Characterization of the pressure fluctuations within a Controlled-Diffusion airfoil boundary layer at large Reynolds numbers

The present investigation targets the generation of airfoil trailing-edge broadband noise that arises from the interaction of turbulent boundary layer with the airfoil trailing edge. Large-eddy simulations, carried out using a massively parallel compressible solver CharLESX, are conducted for a Controlled-Diffusion (CD) airfoil with rounded trailing edge for seven configurations, characterized with a Reynolds number, angle of attack and Mach number. An analysis of the unsteady pressure signals in the boundary layer is proposed in regard to classical trailing edge noise modelling ingredients

Downregulation of Glutamine Synthetase, not glutaminolysis, is responsible for glutamine addiction in Notch1-driven acute lymphoblastic leukemia

The cellular receptor Notch1 is a central regulator of T-cell development, and as a consequence, Notch1 pathway appears upregulated in > 65% of the cases of T-cell acute lymphoblastic leukemia (T-ALL). However, strategies targeting Notch1 signaling render only modest results in the clinic due to treatment resistance and severe side effects. While many investigations reported the different aspects of tumor cell growth and leukemia progression controlled by Notch1, less is known regarding the modifications of cellular metabolism induced by Notch1 upregulation in T-ALL. Previously, glutaminolysis inhibition has been proposed to synergize with anti-Notch therapies in T-ALL models. In this work, we report that Notch1 upregulation in T-ALL induced a change in the metabolism of the important amino acid glutamine, preventing glutamine synthesis through the downregulation of glutamine synthetase (GS). Downregulation of GS was responsible for glutamine addiction in Notch1-driven T-ALL both in vitro and in vivo. Our results also confirmed an increase in glutaminolysis mediated by Notch1. Increased glutaminolysis resulted in the activation of the mammalian target of rapamycin complex 1 (mTORC1) pathway, a central controller of cell growth. However, glutaminolysis did not play any role in Notch1-induced glutamine addiction. Finally, the combined treatment targeting mTORC1 and limiting glutamine availability had a synergistic effect to induce apoptosis and to prevent Notch1-driven leukemia progression. Our results placed glutamine limitation and mTORC1 inhibition as a potential therapy against Notch1-driven leukemia.This work was supported by funds from the followinginstitutions: Agencia Estatal de Investigacion/Euro-pean Regional Development Fund, European Union(PGC2018-096244-B-I00, SAF2016-75442-R), Ministryof Science, Innovation and Universities of Spain,Spanish National Research Council—CSIC, InstitutNational de la Sante et de la Recherche Medicale—INSERM, Ligue Contre le Cancer—Gironde, Univer-site de Bordeaux, Fondation pour la Recherche Medi-cale, the Conseil Regional d’Aquitaine, SIRIC-BRIO,Fondation ARC and Institut Europeen de Chimie etBiologie. MJN was supported by a bourse d’excellencede la Federation Wallonie-Bruxelles (WBI) and a post-doctoral fellowship from Fondation ARC. We thankVincent Pitard (Flow Cytometry Platform, Universitede Bordeaux, France) for technical assistance in flowcytometry experiments. We thank Diana Cabrera(Metabolomics Platform, CIC bioGUNE, Spain) fortechnical assistance in metabolomics analysi

Physiogenomic comparison of human fat loss in response to diets restrictive of carbohydrate or fat

