Mercury and selenium binding biomolecules in terrestrial mammals (Cervus elaphus and Sus scrofa) from a mercury exposed area

Acknowledgements The authors are grateful to Junta de Comunidades de Castilla-La Mancha (PCC-05-004-2, PAI06-0094, PCI-08-0096, PEII09-0032-5329) and the Ministerio de Economía y Competitividad (CTQ2013-48411-P) for financial support. M.J. Patiño Ropero acknowledges the Junta de Comunidades de Castilla-La Mancha for her PhD. fellowship.Peer reviewedPostprin

Microhomology-mediated mechanisms underlie non-recurrent disease-causing microdeletions of the FOXL2 gene or its regulatory domain

Genomic disorders are often caused by recurrent copy number variations (CNVs), with nonallelic homologous recombination (NAHR) as the underlying mechanism. Recently, several microhomology-mediated repair mechanisms-such as microhomology-mediated end-joining (MMEJ), fork stalling and template switching (FoSTeS), microhomology-mediated break-induced replication (MMBIR), serial replication slippage (SRS), and break-induced SRS (BISRS)-were described in the etiology of non-recurrent CNVs in human disease. In addition, their formation may be stimulated by genomic architectural features. It is, however, largely unexplored to what extent these mechanisms contribute to rare, locus-specific pathogenic CNVs. Here, fine-mapping of 42 microdeletions of the FOXL2 locus, encompassing FOXL2 (32) or its regulatory domain (10), serves as a model for rare, locus-specific CNVs implicated in genetic disease. These deletions lead to blepharophimosis syndrome (BPES), a developmental condition affecting the eyelids and the ovary. For breakpoint mapping we used targeted array-based comparative genomic hybridization (aCGH), quantitative PCR (qPCR), long-range PCR, and Sanger sequencing of the junction products. Microhomology, ranging from 1 bp to 66 bp, was found in 91.7% of 24 characterized breakpoint junctions, being significantly enriched in comparison with a random control sample. Our results show that microhomology-mediated repair mechanisms underlie at least 50% of these microdeletions. Moreover, genomic architectural features, like sequence motifs, non-B DNA conformations, and repetitive elements, were found in all breakpoint regions. In conclusion, the majority of these microdeletions result from microhomology-mediated mechanisms like MMEJ, FoSTeS, MMBIR, SRS, or BISRS. Moreover, we hypothesize that the genomic architecture might drive their formation by increasing the susceptibility for DNA breakage or promote replication fork stalling. Finally, our locus-centered study, elucidating the etiology of a large set of rare microdeletions involved in a monogenic disorder, can serve as a model for other clustered, non-recurrent microdeletions in genetic disease

Biological Versus Chronological Aging: JACC Focus Seminar

Aging is the main risk factor for vascular disease and ensuing cardiovascular and cerebrovascular events, the leading causes of death worldwide. In a progressively aging population, it is essential to develop early-life biomarkers that efficiently identify individuals who are at high risk of developing accelerated vascular damage, with the ultimate goal of improving primary prevention and reducing the health care and socioeconomic impact of age-related cardiovascular disease. Studies in experimental models and humans have identified 9 highly interconnected hallmark processes driving mammalian aging. However, strategies to extend health span and life span require understanding of interindividual differences in age-dependent functional decline, known as biological aging. This review summarizes the current knowledge on biological age biomarkers, factors influencing biological aging, and antiaging interventions, with a focus on vascular aspects of the aging process and its cardiovascular disease related manifestations.The CNIC is supported by the MCNU, the ISCIII, and the Pro CNIC Foundation and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Work in Dr. Andrés’ laboratory is supported by the Spanish Ministerio de Ciencia, Innovación y Universidades (MCNU) (SAF2016-79490-R) and the Instituto de Salud Carlos III (ISCIII) (AC16/00091, AC17/00067, and CB16/11/00405) with cofunding from the European Regional Development Fund (ERDF/FEDER, “Una manera de hacer Europa”) and the Fundació Marató TV3 (122/C/2015). Dr. Hamczyk is supported by the MCNU (post-doctoral contract FJCI-2017-33299). Ms. Nevado is supported by the Ministerio de Educación, Cultura y Deporte (pre-doctoral contract FPU16/05027). Ms. Barettino is supported by the MCNU (pre-doctoral contract BES-2017-079705).S

