Charakterisierung der Pathogenbedingten Selektionsmechanismen die auf B4galnt2 in Hausmäusen Wirken.

B4galnt2 is a glycosyltransferase that displays cis-regulatory variation for its tissue-specific expression patterns in house mice: the wild type allele C57BL/6J, directs intestinal expression of B4galnt2 while the alternative allele RIIIS/J drives expression in blood vessels, which leads to a bleeding disorder. Previous studies showed that alternative B4galnt2 alleles are subject to long-term balancing selection in mice and that variation in B4galnt2 expression influences host-microbe interactions. This suggests that the cost of prolonged bleeding in RIIIS/J allele-bearing mice might be outweighed by benefits associated with resistance against gastrointestinal pathogens. To understand and characterize the potential pathogen-driven selection acting on B4galnt2 in the wild, I first developed a mathematical model based on an evolutionary game framework. In particular, I focused on heterozygous mice, which express B4galnt2 in both blood vessels and the gastrointestinal tract. By comparing simulated to natural populations, I found that the genotype frequencies observed in nature can be produced by pathogen-driven selection when (i) the fitness cost of bleeding is roughly half that of infection and (ii) both heterozygotes and RIIIS/J homozygotes are protected against infection. The resistance of the heterozygote individuals indicates that a dominant protective function of the RIIIS/J allele is more likely than a protective loss of intestinal expression. Furthermore, I aimed to identify potential pathogens driving the selection at B4galnt2 by sampling and phenotyping over 200 newly collected mice from Southern France, where an intermediate frequency of the RIIIS/J allele is present. Through the multilayer analysis of genetic patterns, signs of inflammation, and intestinal microbial communities, I could identify several bacterial genera to patterns consistent with genotype-dependent host-pathogen.B4galnt2 ist eine Glykosyltransferase, die in Hausmäusen cis-regulatorische Variation hinsichtlich der gewebsspezifischen Expression aufweist. Das Wildtypallel C57BL/6J führt zur Expression im Intestinaltrakt und die alternative RIIIS/J allele in den Blutgefäßen, die einen Phänotyp zur Folge hat, der dem Typ 1 von-Willebrand-Syndrom ähnelt. Vorherige Studien zeigten, dass die unterschiedlichen B4galnt2-Allele in der Maus langfristig einer Balancing Selection unterliegen und die Variation der B4galnt2-Expression die Interaktion zwischen Wirt und Mikroorganismen beeinflusst. Das impliziert, dass die Nachteile durch eine höhere Blutungsdauer in Mäusen, die das RIIIS/J-Allel tragen, durch Vorteile in der Resistenz gegenüber gastrointestinalen Pathogenen aufgewogen werden. Um die potentiell pathogenbedingten Selektionsmechanismen zu verstehen und charakterisieren, habe ich zunächst ein mathematisches Modell entwickelt. Dabei habe ich mich insbesondere auf heterozygote Mäuse konzentriert. Die Ergebnisse zeigen, dass die Frequenzen der Genotypen, die in der Natur beobachtet werden, durch pathogenbedingte Selektion hervorgerufen werden können, falls (i) die Nachteile der Gerinnungsstörung etwa halb so groß sind wie die durch Infektion sowie (ii) sowohl heterozygote als auch das RIIIS/J-Allel tragende Individuen gegen Infektionen geschützt sind. Eine dominante protektive Eigenschaft des RIIIS/J-Allels ist wahrscheinlicher als eine protektive Wirkung des Verlustes der intestinalen Expression. Weiterhin habe ich mittels „Deep Phenotyping“ in mehr als 200 neugefangenen Mäusen aus Südfrankreich, auf die Identifikation potentieller Pathogene abgezielt, die die Selektion von B4galnt2-Varianten antreiben. Durch die Analyse von genetischen Mustern, Entzündungszeichen und der intestinalen mikrobiellen Gemeinschaften, konnte ich mehrere Bakteriengattungen mit Mustern in Verbindung bringen, die mit genotypabhängigen Wirt-Pathogen-Interaktionen konsistent sind

Determining the instar of a weevil larva (Coleoptera: Curculionidae) using a parsimonious method

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Phenotypic and functional analyses show stem cell-derived hepatocyte-like cells better mimic fetal rather than adult hepatocytes

Background & Aims: Hepatocyte-like cells (HLCs), differentiated from pluripotent stem cells by the use of soluble factors, can model human liver function and toxicity. However, at present HLC maturity and whether any deficit represents a true fetal state or aberrant differentiation is unclear and compounded by comparison to potentially deteriorated adult hepatocytes. Therefore, we generated HLCs from multiple lineages, using two different protocols, for direct comparison with fresh fetal and adult hepatocytes. Methods: Protocols were developed for robust differentiation. Multiple transcript, protein and functional analyses compared HLCs to fresh human fetal and adult hepatocytes. Results: HLCs were comparable to those of other laboratories by multiple parameters. Transcriptional changes during differentiation mimicked human embryogenesis and showed more similarity to pericentral than periportal hepatocytes. Unbiased proteomics demonstrated greater proximity to liver than 30 other human organs or tissues. However, by comparison to fresh material, HLC maturity was proven by transcript, protein and function to be fetal-like and short of the adult phenotype. The expression of 81% phase 1 enzymes in HLCs was significantly upregulated and half were statistically not different from fetal hepatocytes. HLCs secreted albumin and metabolized testosterone (CYP3A) and dextrorphan (CYP2D6) like fetal hepatocytes. In seven bespoke tests, devised by principal components analysis to distinguish fetal from adult hepatocytes, HLCs from two different source laboratories consistently demonstrated fetal characteristics. Conclusions: HLCs from different sources are broadly comparable with unbiased proteomic evidence for faithful differentiation down the liver lineage. This current phenotype mimics human fetal rather than adult hepatocytes

