Novel pharmacological maps of protein lysine methyltransferases: key for target deorphanization

Epigenetic therapies are being investigated for the treatment of cancer, cognitive disorders, metabolic alterations and autoinmune diseases. Among the diferent epigenetic target families, protein lysine methyltransferases (PKMTs), are especially interesting because it is believed that their inhibition may be highly specifc at the functional level. Despite its relevance, there are currently known inhibitors against only 10 out of the 50 SET-domain containing members of the PKMT family. Accordingly, the identifcation of chemical probes for the validation of the therapeutic impact of epigenetic modulation is key. Moreover, little is known about the mechanisms that dictate their substrate specifcity and ligand selectivity. Consequently, it is desirable to explore novel methods to characterize the pharmacological similarity of PKMTs, going beyond classical phylogenetic relationships. Such characterization would enable the prediction of ligand of-target efects caused by lack of ligand selectivity and the repurposing of known compounds against alternative targets. This is particularly relevant in the case of orphan targets with unreported inhibitors. Here, we frst perform a systematic study of binding modes of cofactor and substrate bound ligands with all available SET domain-containing PKMTs. Protein ligand interaction fngerprints were applied to identify conserved hot spots and contact-specifc residues across subfamilies at each binding site; a relevant analysis for guiding the design of novel, selective compounds. Then, a recently described methodology (GPCR-CoINPocket) that incorporates ligand contact information into classical alignment-based comparisons was applied to the entire family of 50 SET-containing proteins to devise pharmacological similarities between them. The main advantage of this approach is that it is not restricted to proteins for which crystallographic data with bound ligands is available. The resulting family organization from the separate analysis of both sites (cofactor and substrate) was retrospectively and prospectively validated. Of note, three hits (inhibition>50% at 10 µM) were identifed for the orphan NSD1

Evaluación del potencial agronómico del fríjol "alado" psophocarpus tetragonolobus (l.) d.c. en las condiciones del valle del cauca

En el ensayo se utilizaron cinco accesiones (lCA-66, UPS-018, UPS-020, UPS-139 y UPS-140) de fríjol alado. Se realizó la caracterización botánica y fenológica del cultivo, aspectos referentes al comportamiento agronómico, fauna insectil que visitó el cultivo, enfermedades que lo afectaron y análisis bromatológico. La accesión de mejor comportamiento fue la ICA-66 ya que registró el mayor rendimiento de semillas por planta (120.13g) y raíces tuberosas por planta (60 g). La accesión UPS–140 presentó el mayor valor de proteína en hojas (25.37 %), vainas (17.86%) y semillas (35.03%).In this research five accessions (ICA-66, UPS-018, UPS-020, UPS-139 and UPS-140) of winged beans were used. The botanycal and phenologycal characterization was accomplished and aspects relating to the agronomicalbehavior, insectile fauna visiting the crop, main diseases and bromatologycal analysis were studied too. The accession with better behavior was ICA-66 because of it showed the greater yield of seeds per plant (120.13 g) and tuberose roots per plant (60 g).The accessi onUPS-140 presented the greater value of protein in leaves (25.37%), pods (17.86%) and seeds (35.03%)

Oracion panegirica euangelica que propone al aue que alaba el orbe Maria Señora Nuestra : con glorias originadas de aver sido sin la original culpa concebida en el primer instante de su ser

Copia digital. Madrid : Ministerio de Cultura. Subdirección General de Coordinación Bibliotecaria, 2008Sign.: [ ]\p4\s, A-D\p4\s, E\p2\sPort. con orla tip

Tesoro inefable de diuinas riquezas, el glorioso Pe. S. Martin, obispo de Turs Sermon

Hay un ejemplar encuadernado con: DOZE portentosos milagros de la insigne virgen y martir Santa Barbara que prometen a sus deuotos la gracia de no morir sin los sacramentos... (XVII/382).Hay un ejemplar encuadernado con: Sermon en la real fiesta de N. Señora del Patrocinio : (XVIII/1699).Sign.: [*]4, A-D4Port. con orla tipGrab. xil. de San Martin y el mendigo enmarcado en por

Sermon de Gracias por el feliz recobro de la salud del Rey nuestro señor ... : celebrolas ... la ... Diputacion de ... Valencia, en su Casa, en 5 de Noviembre de 1696

Copia digital. Madrid : Ministerio de Cultura. Subdirección General de Coordinación Bibliotecaria, 2006Sign. : [calderón]\p4\s, 2 [calderón]\p2\s, A-C\p4\s, D\p2\sPort. con orla tip.Texto a dos col

Sacro enigma en la santisima imagen del Santo Cristo de la parroquia de S. Salvador de la ciudad de Valencia : en sermon panegirico

Copia digital. Madrid : Ministerio de Cultura. Subdirección General de Coordinación Bibliotecaria, 2006Sign.: A\p4\s, A-D\p4\sPort. con orla tip

