Caractérisation de la régulation génétique des microARN plasmatiques en grossesse et leur potentielle implication dans le développement du diabète gestationnel

L'arrivée de nouvelles techniques de séquençage à haut débit a procuré une puissante façon d'étudier le génome humain. Parallèlement, le développement d'outils bio-informatiques adaptés à cette révolution a été essentiel à l'interprétation des quantités titanesques de données générées. Le séquençage de plusieurs génomes complets maintenant accessible ouvre la porte à des découvertes autrefois impensable. Ce mémoire présente deux projets portant sur les variations génétiques chez les individus d'une cohorte de femmes enceintes. Le premier projet porte sur l'étude de la régulation génétique de l'abondance des microARN plasmatiques au premier trimestre de grossesse. La mise en commun de l'abondance des microARN et des variations génétiques à proximité des microARN a permis l'identification de variations génétiques associées aux niveaux de microARN mesurés dans le plasma. Ces associations ont révélé des régions régulatrices permettant une meilleure compréhension des mécanismes de régulation des microARN. L'agglomération des variations génétiques identifiés sous forme de variables instrumentales ont mis en évidence l'importante contribution de la génétique dans la régulation des microARN circulants. Le second projet avait pour objectif d'identifier des microARN plasmatiques en grossesse sécrétés par les tissus fœtaux. Pour ce faire, les variations génétiques contenues dans les séquences des microARN mesurées ont été comparées à celles de l'ADN de la mère et de l'enfant. Toutefois, le haut niveau de conservation de leur séquence ne permet pas d'en faire une distinction claire

Bayesian analysis to identify new star candidates in nearby young stellar kinematic groups

We present a new method based on a Bayesian analysis to identify new members of nearby young kinematic groups. The analysis minimally takes into account the position, proper motion, magnitude and color of a star, but other observables can be readily added (e.g. radial velocity, distance). We use this method to find new young low-mass stars in the \beta Pictoris (\beta PMG) and AB Doradus (ABDMG) moving groups and in the TW Hydrae (TWA), Tucana-Horologium (THA), Columba, Carina and Argus associations. Starting from a sample of 758 mid-KM (K5V-M5V) stars showing youth indicators such as H\alpha\ and X-ray emission, our analysis yields 215 new highly probable low-mass members of the kinematic groups analyzed. One is in TWA, 37 in \beta PMG, 17 in THA, 20 in Columba, 6 in Carina, 50 in Argus, 33 in ABDMG, and the remaining 51 candidates are likely young but have an ambiguous membership to more than one association. The false alarm rate for new candidates is estimated to be 5% for \beta PMG and TWA, 10% for THA, Columba, Carina and Argus, and 14% for ABDMG. Our analysis confirms the membership of 58 stars proposed in the literature. Firm membership confirmation of our new candidates will require measurement of their radial velocity (predicted by our analysis), parallax and lithium 6708 {\AA} equivalent width. We have initiated these follow-up observations for a number of candidates and we have identified two stars (2MASSJ0111+1526, 2MASSJ0524-1601) as very strong candidate members of the \beta PMG and one strong candidate member (2MASSJ0533-5117) of the THA; these three stars have radial velocity measurements confirming their membership and lithium detections consistent with young age. Finally, we proposed that six stars should be considered as new bona fide members of \beta PMG and ABDMG, one of which being first identified in this work, the others being known candidates from the literature.Comment: Accepted for publication in Ap

Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth

A systematic review and meta-analysis of evidence for correlation between molecular markers of parasite resistance and treatment outcome in falciparum malaria

