritja, R.

Genes, 9 (2), art. no. 74, 2018

Oligonucleotide-based therapy has become an alternative to classical approaches in the search of novel therapeutics involving gene-related diseases. Several mechanisms have been described in which demonstrate the pivotal role of oligonucleotide for modulating gene expression. Antisense oligonucleotides (ASOs) and more recently siRNAs and miRNAs have made important contributions either in reducing aberrant protein levels by sequence-specific targeting messenger RNAs (mRNAs) or restoring the anomalous levels of non-coding RNAs (ncRNAs) that are involved in a good number of diseases including cancer. In addition to formulation approaches which have contributed to accelerate the presence of ASOs, siRNAs and miRNAs in clinical trials; the covalent linkage between non-viral vectors and nucleic acids has also added value and opened new perspectives to the development of promising nucleic acid-based therapeutics. This review article is mainly focused on the strategies carried out for covalently modifying siRNA and miRNA molecules. Examples involving cell-penetrating peptides (CPPs), carbohydrates, polymers, lipids and aptamers are discussed for the synthesis of siRNA conjugates whereas in the case of miRNA-based drugs, this review article makes special emphasis in using antagomiRs, locked nucleic acids (LNAs), peptide nucleic acids (PNAs) as well as nanoparticles. The biomedical applications of siRNA and miRNA conjugates are also discussed.


A lamellar body mimetic system for the treatment of oxazolone-induced atopic dermatitis in hairless mice

Moner, V., Fernández, E., Calpena, A.C., Garcia-Herrera, A., Cócera, M., López, O.

Journal of Dermatological Science, 2018

 Background Atopic dermatitis is a common skin disease characterized by a Th2 cell-dominant inflammatory infiltrate, elevated serum IgE levels and impaired epidermal barrier function. It is associated to abnormal epidermal lamellar body secretion, producing alteration in lipid composition and extracellular lamellar membrane organization. Objectives The oxazolone-induced atopic dermatitis in hairless mice was used to evaluate in vivo the effect of the application of a lipid system that mimics the morphology, structure and composition of epidermal lamellar bodies. Methods The skin barrier function was evaluated measuring TEWL and skin hydration in vivo. Inflammation was assessed by analysis of serum IgE levels and histological analysis. The microstructure of the intercellular lipid region was also evaluated before and after treatment. Results The skin condition was improved after 10 days of treatment indicated by decreased TEWL, decreased serum IgE levels, reduced epidermal thickness and reduced lymphocyte-dominated infiltrate. However, the treatment did no improve skin hydration. Conclusions The treatment with this lipid system seems to improve the skin condition by reinforcing the barrier function and reducing the skin inflammation. Therefore, the present study provides evidence that this lipid system combining appropriate lipid composition and morphology could be of interest for the development of future treatments for atopic dermatitis.

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