Sacro enigma en la santisima imagen del Santo Cristo de la parroquia de S. Salvador de la ciudad de Valencia en sermon panegirico

Port. con orla tipSign.: A4, A-D4Apostillas marginale

Decoloración de aguas residuales de una industria de pinturas por la microalga Chlorella sp

Objective. Decoloring wastewater from a paint factory making use of Chlorella sp., microalgae as a biological way of treatment. Materials and methods. Samples of this microalgae previously cultivated with nourishing fertilizer under photoperiods of light and darkness were taken to test the microalgae Chlorella sp., initial concentration effect in the bioremoval process. For this purpose, it was cultivated in 0.10, 0.20 and 0.30 units of absorbance in bioreactors with 200 mL wastewater with and without nutrients. The biotest with the best rate of colour removal was chosen and the DBO5 and DQO were marked out. The immobilized Chlorella sp., in kappa carrageenan was also tested. Results. In the tests colour decrease percentage were 81.7, 69.7 and 58.3% without nutrients in the initial concentrations of 0.10, 0.20 and 0.30 units of absorbance respectively and 72.6, 69.0 and 86.8% for 0.10, 0.20 and 0.30 units of absorbance with nutrients respectively in the day of maximum growth. The immobilized microalgae score were 72.60% and 78.36% of color removal for 0.4 and 1.6 units of absorbance respectively. The higher colour removal test score was that with nutrients at 0.30 units of absorbance with several changes in DBO5 and DQO values. Conclusion. The biological wastewater treatment making use of Chlorella sp., microalgae can be considered as an effective choice in decolorating wastewater.Objetivo. Decolorar aguas residuales obtenidas de una empresa de pinturas, empleando la microalga Chlorella sp., como medio biológico de tratamiento. Materiales y métodos. Muestras de la microalga previamente cultivada con fertilizante como nutriente y fotoperiodos de luz y oscuridad, se tomaron para evaluar el efecto de la concentración inicial de la microalga Chlorella sp., en el proceso de bioremoción. Para tal fin, esta se cultivó a 0.10, 0.20 y 0.30 unidades de absorbancia en biorreactores con 200 mL de aguas residuales en presencia y ausencia de nutrientes. Se seleccionó el bioensayo con mejores porcentajes de remoción del color y se le determinó el DBO5 y DQO. Chlorella sp., inmovilizada en kappa carragenina también se estudió. Resultados. Los porcentajes de reducción de color de los bioensayos en ausencia de nutrientes fueron de 81.7, 69.7 y 58.3% para las concentraciones iniciales de 0.10, 0.20 y 0.30 unidades de absorbancia respectivamente y en presencia de nutrientes fueron 72.6, 69.0 y 86.8% para 0.10, 0.20 y 0.30 unidades de absorbancia respectivamente, en el día de máximo crecimiento. Los resultados de la microalga inmovilizada fueron de 72.60% y 78.36% de remoción del color para 0.4 y 1.6 unidades de absorbancia respectivamente. El bioensayo con mayor rendimiento de remoción fue el realizado en presencia de nutrientes a 0.30 unidades de absorbancia con cambios importantes en los valores de DBO5 y DQO. Conclusión. El tratamiento biológico de aguas empleando la microalga Chlorella sp., puede considerarse una alternativa eficaz en la decoloración de aguas residuales

Sacro enigma en la santisima imagen del Santo Cristo de la parroquia de S. Salvador de la ciudad de Valencia en sermon panegirico

Port. con orla tipSign.: A4, A-D4Apostillas marginale

Multiple ATR-Chk1 Pathway Proteins Preferentially Associate with Checkpoint-Inducing DNA Substrates

The ATR-Chk1 DNA damage checkpoint pathway is a critical regulator of the cellular response to DNA damage and replication stress in human cells. The variety of environmental, chemotherapeutic, and carcinogenic agents that activate this signal transduction pathway do so primarily through the formation of bulky adducts in DNA and subsequent effects on DNA replication fork progression. Because there are many protein-protein and protein-DNA interactions proposed to be involved in activation and/or maintenance of ATR-Chk1 signaling in vivo, we systematically analyzed the association of a number of ATR-Chk1 pathway proteins with relevant checkpoint-inducing DNA structures in vitro. These DNA substrates included single-stranded DNA, branched DNA, and bulky adduct-containing DNA. We found that many checkpoint proteins show a preference for single-stranded, branched, and bulky adduct-containing DNA in comparison to undamaged, double-stranded DNA. We additionally found that the association of checkpoint proteins with bulky DNA damage relative to undamaged DNA was strongly influenced by the ionic strength of the binding reaction. Interestingly, among the checkpoint proteins analyzed the checkpoint mediator proteins Tipin and Claspin showed the greatest differential affinity for checkpoint-inducing DNA structures. We conclude that the association and accumulation of multiple checkpoint proteins with DNA structures indicative of DNA damage and replication stress likely contribute to optimal ATR-Chk1 DNA damage checkpoint responses