Three Leptospira Strains From Western Indian Ocean Wildlife Show Highly Distinct Virulence Phenotypes Through Hamster Experimental Infection

Leptospirosis is one of the most widespread zoonoses worldwide, with highest incidence reported on tropical islands. Recent investigations carried out in a One-Health framework have revealed a wide diversity of pathogenic Leptospira lineages on the different islands of Western Indian Ocean carried out by a large diversity of mammal reservoirs, including domestic and wild fauna. Using golden Syrian hamsters as a model of acute infection, we studied the virulence of Leptospira interrogans, L. mayottensis, and L. borgpetersenii isolates obtained from rats, tenrecs, and bats, respectively. Hamsters were inoculated with 2.108 bacterial cells and monitored for 1 month. The L. interrogans isolate proved to be the most pathogenic while L. mayottensis and L. borgpetersenii isolates induced no clinical symptoms in the infected hamsters. High leptospiral DNA amounts were also detected in the urine and organs of hamsters infected with the L. interrogans isolate while L. mayottensis and L. borgpetersenii isolates mostly failed to disseminate into the organism. In addition, histological damage was more pronounced in the kidneys and lungs of hamsters infected with the L. interrogans isolate. Altogether, these data support that Leptospira strains shed by mammals endemic to this insular ecosystem (L. mayottensis and L. borgpetersenii isolates) are less pathogenic than the L. interrogans rat-borne isolate. These results may provide a relevant framework for understanding the contrasting epidemiology of human leptospirosis observed among Western Indian Ocean islands

“El Sexo no es Malo”: Maternal Values Accompanying Contraceptive Use Advice to Young Latina Adolescent Daughters

In this study, we utilized observational methods to identify maternal values and concerns accompanying contraceptive use advice in Latina mother–daughter sexuality conversations. The sample included non-sexually active early adolescents around 12 years of age and their mostly Spanish-speaking Latina mothers. Videotaped conversations were coded for the prevalence of messages related to four sexual values (abstinence, delay sex until older, sex is “normal”, sex is “improper”) and concerns about pregnancy and STD transmission. We examined whether the duration of time spent conversing about these messages was associated with participant characteristics, general communication openness, and the amount of time the dyads spent discussing contraceptive use. Results indicated that Latina mothers who had fewer years of education and lower family income talked longer to their daughters about the need to delay sex, avoid risky situations that would increase their chances of getting pregnant or acquiring an STD, and engage in self-protective practices. Less perceived openness in general communication as reported by both the mothers and the daughters was associated with increased time discussing that sex is improper. Although the duration of contraceptive use messages was brief, mothers and daughters who discussed the fact that sex is normal, and who communicated more about the importance of delaying sex, talked longer about contraceptive use practices compared to mothers and daughters who engaged in minimal discussion of these sexual values

Repurposing of Drugs as Novel Influenza Inhibitors From Clinical Gene Expression Infection Signatures

Influenza virus infections remain a major and recurrent public health burden. The intrinsic ever-evolving nature of this virus, the suboptimal efficacy of current influenza inactivated vaccines, as well as the emergence of resistance against a limited antiviral arsenal, highlight the critical need for novel therapeutic approaches. In this context, the aim of this study was to develop and validate an innovative strategy for drug repurposing as host-targeted inhibitors of influenza viruses and the rapid evaluation of the most promising candidates in Phase II clinical trials. We exploited in vivo global transcriptomic signatures of infection directly obtained from a patient cohort to determine a shortlist of already marketed drugs with newly identified, host-targeted inhibitory properties against influenza virus. The antiviral potential of selected repurposing candidates was further evaluated in vitro, in vivo, and ex vivo. Our strategy allowed the selection of a shortlist of 35 high potential candidates out of a rationalized computational screening of 1,309 FDA-approved bioactive molecules, 31 of which were validated for their significant in vitro antiviral activity. Our in vivo and ex vivo results highlight diltiazem, a calcium channel blocker currently used in the treatment of hypertension, as a promising option for the treatment of influenza infections. Additionally, transcriptomic signature analysis further revealed the so far undescribed capacity of diltiazem to modulate the expression of specific genes related to the host antiviral response and cholesterol metabolism. Finally, combination treatment with diltiazem and virus-targeted oseltamivir neuraminidase inhibitor further increased antiviral efficacy, prompting rapid authorization for the initiation of a Phase II clinical trial. This original, host-targeted, drug repurposing strategy constitutes an effective and highly reactive process for the rapid identification of novel anti-infectious drugs, with potential major implications for the management of antimicrobial resistance and the rapid response to future epidemic or pandemic (re)emerging diseases for which we are still disarmed