<p>Abstract</p> <p>Background</p> <p>Genetic factors that predict responses to diet may ultimately be used to individualize dietary recommendations. We used physiogenomics to explore associations among polymorphisms in candidate genes and changes in relative body fat (Δ%BF) to low fat and low carbohydrate diets.</p> <p>Methods</p> <p>We assessed Δ%BF using dual energy X-ray absorptiometry (DXA) in 93 healthy adults who consumed a low carbohydrate diet (carbohydrate ~12% total energy) (LC diet) and in 70, a low fat diet (fat ~25% total energy) (LF diet). Fifty-three single nucleotide polymorphisms (SNPs) selected from 28 candidate genes involved in food intake, energy homeostasis, and adipocyte regulation were ranked according to probability of association with the change in %BF using multiple linear regression.</p> <p>Results</p> <p>Dieting reduced %BF by 3.0 ± 2.6% (absolute units) for LC and 1.9 ± 1.6% for LF (p < 0.01). SNPs in nine genes were significantly associated with Δ%BF, with four significant after correction for multiple statistical testing: rs322695 near the retinoic acid receptor beta (<it>RARB</it>) (p < 0.005), rs2838549 in the hepatic phosphofructokinase (<it>PFKL</it>), and rs3100722 in the histamine N-methyl transferase (<it>HNMT</it>) genes (both p < 0.041) due to LF; and the rs5950584 SNP in the angiotensin receptor Type II (<it>AGTR2</it>) gene due to LC (p < 0.021).</p> <p>Conclusion</p> <p>Fat loss under LC and LF diet regimes appears to have distinct mechanisms, with <it>PFKL </it>and <it>HNMT </it>and <it>RARB </it>involved in fat restriction; and <it>AGTR2 </it>involved in carbohydrate restriction. These discoveries could provide clues to important physiologic mechanisms underlying the Δ%BF to low carbohydrate and low fat diets.</p

Type 2 Diabetes Susceptibility Gene Expression in Normal or Diabetic Sorted Human Alpha and Beta Cells: Correlations with Age or BMI of Islet Donors

BACKGROUND: Genome-wide association studies have identified susceptibility genes for development of type 2 diabetes. We aimed to examine whether a subset of these (comprising FTO, IDE, KCNJ11, PPARG and TCF7L2) were transcriptionally restricted to or enriched in human beta cells by sorting islet cells into alpha and beta - specific fractions. We also aimed to correlate expression of these transcripts in both alpha and beta cell types with phenotypic traits of the islet donors and to compare diabetic and non-diabetic cells. METHODOLOGY/PRINCIPAL FINDINGS: Islet cells were sorted using a previously published method and RNA was extracted, reverse transcribed and used as the template for quantitative PCR. Sorted cells were also analysed for insulin and glucagon immunostaining and insulin secretion from the beta cells as well as insulin, glucagon and GLP-1 content. All five genes were expressed in both alpha and beta cells, with significant enrichment of KCNJ11 in the beta cells and of TCF7L2 in the alpha cells. The ratio of KCNJ11 in beta to alpha cells was negatively correlated with BMI, while KCNJ11 expression in alpha cells was negatively correlated with age but not associated with BMI. Beta cell expression of glucagon, TCF7L2 and IDE was increased in cells from islets that had spent more time in culture prior to cell sorting. In beta cells, KCNJ11, FTO and insulin were positively correlated with each other. Diabetic alpha and beta cells had decreased expression of insulin, glucagon and FTO. CONCLUSIONS/SIGNIFICANCE: This study has identified novel patterns of expression of type 2 diabetes susceptibility genes within sorted islet cells and suggested interactions of gene expression with age or BMI of the islet donors. However, expression of these genes in islets is less associated with BMI than has been found for other tissues

Développement d'une méthodologie hybride pour la simulation numérique en aéroacoustique, avec application à la réduction du bruit aéronautique

