Vitamin D and Its Synthetic Analogs

For many individuals, in particular during winter, supplementation with the secosteroid vitamin D3 is essential for the prevention of bone disorders, muscle weakness, autoimmune diseases, and possibly also different types of cancer. Vitamin D3 acts via its metabolite 1α,25-dihydroxyvitamin D3 [1,25(OH)2D3] as potent agonist of the transcription factor vitamin D receptor (VDR). Thus, vitamin D directly affects chromatin structure and gene regulation at thousands of genomic loci, i.e., the epigenome and transcriptome of its target tissues. Modifications of 1,25(OH)2D3 at its side-chain, A-ring, triene system, or C-ring, alone and in combination, as well as nonsteroidal mimics provided numerous potent VDR agonists and some antagonists. The nearly 150 crystal structures of VDR’s ligand-binding domain with various vitamin D compounds allow a detailed molecular understanding of their action. This review discusses the most important vitamin D analogs presented during the past 10 years and molecular insight derived from new structural information on the VDR protein

Pancreas agenesis mutations disrupt a lead enhancer controlling a developmental enhancer cluster.

Sequence variants in cis-acting enhancers are important for polygenic disease, but their role in Mendelian disease is poorly understood. Redundancy between enhancers that regulate the same gene is thought to mitigate the pathogenic impact of enhancer mutations. Recent findings, however, have shown that loss-of-function mutations in a single enhancer near PTF1A cause pancreas agenesis and neonatal diabetes. Using mouse and human genetic models, we show that this enhancer activates an entire PTF1A enhancer cluster in early pancreatic multipotent progenitors. This leading role, therefore, precludes functional redundancy. We further demonstrate that transient expression of PTF1A in multipotent progenitors sets in motion an epigenetic cascade that is required for duct and endocrine differentiation. These findings shed insights into the genome regulatory mechanisms that drive pancreas differentiation. Furthermore, they reveal an enhancer that acts as a regulatory master key and is thus vulnerable to pathogenic loss-of-function mutations

Spectrophotometric study in the near-ir of a sample of MIPS selected galaxies at Z~2

Our main objective is to determine what kind of galaxies dominate the cosmic SFR density at z~2. Our sample consists of 24 galaxies in Chandra Deep Field South, a unique field for the study of galaxy evolution (12 observed with GNIRS/GEMINI and 12 with ISAAC/VLT). We use H alpha together with the already merged X-ray, ultraviolet, optical, near and mid-infrared imaging data to obtain estimations of SFRs, metallicities, stellar and dynamical masses, AGN activity, and extinction properties. We have obtained 15 Hα detections, 4 rotation curves, and SFR relationship for 7 galaxies. The metallicities obtained for 8 galaxies of the sample are compatible with the metallicities of local galaxies

Innovative Three-Step Microwave-Promoted Synthesis of N-Propargyltetrahydroquinoline and 1,2,3-Triazole Derivatives as a Potential Factor Xa (FXa) Inhibitors: Drug Design, Synthesis, and Biological Evaluation