<p>Abstract</p> <p>Background</p> <p>An assessment of the correlation between anti-malarial treatment outcome and molecular markers would improve the early detection and monitoring of drug resistance by <it>Plasmodium falciparum</it>. The purpose of this systematic review was to determine the risk of treatment failure associated with specific polymorphisms in the parasite genome or gene copy number.</p> <p>Methods</p> <p>Clinical studies of non-severe malaria reporting on target genetic markers (SNPs for <it>pfmdr1</it>, <it>pfcrt</it>, <it>dhfr</it>, <it>dhps</it>, gene copy number for <it>pfmdr1</it>) providing complete information on inclusion criteria, outcome, follow up and genotyping, were included. Three investigators independently extracted data from articles. Results were stratified by gene, codon, drug and duration of follow-up. For each study and aggregate data the random effect odds ratio (OR) with 95%CIs was estimated and presented as Forest plots. An OR with a lower 95^thconfidence interval > 1 was considered consistent with a failure being associated to a given gene mutation.</p> <p>Results</p> <p>92 studies were eligible among the selection from computerized search, with information on <it>pfcrt </it>(25/159 studies), <it>pfmdr1 </it>(29/236 studies), <it>dhfr </it>(18/373 studies), <it>dhps </it>(20/195 studies). The risk of therapeutic failure after chloroquine was increased by the presence of <it>pfcrt </it>K76T (Day 28, OR = 7.2 [95%CI: 4.5–11.5]), <it>pfmdr1 </it>N86Y was associated with both chloroquine (Day 28, OR = 1.8 [95%CI: 1.3–2.4]) and amodiaquine failures (OR = 5.4 [95%CI: 2.6–11.3, p < 0.001]). For sulphadoxine-pyrimethamine the <it>dhfr </it>single (S108N) (Day 28, OR = 3.5 [95%CI: 1.9–6.3]) and triple mutants (S108N, N51I, C59R) (Day 28, OR = 3.1 [95%CI: 2.0–4.9]) and <it>dhfr</it>-<it>dhps </it>quintuple mutants (Day 28, OR = 5.2 [95%CI: 3.2–8.8]) also increased the risk of treatment failure. Increased <it>pfmdr1 </it>copy number was correlated with treatment failure following mefloquine (OR = 8.6 [95%CI: 3.3–22.9]).</p> <p>Conclusion</p> <p>When applying the selection procedure for comparative analysis, few studies fulfilled all inclusion criteria compared to the large number of papers identified, but heterogeneity was limited. Genetic molecular markers were related to an increased risk of therapeutic failure. Guidelines are discussed and a checklist for further studies is proposed.</p

Genome-wide association study of placental weight identifies distinct and shared genetic influences between placental and fetal growth

A well-functioning placenta is essential for fetal and maternal health throughout pregnancy. Using placental weight as a proxy for placental growth, we report genome-wide association analyses in the fetal (n = 65,405), maternal (n = 61,228) and paternal (n = 52,392) genomes, yielding 40 independent association signals. Twenty-six signals are classified as fetal, four maternal and three fetal and maternal. A maternal parent-of-origin effect is seen near KCNQ1. Genetic correlation and colocalization analyses reveal overlap with birth weight genetics, but 12 loci are classified as predominantly or only affecting placental weight, with connections to placental development and morphology, and transport of antibodies and amino acids. Mendelian randomization analyses indicate that fetal genetically mediated higher placental weight is causally associated with preeclampsia risk and shorter gestational duration. Moreover, these analyses support the role of fetal insulin in regulating placental weight, providing a key link between fetal and placental growth

抗腫瘍性トロポロン誘導体の創製と作用機序に関する研究

We image the lithospheric and upper asthenospheric structure of western continental Yemen with 24 broadband stations to evaluate the role of the Afar plume on the evolution of the continental margin and its extent eastward along the Gulf of Aden. We use teleseismic tomography to compute relative P wave velocity variations in south-western Yemen down to 300 km depth. Published receiver function analysis suggest a dramatic and localized thinning of the crust in the vicinity of the Red Sea and the Gulf of Aden, consistent with the velocity structure that we retrieve in our model. The mantle part of the model is dominated by the presence of a low-velocity anomaly in which we infer partial melting just below thick Oligocene flood basalts and recent off-axis volcanic events (from 15 Ma to present). This low-velocity anomaly could correspond to an abnormally hot mantle and could be responsible for dynamic topography and recent magmatism in western Yemen. Our new P wave velocity model beneath western Yemen suggests the young rift flank volcanoes beneath margins and on the flanks of the Red Sea rift are caused by focused small-scale diapiric upwelling from a broad region of hot mantle beneath the area. Our work shows that relatively hot mantle, along with partial melting of the mantle, can persist beneath rifted margins after breakup has occurred

TRY plant trait database – enhanced coverage and open access

Plant traits - the morphological, anatomical, physiological, biochemical and phenological characteristics of plants - determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait‐based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits - almost complete coverage for ‘plant growth form’. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait–environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Search for gravitational-lensing signatures in the full third observing run of the LIGO-Virgo network

Gravitational lensing by massive objects along the line of sight to the source causes distortions of gravitational wave-signals; such distortions may reveal information about fundamental physics, cosmology and astrophysics. In this work, we have extended the search for lensing signatures to all binary black hole events from the third observing run of the LIGO--Virgo network. We search for repeated signals from strong lensing by 1) performing targeted searches for subthreshold signals, 2) calculating the degree of overlap amongst the intrinsic parameters and sky location of pairs of signals, 3) comparing the similarities of the spectrograms amongst pairs of signals, and 4) performing dual-signal Bayesian analysis that takes into account selection effects and astrophysical knowledge. We also search for distortions to the gravitational waveform caused by 1) frequency-independent phase shifts in strongly lensed images, and 2) frequency-dependent modulation of the amplitude and phase due to point masses. None of these searches yields significant evidence for lensing. Finally, we use the non-detection of gravitational-wave lensing to constrain the lensing rate based on the latest merger-rate estimates and the fraction of dark matter composed of compact objects