Ces travaux de recherche ont porté sur la simulation numérique en aéroacoustique, et son application à l'atténuation du bruit aéronautique.Plus précisément, et dans le but de répondre aux besoins actuels de prévision / réduction des émissions sonores par les aéronefs civils, les travaux ont consisté à développer une approche numérique avancée permettant de simuler numériquement des problèmes aéroacoustiques réalistes. Cette approche est basée sur une philosophie hybride, suivant laquelle les étapes de génération, propagation et rayonnement sonores sont calculées séquentiellement (par opposition à l'approche directe, où elles sont calculées simultanément). Dans cette perspective, les travaux ont tout d'abord consisté à développer une méthode de Calcul AéroAcoustique (CAA) et un solveur associé (code sAbrinA). Dans un deuxième temps, les efforts ont consisté à insérer ce noyau / code CAA dans une chaîne de calcul plus large, via des couplages spécifiques avec d'autres techniques / outils numériques de génération (e.g. CFD) et / ou rayonnement (e.g. Méthodes Intégrales) acoustiques. Enfin, les travaux ont porté sur l'application de tout ou partie de la chaîne de calcul résultante à de nombreux problèmes acoustiques de nature fondamentale ou appliquée.Ces activités de R & D ont non seulement permis de répondre à des besoins pratiques d'atténuation et / ou caractérisation du bruit d’aéronefs, mais elles ont également ouvert la voie à une utilisation plus systématique des approches aéroacoustique hybrides, lesquelles constituent à ce jour la meilleure stratégie pour traiter numériquement des problèmes acoustiques réalistes issus de l'industrie aérospatiale.Ces activités de recherche ont été conduites sur une quinzaine d'années (thèse incluse) au sein de l’ONERA, dans le cadre de plusieurs cadres (efforts internes ONERA, projets nationaux et européens, collaborations internationales), et parfois en étroite collaboration avec d'autres acteurs clés du secteur aérospatial (e.g. NASA, Airbus). Ils ont débouché sur des retombées à la fois fondamentales et appliquées, lesquelles ont été documentées via de nombreuses publications dans des journaux de rang A ou communications dans des conférences internationales à comité de lecture (plus de 70 papiers, à ce jour).The present R&D activities concerned the numerical simulation in aeroacoustics, and its application to the mitigation of aeronautic noise. More precisely, with the view of answering the current needs of predicting / reducing the noise emission by civil aircraft, the present works consisted in developing an advanced numerical approach that offers numerically simulating real-life aeroacoustics problems. The latter approach is based on a hybrid philosophy, following which the noise generation, propagation and radiation stages are computed sequentially (as opposed to the direct approach, where they are calculated simultaneously). To this end, the research works first consisted in developing a Computational AeroAcoustics (CAA) method, and associated solver (sAbrinA code). In a second time, the works consisted in the inclusion of such CAA kernel/code within a wider calculation chain, through specific couplings with other numerical techniques/tools of noise generation (e.g. CFD) and/or radiation (e.g. Integral Methods). Finally, the efforts concerned the application of all or part of the resulting calculation chain to numerous noise problems of either fundamental or applied nature. These R&D activities not only offered answering practical needs of aircraft noise mitigation and/or characterization, but they also paved the way to a more systematic use of advanced hybrid approaches in aeroacoustics, which - to date - constitute the best viable way to address realistic noise problems coming from the aerospace industry. Being conducted at ONERA over roughly fifteen years (PhD thesis included), these research activities were achieved within several frameworks (ONERA internal efforts, national and European projects, international collaborative efforts), sometimes in close collaboration with other key stakeholders of the aerospace sector (e.g. NASA, Airbus, etc.). They led to both fundamental insights and methodological outcomes, which were documented through numerous publications in A-rank journal or communications in international peer-reviewed conferences (more than 70 papers, so far)

Numerical Assessment of Acoustic Installation Effects Characterizing NASA/LaRC Quiet Flow Facility using Computational AeroAcoustics

This paper presents a numerical assessment of acoustic installation effects characterizing the NASA Langley Quiet Flow Facility (QFF), an open-jet, anechoic wind tunnel. Several Computational Aeroacoustics (CAA) calculations based on equivalent simplistic sources are conducted, enabling the estimation of the installation effects possibly induced by the QFF environment on the measured acoustic signatures during typical airframe noise experiments. First, the conclusions that had been previously made by the present author in an earlier assessment of QFF installation effects onto the so-called Tandem Cylinder experiments are reproduced. Then, these conclusions are extended to various situations which are more representative of the usual airframe noise tests that are typically conducted in the QFF. In particular, this provides an opportunity to compare the refraction/convection effects of the QFF jet flow to the reflection/diffraction induced by the experimental apparatus. All this further aids in the identification of acoustic installation effects that may be important in the type of testing typically done in the NASA/LARC QFF facility