Testing procedures for selection of new pinewood preservation products

In this work we compare the results of three experimental series of tests used as a first approach on selection of natural products for wood preservation

Mutations in the EXT1 and EXT2 genes in Spanish patients with multiple osteochondromas

Multiple osteochondromas is an autosomal dominant skeletal disorder characterized by the formation of multiple cartilage-capped tumours. Two causal genes have been identified, EXT1 and EXT2, which account for 65% and 30% of cases, respectively. We have undertaken a mutation analysis of the EXT1 and EXT2 genes in 39 unrelated Spanish patients, most of them with moderate phenotype, and looked for genotype-phenotype correlations. We found the mutant allele in 37 patients, 29 in EXT1 and 8 in EXT2. Five of the EXT1 mutations were deletions identified by MLPA. Two cases of mosaicism were documented. We detected a lower number of exostoses in patients with missense mutation versus other kinds of mutations. In conclusion, we found a mutation in EXT1 or in EXT2 in 95% of the Spanish patients. Eighteen of the mutations were novel.Fil: Sarrión, P.. Universidad de Barcelona; EspañaFil: Sangorrin, A.. Hospital Sant Joan de Déu; EspañaFil: Urreizti, R.. Universidad de Barcelona; EspañaFil: Delgado, María Andrea. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional de Córdoba; ArgentinaFil: Artuch, R.. Hospital Sant Joan de Déu; EspañaFil: Martorell, L.. Hospital Sant Joan de Déu; EspañaFil: Armstrong, J.. Hospital Sant Joan de Déu; EspañaFil: Anton, J.. Hospital Sant Joan de Déu; EspañaFil: Torner, F.. Hospital Sant Joan de Déu; EspañaFil: Vilaseca, M. A.. Hospital Sant Joan de Déu; EspañaFil: Nevado, J.. Hospital Universitario La Paz; EspañaFil: Lapunzina, P.. Hospital Universitario La Paz; EspañaFil: Asteggiano, Carla Gabriela. Universidad Nacional de Córdoba; Argentina. Universidad Católica de Córdoba; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Balcells, S.. Universidad de Barcelona; EspañaFil: Grinberg, D.. Universidad de Barcelona; Españ

Phenotype-loci associations in networks of patients with rare disorders: application to assist in the diagnosis of novel clinical cases

Copy number variations (CNVs) are genomic structural variations (deletions, duplications, or translocations) that represent the 4.8–9.5% of human genome variation in healthy individuals. In some cases, CNVs can also lead to disease, being the etiology of many known rare genetic/genomic disorders. Despite the last advances in genomic sequencing and diagnosis, the pathological effects of many rare genetic variations remain unresolved, largely due to the low number of patients available for these cases, making it difficult to identify consistent patterns of genotype–phenotype relationships. We aimed to improve the identification of statistically consistent genotype–phenotype relationships by integrating all the genetic and clinical data of thousands of patients with rare genomic disorders (obtained from the DECIPHER database) into a phenotype–patient–genotype tripartite network. Then we assessed how our network approach could help in the characterization and diagnosis of novel cases in clinical genetics. The systematic approach implemented in this work is able to better define the relationships between phenotypes and specific loci, by exploiting large-scale association networks of phenotypes and genotypes in thousands of rare disease patients. The application of the described methodology facilitated the diagnosis of novel clinical cases, ranking phenotypes by locus specificity and reporting putative new clinical features that may suggest additional clinical follow-ups. In this work, the proof of concept developed over a set of novel clinical cases demonstrates that this network-based methodology might help improve the precision of patient clinical records and the characterization of rare syndromes

