Análisis de la problemática en la tributación de las sociedades profesionales y de sus socios en la prestación de servicios profesionales

El cuerpo del presente trabajo se dedica a analizar la problemática suscitada en relación al régimen de tributación de las sociedades profesionales, asimismo, se aborda la tributación en sede del IRPF, de los servicios profesionales prestados por el socio a la sociedad, atendiendo a tales efectos, al recientemente incorporado párrafo tercero al articulo 27.1 de la Ley de IRPF, en virtud de Ley 26/2014 de 27 de noviembre de 2014, de IRPF. <br /

Cell-penetrating peptide-conjugated copper complexes for redox-mediated anticancer therapy

Metal-based chemotherapeutics like cisplatin are widely employed in cancer treatment. In the last years, the design of redox-active (transition) metal complexes, such as of copper (Cu), has attracted high interest as alternatives to overcome platinum-induced side-effects. However, several challenges are still faced, including optimal aqueous solubility and efficient intracellular delivery, and strategies like the use of cell-penetrating peptides have been encouraging. In this context, we previously designed a Cu(II) scaffold that exhibited significant reactive oxygen species (ROS)-mediated cytotoxicity. Herein, we build upon the promising Cu(II) redox-active metallic core and aim to potentiate its anticancer activity by rationally tailoring it with solubility- and uptake-enhancing functionalizations that do not alter the ROS-generating Cu(II) center. To this end, sulfonate, arginine and arginine-rich cell-penetrating peptide (CPP) derivatives have been prepared and characterized, and all the resulting complexes preserved the parent Cu(II) coordination core, thereby maintaining its reported redox capabilities. Comparative in vitro assays in several cancer cell lines reveal that while specific solubility-targeting derivatizations (i.e., sulfonate or arginine) did not translate into an improved cytotoxicity, increased intracellular copper delivery via CPP-conjugation promoted an enhanced anticancer activity, already detectable at short treatment times. Additionally, immunofluorescence assays show that the Cu(II) peptide-conjugate distributed throughout the cytosol without lysosomal colocalization, suggesting potential avoidance of endosomal entrapment. Overall, the systematic exploration of the tailored modifications enables us to provide further understanding on structure-activity relationships of redox-active metal-based (Cu(II)) cytotoxic complexes, which contributes to rationalize and improve the design of more efficient redox-mediated metal-based anticancer therapy

Characterization of Plasma Labile Heme in Hemolytic Conditions

The deposited article is the accepted manuscript (post-print version) posted online 7 August 2017 and provided by The Febs Journal. This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process, which may lead to differences between this version and the Version of Record. The deposited article version contains attached the supplementary materials within the pdf. This publication hasn't any creative commons license associated, although it is in open access.Extracellular hemoglobin (Hb), a byproduct of hemolysis, can release its prosthetic heme groups upon oxidation. This produces metabolically active heme that is exchangeable between acceptor proteins, macromolecules and low molecular weight ligands, termed here labile heme. As it accumulates in plasma labile heme acts in a pro-oxidant manner and regulates cellular metabolism while exerting pro-inflammatory and cytotoxic effects that foster the pathogenesis of hemolytic diseases. Here we developed and characterized a panel of heme-specific single domain antibodies (sdAbs) that together with a cellular-based heme reporter assay, allow for quantification and characterization of labile heme in plasma during hemolytic conditions. Using these approaches we demonstrate that labile heme generated during hemolytic conditions is bound to plasma molecules with an affinity higher than 10(-7) M and that 2-8% (~2-5 μM) of the total amount of heme detected in plasma can be internalized by bystander cells, i.e. bioavailable heme. Acute, but not chronic, hemolysis is associated with transient reduction of plasma heme binding capacity (HBC1/2 ), that is, the ability of plasma molecules to bind labile heme with an affinity higher than 10(-7) M. The heme-specific sdAbs neutralize the pro-oxidant activity of soluble heme in vitro, suggesting that these maybe used to counter the pathologic effects of labile heme during hemolytic conditions. Finally, we show that heme-specific sdAbs can be used to visualize cellular heme. In conclusion, we describe a panel of heme-specific sdAbs that when used with other approaches provide novel insights to the pathophysiology of heme. This article is protected by copyright. All rights reserved.Fundação para a Ciência e Tecnologia grants: (RECI-IMI-IMU-0038-2012, PTDC/SAU-TOX/116627/2010, HMSP-ICT/0018/2011, SFRH/BD/44828/2008, SFRH/BPD/47477/2008, PTDC/SAU-FAR/119173/2010, IF/01010/2013/CP1183/CT0001); ERC grants: (ERC-2011-AdG 294709-DAMAGECONTROL); NHMRC Senior Principal Research Fellowship: (1003484).info:eu-repo/semantics/acceptedVersio

Copper(II) N, N, O -Chelating Complexes as Potential Anticancer Agents

Altres ajuts: Acord transformatiu CRUE-CSICThree novel dinuclear Cu(II) complexes based on a N,N,O-chelating salphen-like ligand scaffold and bearing varying aromatic substituents (−H, −Cl, and −Br) have been synthesized and characterized. The experimental and computational data obtained suggest that all three complexes exist in the dimeric form in the solid state and adopt the same conformation. The mass spectrometry and electron paramagnetic resonance results indicate that the dimeric structure coexists with the monomeric form in solution upon solvent (dimethyl sulfoxide and water) coordination. The three synthesized Cu(II) complexes exhibit high potentiality as ROS generators, with the Cu(II)/Cu(I) redox potential inside the biological redox window, and thus being able to biologically undergo Cu(II)/Cu(I) redox cycling. The formation of ROS is one of the most promising reported cell death mechanisms for metal complexes to offer an inherent selectivity to cancer cells. In vitro cytotoxic studies in two different cancer cell lines (HeLa and MCF7) and in a normal fibroblast cell line show promising selective cytotoxicity for cancer cells (IC50 about 25 μM in HeLa cells, which is in the range of cisplatin and improved with respect to carboplatin), hence placing this N,N,O-chelating salphen-like metallic core as a promising scaffold to be explored in the design of future tailor-made Cu(II) cytotoxic compounds

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

An in silico and chemical approach towards small protein production and application in phosphoproteomics

International audienceThe human Pin1 WW domain (hPin1_WW) is a 38 residue protein which specifically recognizes ligands rich in proline and phosphorylated in Ser and Thr residues. This work presents a protocol for the improved chemical synthesis and modification of this protein through automated microwave assisted synthesis combined with the incorporation of pseudoproline units in the protein sequence. After purification, the protein was characterized by Mass Spectrometry and Circular Dichroism spectroscopy with results comparable to the same WW domain chemically synthesized by other strategies or biologically expressed. The protein was further immobilized on a matrix and tested for the selective binding and mild elution of phosphorylated sequences at Ser, Thr and Tyr residues. These results suggest that hPin1_WW is a useful protein scaffold for the purification of phosphorylated species in pTyr and pSer, which can be easily produced and modified by chemical methods

Cover Picture: Heterochromia in Designed Metallopeptides: Geometry-Selective Binding of Cd II in a De 14Novo Peptide (Angew. Chem. Int. Ed. 35/2007)

No AbstractPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56155/1/6559_ftp.pd

Titelbild: Heterochromia in Designed Metallopeptides: Geometry-Selective Binding of Cd II in a De 14Novo Peptide (Angew. Chem. 35/2007)

No AbstractPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56119/1/6679_ftp.pd