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Calahorro A.J.,University of Granada | Penas-Sanjuan A.,University of Jaen | Melguizo M.,University of Jaen | Fairen-Jimenez D.,Northwestern University | And 4 more authors.
Inorganic Chemistry | Year: 2013

We report the synthesis of a novel ligand, 3,3′-(1,2,4,5-tetrazine-3, 6-diyl)dibenzoic acid (1). In this fragment, we have introduced two carboxylate groups with the aim of using this ligand as a linker to construct three-dimensional metal-organic frameworks (MOFs). We have been successful in the formation of zinc (2) and lanthanum (3) MOFs. The zinc compound is a two-dimensional structure, while the lanthanum material is a three-dimensional MOF with interesting channels. We include the luminescence and adsorption studies of these materials. Moreover, we have evaluated the in vitro toxicity of this novel ligand, concluding that it can be considered negligible. © 2013 American Chemical Society. Source


Fernandez-Orgiler A.,CSIC - Biological Research Center | Alonso A.,CSIC - Biological Research Center | Alcolea P.J.,CSIC - Biological Research Center | Thomas M.C.,Institute Parasitologia y Biomedicina Lopez Neyra CSIC | Larraga V.,CSIC - Biological Research Center
Nucleic Acids Research | Year: 2016

Leishmania infantum is a protozoan parasite that is phagocytized by human macrophages. The host macrophages kill the parasite by generating oxidative compounds that induce DNA damage. We have identified, purified and biochemically characterized a DNA polymerase θ from L. infantum (LiPolθ), demonstrating that it is a DNA-dependent DNA polymerase involved in translesion synthesis of 8oxoG, abasic sites and thymine glycol lesions. Stably transfected L. infantum parasites expressing LiPolθ were significantly more resistant to oxidative and interstrand cross-linking agents, e.g. hydrogen peroxide, cisplatin and mitomycin C. Moreover, LiPolθ-overexpressing parasites showed an increased infectivity toward its natural macrophage host. Therefore, we propose that LiPolθ is a translesion synthesis polymerase involved in parasite DNA damage tolerance, to confer resistance against macrophage aggression. © 2016 The Author(s). Source


Garcia-Montojo M.,Institute Investigacion Sanitaria Del Hospital Clinico San Carlos | de la Hera B.,Institute Investigacion Sanitaria Del Hospital Clinico San Carlos | Varade J.,Institute Investigacion Sanitaria Del Hospital Clinico San Carlos | de la Encarnacion A.,Institute Investigacion Sanitaria Del Hospital Clinico San Carlos | And 13 more authors.
Retrovirology | Year: 2014

Background: Multiple Sclerosis (MS) is an autoimmune demyelinating disease that occurs more frequently in women than in men. Multiple Sclerosis Associated Retrovirus (MSRV) is a member of HERV-W, a multicopy human endogenous retroviral family repeatedly implicated in MS pathogenesis. MSRV envelope protein is elevated in the serum of MS patients and induces inflammation and demyelination but, in spite of this pathogenic potential, its exact genomic origin and mechanism of generation are unknown. A possible link between the HERV-W copy on chromosome Xq22.3, that contains an almost complete open reading frame, and the gender differential prevalence in MS has been suggested.Results: MSRV transcription levels were higher in MS patients than in controls (U-Mann-Whitney; p = 0.004). Also, they were associated with the clinical forms (Spearman; p = 0.0003) and with the Multiple Sclerosis Severity Score (MSSS) (Spearman; p = 0.016). By mapping a 3 kb region in Xq22.3, including the HERV-W locus, we identified three polymorphisms: rs6622139 (T/C), rs6622140 (G/A) and rs1290413 (G/A). After genotyping 3127 individuals (1669 patients and 1458 controls) from two different Spanish cohorts, we found that in women rs6622139 T/C was associated with MS susceptibility: [χ2; p = 0.004; OR (95% CI) = 0.50 (0.31-0.81)] and severity, since CC women presented lower MSSS scores than CT (U-Mann-Whitney; p = 0.039) or TT patients (U-Mann-Whitney; p = 0.031). Concordantly with the susceptibility conferred in women, rs6622139*T was associated with higher MSRV expression (U-Mann-Whitney; p = 0.003).Conclusions: Our present work supports the hypothesis of a direct involvement of HERV-W/MSRV in MS pathogenesis, identifying a genetic marker on chromosome X that could be one of the causes underlying the gender differences in MS. © 2014 García-Montojo et al.; licensee BioMed Central Ltd. Source