Characterization of surface layers in Zn-diffused LiNbO3 waveguides by heavy ion elastic recoil detection

Copyright (2002) American Institute of Physics. This article may be downloaded for personal use only. Any other use requires prior permission of the author and the American Institute of Physics. The following article appeared in Applied Physics Letters 81.11 (2002): 1981-1983 and may be found at http://apl.aip.org

Quantifying the complexities of Saccharomyces cerevisiae's ecosystem engineering via fermentation

The theory of niche construction suggests that organisms may engineer environments via their activities. Despite the potential of this phenomenon being realized by Darwin, the capability of niche construction to generally unite ecological and evolutionary biology has never been empirically quantified. Here I quantify the fitness effects of Saccharomyces cerevisiae's ecosystem engineering in a natural ferment in order to understand the interaction between ecological and evolutionary processes. 1 show that S. cerevisiae eventually dominates in fruit niches, where it is naturally initially rare, by modifying the environment through fermentation (the Crabtree effect) in ways which extend beyond just considering ethanol production. These data show that an additional cause of S. cerevisiae's competitive advantage over the other yeasts in the community is due to the production of heat via fermentation. Even though fermentation is less energetically efficient than respiration, it seems that this trait has been selected for because its net effect provides roughly a 7% fitness advantage over the other members of the community. These data provide an elegant example of niche construction because this trait clearly modifies the environment and therefore the selection pressures to which S. cerevisiae, and other organisms that access the fruit resource, including humans, are exposed to. © 2008 by the Ecological Society of America

Identifying predictors of suicide in severe mental illness : a feasibility study of a clinical prediction rule (Oxford Mental Illness and Suicide tool or OxMIS)

Background: Oxford Mental Illness and Suicide tool (OxMIS) is a brief, scalable, freely available, structured risk assessment tool to assess suicide risk in patients with severe mental illness (schizophrenia-spectrum disorders or bipolar disorder). OxMIS requires further external validation, but a lack of large-scale cohorts with relevant variables makes this challenging. Electronic health records provide possible data sources for external validation of risk prediction tools. However, they contain large amounts of information within free-text that is not readily extractable. In this study, we examined the feasibility of identifying suicide predictors needed to validate OxMIS in routinely collected electronic health records. Methods: In study 1, we manually reviewed electronic health records of 57 patients with severe mental illness to calculate OxMIS risk scores. In study 2, we examined the feasibility of using natural language processing to scale up this process. We used anonymized free-text documents from the Clinical Record Interactive Search database to train a named entity recognition model, a machine learning technique which recognizes concepts in free-text. The model identified eight concepts relevant for suicide risk assessment: medication (antidepressant/antipsychotic treatment), violence, education, self-harm, benefits receipt, drug/alcohol use disorder, suicide, and psychiatric admission. We assessed model performance in terms of precision (similar to positive predictive value), recall (similar to sensitivity) and F1 statistic (an overall performance measure). Results: In study 1, we estimated suicide risk for all patients using the OxMIS calculator, giving a range of 12 month risk estimates from 0.1-3.4%. For 13 out of 17 predictors, there was no missing information in electronic health records. For the remaining 4 predictors missingness ranged from 7-26%; to account for these missing variables, it was possible for OxMIS to estimate suicide risk using a range of scores. In study 2, the named entity recognition model had an overall precision of 0.77, recall of 0.90 and F1 score of 0.83. The concept with the best precision and recall was medication (precision 0.84, recall 0.96) and the weakest were suicide (precision 0.37), and drug/alcohol use disorder (recall 0.61). Conclusions: It is feasible to estimate suicide risk with the OxMIS tool using predictors identified in routine clinical records. Predictors could be extracted using natural language processing. However, electronic health records differ from other data sources, particularly for family history variables, which creates methodological challenges