An integrated study of molecular, cellular, tissue level and transgenerational effects of silver nanoparticles on dietarily exposed mussels at different seasons.

266 p.Las nanopartículas de plata (NPs de Ag) se encuentran en numerosos productos de consumo debido a sus propiedades antimicrobianas así como a otras propiedades únicas que presentan. Por ello, la preocupación acerca de su entrada en los ecosistemas acuáticos está creciendo. La toxicidad de las NPs de Ag ya se está estudiando en organismos acuáticos, sin embargo, apenas hay estudios que evalúen su posible toxicidad tras la ingestión a través de la dieta, especialmente a concentraciones ambientalmente relevantes. Además. la posibilidad de que estos efectos difieran dependiendo de la estación del año sigue siendo desconocida. Por tanto, el objetivo de la presente tesis doctoral ha sido ampliar el conocimiento sobre las respuestas a nivel molecular, celular y tisular, así como los efectos tr ansgeneracionales causados por las NPs de Ag inger idas a través de la dieta y a dosis cercanas a concentraciones ambientalmente relevantes en los mejillones de Mytilus galloprovincialis expuestos en dos estaciones del año diferentes (otoño y primavera). En general, considerando todas las respuestas medidas en los diferentes niveles de organización biológica tanto en otoño como en primavera, los efectos observados en los mejillones dependieron del tiempo de exposición, la concentración de NPs de Ag y la estación del año. Por lo tanto, para futuros estudios, la estación del año es un factor que debe ser considerado a la hora de evaluar los posibles efectos de NPs manufacturadas en bivalvos marinos. especialmente en hembras y especialmente en estudios a nivel de transcripción génica y expresión proteica

An integrated study of molecular, cellular, tissue level and transgenerational effects of silver nanoparticles on dietarily exposed mussels at different seasons.

266 p.Las nanopartículas de plata (NPs de Ag) se encuentran en numerosos productos de consumo debido a sus propiedades antimicrobianas así como a otras propiedades únicas que presentan. Por ello, la preocupación acerca de su entrada en los ecosistemas acuáticos está creciendo. La toxicidad de las NPs de Ag ya se está estudiando en organismos acuáticos, sin embargo, apenas hay estudios que evalúen su posible toxicidad tras la ingestión a través de la dieta, especialmente a concentraciones ambientalmente relevantes. Además. la posibilidad de que estos efectos difieran dependiendo de la estación del año sigue siendo desconocida. Por tanto, el objetivo de la presente tesis doctoral ha sido ampliar el conocimiento sobre las respuestas a nivel molecular, celular y tisular, así como los efectos tr ansgeneracionales causados por las NPs de Ag inger idas a través de la dieta y a dosis cercanas a concentraciones ambientalmente relevantes en los mejillones de Mytilus galloprovincialis expuestos en dos estaciones del año diferentes (otoño y primavera). En general, considerando todas las respuestas medidas en los diferentes niveles de organización biológica tanto en otoño como en primavera, los efectos observados en los mejillones dependieron del tiempo de exposición, la concentración de NPs de Ag y la estación del año. Por lo tanto, para futuros estudios, la estación del año es un factor que debe ser considerado a la hora de evaluar los posibles efectos de NPs manufacturadas en bivalvos marinos. especialmente en hembras y especialmente en estudios a nivel de transcripción génica y expresión proteica

Cell and tissue level responses in mussels Mytilus galloprovincialis dietarily exposed to PVP/PEI coated Ag nanoparticles at two seasons

Silver nanoparticles (Ag NPs) are present in numerous consumer products due to their antimicrobial and other unique properties, thus concerns about their potential input into aquatic ecosystems are increasing. Toxicity of Ag NPs in waterborne exposed aquatic organisms has been widely investigated, but studies assessing the potential toxic effects caused after ingestion through the food web, especially at low realistic concentrations, remain scarce. Moreover, it is not well known whether season may influence toxic effects of Ag NPs. The main objective of this study was to determine cell and tissue level responses in mussels Mytilus galloprovincialis dietarily exposed to poly-N-vinyl-2-pirrolidone/polyethyleneimine (PVP/PEI) coated 5 nm Ag NPs for 1, 7 and 21 days both in autumn and spring. Mussels were fed every day with microalgae Isochrysis galbana exposed for 24 h to a low dose (1 mu g Ag/L Ag NPs) in spring and to a higher dose (10 mu g Ag/L Ag NPs) in spring and autumn. Mussels fed with microalgae exposed to the high dose accumulated Ag significantly after 21 days in both seasons, higher levels being measured in autumn compared to spring. Intralysosomal metal accumulation measured in mussel digestive gland and time- and dose-dependent reduction of mussels health status was similar in both seasons. DNA strand breaks increased significantly in hemocytes at both exposure doses along the 21 days in spring and micronuclei frequency showed an increasing trend after 1 and 7 days of exposure to 1 mu g Ag/L Ag NPs in spring and to 10 mu g Ag/L in both seasons. Values decreased after 21 days of exposure in all the cases. In conclusion, PVP/PEI coated 5 nm Ag NPs ingested through the food web were significantly accumulated in mussel tissues and caused adverse cell and tissue level effects both in autumn and in spring.This work has been funded by the Spanish Ministry of Economy and Competitiveness (Nano Silver Omics project MAT2012-39372), Basque Government (SAIOTEK project S-PE13UN142 and Consolidated Research Group GIC IT810-13 and IT1302-19), the University of the Basque Country UPV/EHU (UFI 11/37 and PhD fellowship to N.D.) and French Ministry of Higher Education and Research (PhD fellowship to M.M.)