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of diseas

Genetic effects on gene expression across human tissues

Characterization of the molecular function of the human genome and its variation across individuals is essential for identifying the cellular mechanisms that underlie human genetic traits and diseases. The Genotype-Tissue Expression (GTEx) project aims to characterize variation in gene expression levels across individuals and diverse tissues of the human body, many of which are not easily accessible. Here we describe genetic effects on gene expression levels across 44 human tissues. We find that local genetic variation affects gene expression levels for the majority of genes, and we further identify inter-chromosomal genetic effects for 93 genes and 112 loci. On the basis of the identified genetic effects, we characterize patterns of tissue specificity, compare local and distal effects, and evaluate the functional properties of the genetic effects. We also demonstrate that multi-tissue, multi-individual data can be used to identify genes and pathways affected by human disease-associated variation, enabling a mechanistic interpretation of gene regulation and the genetic basis of disease

Genomics and epigenomics integrative analysis of prolactin pituitary tumors

De nombreux modèles ont été proposés pour expliquer les mécanismes de développement et de progression tumorale, néanmoins certains aspects comme la nature et la hiérarchie des altérations primaires et secondaires sont encore discutés. Pour répondre à ces questions, nous nous sommes intéressés à la progression tumorale des tumeurs hypophysaires à prolactine humaines. Ces tumeurs d'origine monoclonale sont souvent bénignes mais certaines présentent un phénotype agressif voire malin. Afin d'identifier les mécanismes impliqués dans la progression vers le phénotype agressif nous avons utilisé des techniques de génomique intégrative (puces à ADN, séquençage haut débit) couplant l'étude du transcriptome, du génome (variation du nombre de copie chromosomique, polymorphismes) et du miRNome à partir des mêmes échantillons tumoraux. Par cette stratégie nous avons identifié et hierarchisé des altérations spécifiques des tumeurs agressives et / ou malignes dans un modèle expliquant la progression tumorale des tumeurs hypophysaires à prolactine humaines. Nous avons montré que la sous-expression des microARNs miR-183, miR-744 et miR-98 stimule la prolifération via la surexpression de leurs cibles KIAA0101, TGFB1 et E2F2 spécifiquement dans les tumeurs agressives. Ceci entraine l'acquisition d'altérations chromosomiques (perte du chromosome 11 et le gain du chromosome 1q) permettant l'activation de la dissémination métastatique. Enfin, ce travail montre que l'approche de génomique intégrative multidimensionnelle permet d'apporter de nouveaux éléments pour la caractérisation des phénotypes tumoraux, le diagnostic des tumeurs agressives et la prédiction du comportement tumoralNumerous models have been proposed to explain the mechanisms of tumor development and progression. Nevertheless some aspects such as the nature and hierarchy of primary and secondary alterations are still debated. To answer these questions, we decided to focus on the tumoral progression of human prolactin pituitary tumors. These monoclonal tumors are usually benign but some present an aggressive or malignant phenotype. To identify the molecular events involved in tumoral progression of human PRL towards aggressive phenotype we used an integrative genomics approach (microarrays, high-throughput sequencing) coupling analysis of transcriptome, genome (variation in the number of chromosomal copy polymorphisms) and miRNome from the same human tumor. Using this strategy we identified and prioritized specific alterations of aggressive and / or malignant tumors in a model explaining the tumor progression of human prolactin pituitary tumors. We have shown that under-expression of micro-RNA miR-183, miR-744 and miR-98 stimulates proliferation through overexpression of their targets KIAA0101, TGFB1 and E2F2 specifically in aggressive tumors. This leads to the acquisition of chromosomal damage (loss of chromosome 11 and gain of chromosome 1q) which allowed the activation of the metastatic processes. Finally, this work shows that the integrative genomic multi-dimensional approach can provide new clues for the characterization of tumor phenotypes, diagnosis of aggressive tumors and prediction of tumor behavio

Analyse intégrative génomique et épigénomique de tumeurs hypophysaires à prolactine