The coagulation cascade is the process of the conversion of soluble fibrinogen to insoluble fibrin that terminates in production of a clot. Factor Xa (FXa) is a serine protease involved in the blood coagulation cascade. Moreover, FXa plays a vital role in the enzymatic sequence which ends with the thrombus production. Thrombosis is a common causal pathology for three widespread cardiovascular syndromes: acute coronary syndrome (ACS), venous thromboembolism (VTE), and strokes. In this research a series of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives as a potential factor Xa (FXa) inhibitor were designed, synthesized, and evaluated for their FXa inhibitor activity, cytotoxicity activity and coagulation parameters. Rational design for the desired novel molecules was performed through protein-ligand complexes selection and ligand clustering. The microwave-assisted synthetic strategy of selected compounds was carried out by using Ullmann-Goldberg, N-propargylation, Mannich addition, Friedel-Crafts, and 1,3-dipolar cycloaddition type reactions under microwave irradiation. The microwave methodology proved to be an efficient way to obtain all novel compounds in high yields (73–93%). Furthermore, a thermochemical analysis, optimization and reactivity indexes such as electronic chemical potential (μ), chemical hardness (η), and electrophilicity (ω) were performed to understand the relationship between the structure and the energetic behavior of all the series. Then, in vitro analysis showed that compounds 27, 29–31, and 34 exhibited inhibitory activity against FXa and the corresponding half maximal inhibitory concentration (IC50) values were calculated. Next, a cell viability assay in HEK293 and HepG2 cell lines, and coagulation parameters (anti FXa, Prothrombin time (PT), activated Partial Thromboplastin Time (aPTT)) of the most active novel molecules were performed to determine the corresponding cytotoxicity and possible action on clotting pathways. The obtained results suggest that compounds 27 and 29 inhibited FXa targeting through coagulation factors in the intrinsic and extrinsic pathways. However, compound 34 may target coagulation FXa mainly by the extrinsic and common pathway. Interestingly, the most active compounds in relation to the inhibition activity against FXa and coagulation parameters did not show toxicity at the performed coagulation assay concentrations. Finally, docking studies confirmed the preferential binding mode of N-propargyltetrahydroquinoline and 1,2,3-triazole derivatives inside the active site of FXa.Fil: Santana Romo, Fabián. Pontificia Universidad Católica de Chile; ChileFil: Lagos, Carlos F.. Universidad San Sebastián; ChileFil: Duarte, Yorley. Universidad Andrés Bello; ChileFil: Castillo, Francisco. Pontificia Universidad Católica de Chile; ChileFil: Moglie, Yanina Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Bahía Blanca. Instituto de Química del Sur. Universidad Nacional del Sur. Departamento de Química. Instituto de Química del Sur; ArgentinaFil: Maestro, Miguel A.. University of A Coruña; EspañaFil: Charbe, Nitin. Pontificia Universidad Católica de Chile; ChileFil: Zacconi, Flavia Cristina Milagro. Pontificia Universidad Católica de Chile; Chil

Red de seguimiento y coordinación del Máster en Ciencia de Materiales

El Máster en Ciencia de Materiales se imparte en la Facultad de Ciencias de la Universidad de Alicante, consta de 60 créditos ECTS que se cursan durante 1 año académico. El máster está implantado desde el curso 2010-2011 por lo que durante el actual curso 2014-2015 tendremos la quinta promoción de egresados. La red docente está formada por la comisión académica del Máster en Ciencia de Materiales. Esta comisión (profesorado, alumno y personal de administración y servicios) lleva realizando un seguimiento de la titulación durante los 4 cursos anteriores. Por tanto la red tiene como objetivo principal el seguimiento, coordinación, evaluación y mejora de la planificación realizada con las experiencias recogidas a lo largo de estos años. Además, se realizará un estudio de los diferentes indicadores de calidad que utilizan las agencias de acreditación puesto que este año el Máster se someterá a la renovación de la acreditación

A novel VIVO–pyrimidinone complex: synthesis, solution speciation and human serum protein binding

The pyrimidinones mhcpe, 2-methyl-3H-5-hydroxy-6-carboxy-4-pyrimidinone ethyl ester (mhcpe, 1), 2,3- dimethyl-5-benzyloxy-6-carboxy-4-pyrimidinone ethyl ester (dbcpe, 2) and N-methyl-2,3-dimethyl-5- hydroxy-6-carboxyamido-4-pyrimidinone (N-MeHOPY, 3), are synthesized and their structures determined by single crystal X-ray diffraction. The acid–base properties of 1 are studied by potentiometric and spectrophotometric methods, the pKa values being 1.14 and 6.35. DFT calculations were carried out to determine the most stable structure for each of the H2L+, HL and L− forms (HL = mhcpe) and assign the groups involved in the protonation–deprotonation processes. The mhcpe− ligand forms stable complexes with VIVO2+ in the pH range 2 to 10, and potentiometry, EPR and UV-Vis techniques are used to identify and characterize the VIVO–mhcpe species formed. The results are consistent with the formation of VIVO, (VIVO)L, (VIVO)L2, (VIVO)2L2H−2, (VIVO)L2H−1, (VIVO)2L2H−3, (VIVO)LH−2 species and VIVO-hydrolysis products. Calculations indicate that the global binding ability of mhcpe towards VIVO2+ is similar to that of maltol (Hmaltol = 3-hydroxy-2-methyl-4H-pyran-4-one) and lower than that of 1,2-dimethyl-3-hydroxy-4- pyridinone (Hdhp). The interaction of VIVO-complexes with human plasma proteins (transferrin and albumin) is studied by circular dichroism (CD), EPR and 51V NMR spectroscopy. VIVO–mhcpe–protein ternary complexes are formed in both cases. The binding of VIVO2+ to transferrin (hTF) in the presence of mhcpe involves mainly (VIVO)1(hTF)(mhcpe)1, (VIVO)2(hTF)(mhcpe)1 and (VIVO)2(hTF)(mhcpe)2 species, bound at the FeIII binding sites, and the corresponding conditional formation constants are determined. Under the conditions expected to prevail in human blood serum, CD data indicate that the VIVO–mhcpe complexes mainly bind to hTF; the formation of VIVO–hTF–mhcpe complexes occurs in the presence of FeIII as well, distinct EPR signals being clearly obtained for FeIII–hTF and to VIVO–hTF–mhcpe species. Thus this study indicates that transferrin plays the major role in the transport of VIVO–mhcpe complexes under blood plasma conditions in the form of ternary VIV–ligand–protein complexes.The authors are grateful to the Fundo Europeu para o Desenvolvimento Regional, Fundação para a Ciência e Tecnologia (FCT), the POCI 2010 Programme, the Portuguese NMR Network (IST-UTL Center), PEst-OE/QUI/UI0100/2011, University of A Coruña and the Spanish-Portuguese Bilateral Programme (Acção Integrada E-56/05, Acción integrada HP2004- 0074)