Knockout of 5-Lipoxygenase Results in Age-Dependent Anxiety-Like Behavior in Female Mice

The enzyme 5-lipoxygenase (5LO) has been implicated in a variety of neurological and psychiatric disorders including anxiety. Knockout of 5LO has previously been shown to alter anxiety-like behavior in mice at a young age but the effect of 5LO knockout on older animals has not been characterized.Here we used the elevated plus maze behavioral paradigm to measure anxiety-like behavior in female mice lacking 5LO (5LO-KO) at three different ages. Adolescent 5LO-KO animals did not significantly differ from wild-type (WT) animals in anxiety-like behavior. However, adult and older mice exhibited increased anxiety-like behavior compared to WT controls.These results indicate that 5LO plays a role in the development of the anxiety-like phenotype in an age-dependent manner in female mice. Future work should further investigate this interaction as 5LO may prove to be an important molecular target for the development of novel anxiolytic therapies

Changes in protein expression in mussels Mytilus galloprovincialis dietarily exposed to PVP/PEI coated silver nanoparticles at different seasons

Potential toxic effects of Ag NPs ingested through the food web and depending on the season have not been addressed in marine bivalves. This work aimed to assess differences in protein expression in the digestive gland of female mussels after dietary exposure to Ag NPs in autumn and spring. Mussels were fed daily with microalgae previously exposed for 24 hours to 10 µg/L of PVP/PEI coated 5 nm Ag NPs. After 21 days, mussels significantly accumulated Ag in both seasons and Ag NPs were found within digestive gland cells and gills. Two-dimensional electrophoresis distinguished 104 differentially expressed protein spots in autumn and 142 in spring. Among them, chitinase like protein-3, partial and glyceraldehyde-3-phosphate dehydrogenase, that are involved in amino sugar and nucleotide sugar metabolism, carbon metabolism, glycolysis/gluconeogenesis and the biosynthesis of amino acids KEGG pathways, were overexpressed in autumn but underexpressed in spring. In autumn, pyruvate metabolism, citrate cycle, cysteine and methionine metabolism and glyoxylate and dicarboxylate metabolism were altered, while in spring, proteins related to the formation of phagosomes and hydrogen peroxide metabolism were differentially expressed. Overall, protein expression signatures depended on season and Ag NPs exposure, suggesting that season significantly influences responses of mussels to NP exposure.This work has been funded by the Spanish Ministry of Economy and Competitiveness (NanoSilverOmics project MAT2012-39372), Basque Government (SAIOTEK project S-PE13UN142 and Consolidated Research Group GIC IT810-13) and the University of the Basque Country UPV/EHU (UFI 11/37 and PhD fellowship to N.D.). This study had also the support of Fundação para a Ciência e Tecnologia (FCT) from Portugal through the Strategic Project UID/MAH00350/2013 granted to CIMA. The contribution of K. Mehennaoui was possible within the project NanoGAM (AFR-PhD-9229040) and M. Mikolaczyk was supported by a PhD fellowship from the French Ministry of Higher Education and Research.info:eu-repo/semantics/acceptedVersio

Genetic basis for personalized medicine in asthma

There is heterogeneity in patient responses to current asthma medications. Significant progress has been made identifying genetic polymorphisms that influence the efficacy and potential for adverse effects to asthma drugs, including; β2-adrenergic receptor agonists, corticosteroids and leukotriene modifiers. Pharmacogenetics holds great promise to maximise clinical outcomes and minimize adverse effects. Asthma is heterogeneous with respect to clinical presentation and inflammatory mechanisms underlying the disease, which is likely to contribute to variable results in clinical trials targeting specific inflammatory mediators. Genome-wide association studies have begun to identify genes underlying asthma (e.g., IL1RL1), which represent future therapeutic targets. In this article, we review and update the pharmacogenetics of current asthma therapies and discuss the genetics underlying selected Phase II and future targets

The role of ALOX5AP, LTA4H and LTB4R polymorphisms in determining baseline lung function and COPD susceptibility in UK smokers