Numerous models have been proposed to explain the mechanisms of tumor development and progression. Nevertheless some aspects such as the nature and hierarchy of primary and secondary alterations are still debated. To answer these questions, we decided to focus on the tumoral progression of human prolactin pituitary tumors. These monoclonal tumors are usually benign but some present an aggressive or malignant phenotype. To identify the molecular events involved in tumoral progression of human PRL towards aggressive phenotype we used an integrative genomics approach (microarrays, high-throughput sequencing) coupling analysis of transcriptome, genome (variation in the number of chromosomal copy polymorphisms) and miRNome from the same human tumor. Using this strategy we identified and prioritized specific alterations of aggressive and / or malignant tumors in a model explaining the tumor progression of human prolactin pituitary tumors. We have shown that under-expression of micro-RNA miR-183, miR-744 and miR-98 stimulates proliferation through overexpression of their targets KIAA0101, TGFB1 and E2F2 specifically in aggressive tumors. This leads to the acquisition of chromosomal damage (loss of chromosome 11 and gain of chromosome 1q) which allowed the activation of the metastatic processes. Finally, this work shows that the integrative genomic multi-dimensional approach can provide new clues for the characterization of tumor phenotypes, diagnosis of aggressive tumors and prediction of tumor behaviorDe nombreux modèles ont été proposés pour expliquer les mécanismes de développement et de progression tumorale, néanmoins certains aspects comme la nature et la hiérarchie des altérations primaires et secondaires sont encore discutés. Pour répondre à ces questions, nous nous sommes intéressés à la progression tumorale des tumeurs hypophysaires à prolactine humaines. Ces tumeurs d'origine monoclonale sont souvent bénignes mais certaines présentent un phénotype agressif voire malin. Afin d'identifier les mécanismes impliqués dans la progression vers le phénotype agressif nous avons utilisé des techniques de génomique intégrative (puces à ADN, séquençage haut débit) couplant l'étude du transcriptome, du génome (variation du nombre de copie chromosomique, polymorphismes) et du miRNome à partir des mêmes échantillons tumoraux. Par cette stratégie nous avons identifié et hierarchisé des altérations spécifiques des tumeurs agressives et / ou malignes dans un modèle expliquant la progression tumorale des tumeurs hypophysaires à prolactine humaines. Nous avons montré que la sous-expression des microARNs miR-183, miR-744 et miR-98 stimule la prolifération via la surexpression de leurs cibles KIAA0101, TGFB1 et E2F2 spécifiquement dans les tumeurs agressives. Ceci entraine l'acquisition d'altérations chromosomiques (perte du chromosome 11 et le gain du chromosome 1q) permettant l'activation de la dissémination métastatique. Enfin, ce travail montre que l'approche de génomique intégrative multidimensionnelle permet d'apporter de nouveaux éléments pour la caractérisation des phénotypes tumoraux, le diagnostic des tumeurs agressives et la prédiction du comportement tumora

Evaluation prospective du statut iodé et de la fonction thyroïdienne chez 330 femmes enceintes de la région niçoise

NICE-BU Médecine Odontologie (060882102) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Y a-t-il des phénomènes de densification ou de dédensification ? Approche de la question et proposition d'indicateurs

La problématique de l’étalement et du renouvellement urbain est au cœur des préoccupations actuelles en matière de planification, d’aménagement et de développement durable des territoires. Elle entretient une relation étroite avec l’évolution du peuplement des différents espaces. Ce document, qui s’inscrit dans ce contexte, vise à proposer une approche possible pour localiser et quantifier les phénomènes de densification ou de dédensification à l’œuvre sur les territoires urbains. Nous limiterons notre étude à l’occupation de l’espace par ses habitants. La simplicité apparente de cette question liée à la difficulté de transmettre un message réaliste nécessitent une réflexion préalable importante pour « problématiser» l’observation et sélectionner des indicateurs pertinents pour répondre aux questions sous-jacentes à l’étude de ces différents phénomènes.L’approche repose sur un découpage de la question selon différents objets d’observation, et présente de façon détaillée les indicateurs qu’il est possible d’utiliser pour y répondre. Chacun d’eux est documenté de façon très précise : liens entretenus avec la question, modes de calculs et sources utilisables, illustrations issues de tests réalisés sur plusieurs sites expérimentaux, sans oublier les extensions possibles, ainsi que les limites et précautions à prendre en compte pour leur utilisation.Traitant essentiellement de la mesure de la densité et de son évolution, ce rapport d’étude privilégie les aspects techniques des méthodes de représentation graphiques et cartographiques de l’information. Il accorde une place importante aux procédés de lissage qui contribuent à faciliter la transmission et l’analyse des résultats obtenus.Les professionnels de l’observation y trouveront tous les éléments leur permettant de mettre en œuvre les indicateurs proposés sur leurs territoires pour procéder à leurs propres analyses, dès lors qu’ils possèdent localement les données nécessaires