A polyphenol-rich plant extract prevents hypercholesterolemia and modulates gut microbiota in western diet-fed mice

IntroductionTotum-070 is a combination of five plant extracts enriched in polyphenols to target hypercholesterolemia, one of the main risk factors for cardiovascular diseases. The aim of this study was to investigate the effects of Totum-070 on cholesterol levels in an animal model of diet-induced hypercholesterolemia.MethodsC57BL/6JOlaHsd male mice were fed a Western diet and received Totum-070, or not, by daily gavage (1g/kg and 3g/kg body weight) for 6 weeks.ResultsThe Western diet induced obesity, fat accumulation, hepatic steatosis and increased plasma cholesterol compared with the control group. All these metabolic perturbations were alleviated by Totum-070 supplementation in a dose-dependent manner. Lipid excretion in feces was higher in mice supplemented with Totum-070, suggesting inhibition of intestinal lipid absorption. Totum-070 also increased the fecal concentration of short chain fatty acids, demonstrating a direct effect on intestinal microbiota.DiscussionThe characterization of fecal microbiota by 16S amplicon sequencing showed that Totum-070 supplementation modulated the dysbiosis associated with metabolic disorders. Specifically, Totum-070 increased the relative abundance of Muribaculum (a beneficial bacterium) and reduced that of Lactococcus (a genus positively correlated with increased plasma cholesterol level). Together, these findings indicate that the cholesterol-lowering effect of Totum-070 bioactive molecules could be mediated through multiple actions on the intestine and gut microbiota

Measurement of the CP-violating phase β in B0→J/ψπ+π− decays and limits on penguin effects

18 pages, 6 figures - See paper for full list of authorsInternational audienceTime-dependent CP violation is measured in the B0→J/ψπ+π− channel for each π+π− resonant final state using data collected with an integrated luminosity of 3.0 fb−1 in pp collisions using the LHCb detector. The final state with the largest rate, J/ψρ0(770), is used to measure the CP-violating angle 2βeff to be (41.7±9.6+2.8−6.3)∘. This result can be used to limit the size of penguin amplitude contributions to CP violation measurements in, for example, B0s→J/ψϕ decays. Assuming approximate SU(3) flavour symmetry and neglecting higher order diagrams, the shift in the CP-violating phase ϕs is limited to be within the interval [−1.05∘, +1.18∘] at 95% confidence level. Changes to the limit due to SU(3) symmetry breaking effects are also discussed

Measurement of the lifetime of the B+c meson using the B+c→J/ψπ+ decay mode

See paper for full list of authors - 19 pages, 3 figuresInternational audienceThe difference in total widths between the B+c and B+ mesons is measured using 3.0fb−1 of data collected by the LHCb experiment in 7 and 8 TeV centre-of-mass energy proton-proton collisions at the LHC. Through the study of the time evolution of B+c→J/ψπ+ and B+→J/ψK+ decays, the width difference is measured to beΔΓ≡ΓB+c−ΓB+=4.46±0.14±0.07mm−1c,where the first uncertainty is statistical and the second systematic. The known lifetime of the B+ meson is used to convert this to a precise measurement of the B+c lifetime,τB+c=513.4±11.0±5.7fs,where the first uncertainty is statistical and the second systematic

Determination of gamma and -2beta_s from charmless two-body decays of beauty mesons

See paper for full list of authorsInternational audienceUsing the latest LHCb measurements of time-dependent CP violation in the B^0_s -> K^+K^- decay, a U-spin relation between the decay amplitudes of B^0_s -> K^+K^- and B^0 -> \pi^+\pi^- decay processes allows constraints to be placed on the angle gamma of the unitarity triangle and on the B^0_s mixing phase -2\beta_s. Results from an extended approach, which uses additional inputs on B^0 -> \pi^0\pi^0 and B^+ -> \pi^+\pi^0 decays from other experiments and exploits isospin symmetry, are also presented. The dependence of the results on the maximum allowed amount of U-spin breaking is studied. At 68% probability, the value \gamma = ( 63.5 +7.2 -6.7 ) degrees modulo 180 degrees is determined. In an alternative analysis, the value -2\beta_s = -0.12 +0.14 -0.16 rad is found. In both measurements, the uncertainties due to U-spin breaking effects up to 50% are included

Study of the rare B0s and B0 decays into the π+π−μ+μ− final state

See paper for full list of authors - Submitted to Phys. Lett. BInternational audienceA search for the rare decays B0s→π+π−μ+μ− and B0→π+π−μ+μ− is performed in a data set corresponding to an integrated luminosity of 3.0 fb−1 collected by the LHCb detector in proton-proton collisions at centre-of-mass energies of 7 and 8 TeV. Decay candidates with pion pairs that have invariant mass in the range 0.5-1.3 GeV/c2 and with muon pairs that do not originate from a resonance are considered. The first observation of the decay B0s→π+π−μ+μ− and the first evidence of the decay B0→π+π−μ+μ− are obtained and the branching fractions are measured to be B(B0s→π+π−μ+μ−)=(8.6±1.5(stat)±0.7(syst)±0.7(norm))×10−8 and B(B0→π+π−μ+μ−)=(2.11±0.51(stat)±0.15(syst)±0.16(norm))×10−8, where the third uncertainty is due to the branching fraction of the decay B0→J/ψ(→μ+μ−)K∗(890)0(→K+π−), used as a normalisation