Clinical efficacy of β-lactam/β-lactamase inhibitor combinations for the treatment of bloodstream infection due to extended-spectrum β-lactamase-producing Enterobacteriaceae in haematological patients with neutropaenia: a study protocol for a retrospective observational study (BICAR)

Introduction: Bloodstream infection (BSI) due to extended-spectrum β-lactamase-producing Gram-negative bacilli (ESBL-GNB) is increasing at an alarming pace worldwide. Although β-lactam/β-lactamase inhibitor (BLBLI) combinations have been suggested as an alternative to carbapenems for the treatment of BSI due to these resistant organisms in the general population, their usefulness for the treatment of BSI due to ESBL-GNB in haematological patients with neutropaenia is yet to be elucidated. The aim of the BICAR study is to compare the efficacy of BLBLI combinations with that of carbapenems for the treatment of BSI due to an ESBL-GNB in this population. Methods and analysis: A multinational, multicentre, observational retrospective study. Episodes of BSI due to ESBL-GNB occurring in haematological patients and haematopoietic stem cell transplant recipients with neutropaenia from 1 January 2006 to 31 March 2015 will be analysed. The primary end point will be case-fatality rate within 30 days of onset of BSI. The secondary end points will be 7-day and 14-day case-fatality rates, microbiological failure, colonisation/infection by resistant bacteria, superinfection, intensive care unit admission and development of adverse events. Sample size: The number of expected episodes of BSI due to ESBL-GNB in the participant centres will be 260 with a ratio of control to experimental participants of 2. Ethics and dissemination: The protocol of the study was approved at the first site by the Research Ethics Committee (REC) of Hospital Universitari de Bellvitge. Approval will be also sought from all relevant RECs. Any formal presentation or publication of data from this study will be considered as a joint publication by the participating investigators and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE). The study has been endorsed by the European Study Group for Bloodstream Infection and Sepsis (ESGBIS) and the European Study Group for Infections in Compromised Hosts (ESGICH)

Targeted Deficiency of the Transcriptional Activator Hnf1α Alters Subnuclear Positioning of Its Genomic Targets

DNA binding transcriptional activators play a central role in gene-selective regulation. In part, this is mediated by targeting local covalent modifications of histone tails. Transcriptional regulation has also been associated with the positioning of genes within the nucleus. We have now examined the role of a transcriptional activator in regulating the positioning of target genes. This was carried out with primary β-cells and hepatocytes freshly isolated from mice lacking Hnf1α, an activator encoded by the most frequently mutated gene in human monogenic diabetes (MODY3). We show that in Hnf1a−/− cells inactive endogenous Hnf1α-target genes exhibit increased trimethylated histone H3-Lys27 and reduced methylated H3-Lys4. Inactive Hnf1α-targets in Hnf1a−/− cells are also preferentially located in peripheral subnuclear domains enriched in trimethylated H3-Lys27, whereas active targets in wild-type cells are positioned in more central domains enriched in methylated H3-Lys4 and RNA polymerase II. We demonstrate that this differential positioning involves the decondensation of target chromatin, and show that it is spatially restricted rather than a reflection of non-specific changes in the nuclear organization of Hnf1a-deficient cells. This study, therefore, provides genetic evidence that a single transcriptional activator can influence the subnuclear location of its endogenous genomic targets in primary cells, and links activator-dependent changes in local chromatin structure to the spatial organization of the genome. We have also revealed a defect in subnuclear gene positioning in a model of a human transcription factor disease