Risso V.A.,University of Granada | Manssour-Triedo F.,University of Granada | Delgado-Delgado A.,University of Granada | Arco R.,University of Granada | And 7 more authors.
Molecular Biology and Evolution | Year: 2014

Local protein interactions ("molecular context" effects) dictate amino acid replacements and can be described in terms of site-specific, energetic preferences for any different amino acid. It has been recently debated whether these preferences remain approximately constant during evolution or whether, due to coevolution of sites, they change strongly. Such research highlights an unresolved and fundamental issue with far-reaching implications for phylogenetic analysis and molecular evolution modeling. Here, we take advantage of the recent availability of phenotypically supported laboratory resurrections of Precambrian thioredoxins and β-lactamases to experimentally address the change of site-specific amino acid preferences over long geological timescales. Extensive mutational analyses support the notion that evolutionary adjustment to a new amino acid may occur, but to a large extent this is insufficient to erase the primitive preference for amino acid replacements. Generally, site-specific amino acid preferences appear to remain conserved throughout evolutionary history despite local sequence divergence. We show such preference conservation to be readily understandable in molecular terms and we provide crystallographic evidence for an intriguing structural-switch mechanism: Energetic preference for an ancestral amino acid in a modern protein can be linked to reorganization upon mutation to the ancestral local structure around the mutated site. Finally, we point out that site-specific preference conservation naturally leads to one plausible evolutionary explanation for the existence of intragenic global suppressor mutations. © The Author 2014. Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution. Source


Roberts R.L.,University of Otago | Diaz-Gallo L.-M.,Institute Parasitologia y Biomedicina Lopez Neyra CSIC | Barclay M.L.,University of Otago | Gomez-Garcia M.,Hospital Virgen de Las Nieves | And 4 more authors.
Inflammatory Bowel Diseases | Year: 2012

Background: A recent genome-wide association study (GWAS) of copy number variants (CNVs) in Crohn's disease (CD) confirmed association of three CNVs. The GWAS also provided evidence that a fourth CNV, CNVR7113.6, on chromosome 17 may alter susceptibility to CD (P = 0.0018). The aim of our study was to confirm the CNVR7113.6 association by genotyping two independent inflammatory bowel disease (IBD) cohorts and by conducting a subsequent meta-analysis. Methods: In all, 1369 New Zealand Caucasians (489 CD patients, 463 ulcerative colitis [UC] patients, and 417 controls) and 2737 Spanish Caucasians (711 CD patients, 549 UC patients, and 1477 controls) were genotyped for a single nucleotide polymorphism (SNP), rs413778, in high linkage disequilibrium (r 2 = >0.99) with CNVR7113.6. Chi-square analysis was conducted to test for association of rs413778 with overall CD, UC, IBD, and with disease phenotype. New Zealand and Spanish genotypes were then combined with imputed rs413778 genotypes from the Wellcome Trust Case Control Consortium (WTCCC) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) CD datasets to conduct a meta-analysis. Results: The minor allele of rs413778 conferred protection against CD in the Spanish cohort (CD: P = 0.004, odds ratio [OR] = 0.82, 95% confidence interval [CI]: 0.71-0.94). A similar, albeit nonsignificant protective effect was observed in New Zealand CD patients (P = 0.098, OR = 0.83, 95% CI: 0.66-1.04). No association with UC or disease phenotypes was detected in either cohort. Meta-analysis found significant cumulative evidence for a protective effect of rs413778 in Caucasian CD (P = 1.19E-05, OR = 0.86, 95% CI: 0.80-0.92). Conclusions: This study provides the first independent replication of the association of CNVR7113.6 with CD. Copyright © 2011 Crohn's & Colitis Foundation of America, Inc. Source

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