<p>Abstract</p> <p>Background</p> <p>We have previously shown evidence that polymorphisms within genes controlling leukotriene B₄(LTB₄) production (<it>ALOX5AP </it>and <it>LTA4H</it>) are associated with asthma susceptibility in children. Evidence also suggests a potential role of LTB₄in COPD disease mechanisms including recruitment of neutrophils to the lung. The aim of the current study was to see if these SNPs and those spanning the receptor genes for LTB₄(<it>LTB4R1 </it>and <it>LTB4R2</it>) influence baseline lung function and COPD susceptibility/severity in smokers.</p> <p>Methods</p> <p>Eight <it>ALOX5AP</it>, six <it>LTA4H </it>and six <it>LTB4R </it>single nucleotide polymorphisms (SNPs) were genotyped in a UK Smoking Cohort (n = 992). Association with baseline lung function (FEV₁and FEV₁/FVC ratio) was determined by linear regression. Logistic regression was used to compare smoking controls (n = 176) with spirometry-defined COPD cases (n = 599) and to more severe COPD cases (GOLD stage 3 and 4, n = 389).</p> <p>Results</p> <p>No association with <it>ALOX5AP</it>, <it>LTA4H </it>or <it>LTB4R </it>survived correction for multiple testing. However, we showed modest association with <it>LTA4H </it>rs1978331C (intron 11) with increased FEV₁(p = 0.029) and with increased FEV₁/FVC ratio (p = 0.020).</p> <p>Conclusions</p> <p>These data suggest that polymorphisms spanning <it>ALOX5AP</it>, <it>LTA4H </it>and the <it>LTB4R </it>locus are not major determinants of baseline lung function in smokers, but provide tentative evidence for <it>LTA4H </it>rs1978331C (intron 11) in determining baseline FEV₁and FEV₁/FVC ratio in Caucasian Smokers in addition to our previously identified role in asthma susceptibility.</p

Segregations and discontinuities in the U.S. intermediate cities

Cette thèse analyse la ségrégation dans les villes intermédiaires des États-Unis, souvent laissées dans l’ombre d’un discours dominant sur les grandes métropoles, mais pour lesquelles on fait l’hypothèse que la moindre taille est à même de changer l’intensité et les configurations de la division sociale de l’espace. L’analyse repose d’abord sur une procédure de définition opératoire selon des critères de taille et de fonctions permettant d’identifier 29 villes intermédiaires. La ségrégation de ces villes est mesurée à partir des indices classiques de ségrégation, et discutant les effets de la ségrégation dans ces villes en fonction des structurations hiérarchique et régionale dont les analyses montrent des effets emboîtés. L’approche privilégiée, en analyse spatiale, se fonde ensuite sur la notion de discontinuité, pour capturer les formes géographiques fines de la ségrégation sociale. Les discontinuités sont définies comme une forte différenciation à l’échelle locale du voisinage et mesurées par la dissemblance entre les block groups contigus. Sur les terrains principaux et comparés de Raleigh (NC) et de Seattle (WA), l’analyse porte sur les discontinuités structurelles et systémiques qui émergent pour plusieurs dimensions sociales importantes dans le contexte états-unien (appartenance ethno-raciale, âge, éducation, revenus) et pour trois décennies entre 1980 et 2010, à partir de données harmonisées. Au final, la thèse renouvelle le regard sur les débats de mesures de la ségrégation, sur les approches théoriques et méthodologiques des morphologies urbaines, tout en éclairant les modèles métropolitains et les mécanismes ségrégatifs.While segregation has been mainly described in major cities, this dissertation investigates intermediate cities in the United States. It elaborates on the following hypothesis: intermediate cities, smaller in size and sprawl, yield less intense but distinctive spatial patterns of segregation. The analysis eloborates on a theoretical and methodological approach that combines size and functionnal criteria to subset 29 intermediate cities in the U.S. Segregation indices are analyzed within this set of cities, and discussed, so as to characterize the similarities between cities, and to examine the hierarchical and regional embedded effects explaining the differences. Elaborating on the notion of discontinuity in spatial analysis, the thesis then aims at better mapping segregation at the intra-urban level. Discontinuites are defined as being significant dissimilarities at the local neighborhood level and measured by a social distance index between contiguous neighborhoods (block groups). Focusing on the notion of structural and systemic discontinuities, that combine the permutation between major social dimensions in american cities (race & ethnicity, age, education and income), the analysis captures spatial patterns, and by doing so compare two contextualized case studies, Raleigh (NC) and Seattle (WA). By the means of harmonized datasets, the study further analyzes the dynamics of segregation and discontinuities between 1980 and 2010. The discussions of results highlight a renewed approach on segregation measures, theoretical and methodological approaches of spatial patterns, and do so by discussing metropolitan models and segregative mechanisms