Capturing transition features around a wing by reduced-order modeling based on compressible Navier-Stokes equations

The three-dimensional transition in the flow around a NACA0012 wing of constant spanwise section at Mach number 0.3, Reynolds number 800, and incidence 20° is investigated by direct numerical simulation and reduced-order modeling. The interaction between the von Kármán and the secondary instabilities is analyzed. Irregular events in the flow transition modulating the spanwise undulation are highlighted and quantified. These transition features, including "local intermittencies" in the secondary instability pattern, are efficiently captured by a reduced-order model derived by means of the Galerkin projection of the compressible flow Navier-Stokes equations onto a truncated proper orthogonal decomposition basis

Glyco-Phospho-Glycero Ether Lipids (GPGEL): synthesis and evaluation as small conductance Ca2+-activated K+ channel (SK3) inhibitors

International audienceThe SK3 channel, a member of the small conductance calcium-dependent potassium channels (SKCa), plays a central role with respect to the motility of highly metastatic cancerous cells (e.g. MDA-MB435s – breast cancer cell). Edelfosine, an ether lipid derivative, is able to partially inhibit this channel activity and thus reduce the SK3-dependent cell motility, but, due to its toxicity, analogues of this compound were highly desired. Ohmline, an edelfosine analogue that possesses a lactose unit in its polar domain, was the first efficient and non-toxic SK3 inhibitor that exhibits an amphiphilic structure. In the present work, we have modified the polar head of Ohmline by placing a disubstituted phosphate group between a disaccharide unit (lactose, maltose, and melibiose) and the glycerol ether-lipid moiety. It was first observed that this modification increases the water solubility of these compounds. All these novel compounds are efficient SK3 channel inhibitors with an activity comparable to Ohmline (patch-clamp measurements). These compounds are also able to reduce the SK3-dependent cell motility with similar efficacies to Ohmline. In a broader perspective it is shown that the presence of one anionic charge (coming from the presence of a phosphate group) in the polar head group does not alter the SK3 channel inhibition and provides insights into the future development of a class of migration-targeted anticancer agents

DiGalactosyl-Glycero-Ether Lipid: synthetic approaches and evaluation as SK3 channel inhibitor.

International audienceThe recent discoveries of the involvement of SK3 channel in some cell motility mechanisms occurring in cancer disease have opened up the way to the synthesis of inhibitors that could reduce metastasis formation. On the basis of our recent previous works showing that both lactose-glycero-ether lipid () and some phosphate analogues () were efficient compounds to modulate SK3 channel activity, the present study, which found its inspiration in the structure of the natural glycolipid DiGalactosylDiacylGlycerol (DGDG), reports the incorporation of a digalactosyl moiety (α-galactopyranosyl-(1→6)-β-galactopyranosyl-) as the polar head of a glycero ether lipid. For the construction of the digalactosyl fragment, two synthetic approaches were compared. The standard strategy which is based on the use of the benzyl protecting group to produce 1→6 disaccharide unit, was compared with a second method that made use of the trimethylsilyl moiety as a protecting group. This second strategy, which is applied for the first time to the synthesis of (1→6)-disaccharide unit, presents a net advantage in terms of efficacy (better global yield) and cost. Finally, compound , which is characterized by a (1→6) DiGalactosyl unit (DG) as the polar head of the amphiphilic structure, was tested as a modulator of the SK3 channel activity. Patch-clamp experiments have shown that compound reduced SK3 currents (-28.2 ± 2.0% at 5 μM) and cell migration assays performed at 300 nM have shown a reduction of cell migration (SK3 + HEK293T) by 19.6 ± 2.7%

Lipothiophosphoramidates for gene delivery: critical role of the cationic polar headgroup

International audienceWhen considering a family of cationic lipids designed for gene delivery, the nature of the cationic polar head probably has a great influence on both the transfection efficacy and toxicity. Starting from a cationic lipothiophosphoramidate bearing a trimethylammonium headgroup, we report herein the impact on gene transfection activity of the replacement of the trimethylammonium moiety by a trimethylphosphonium or a trimethylarsonium group. A series of three different human epithelial cell lines were used for the experimental transfection studies (HeLa, A549 and 16HBE14o(−)). The results basically showed that such structural modifications of the cationic headgroup can lead to a high transfection efficacy at low lipid/DNA charge ratios together with a low cytotoxicity. It thus appears that the use of a trimethylarsonium cationic headgroup for the design of efficient gene carriers, which was initially proposed in the lipophosphoramidate series, can be extended to other series of cationic lipids and might therefore have great potential for the development of novel non-viral vectors in general

Glyco-phospho-glycero-ether lipid as modulator of SK3 ion channel and SK3-dependent cancer cell migration

International audienceIn this short review paper, we report our efforts to design new inhibitors of SK3 ion channel that are involved in cancer cell migration and metastases formation. The originality of the new SK3 inhibitors comes from their amphiphilic nature and contrast form others inhibitors that are peptides or heterocyclic compounds. We found that ether lipids and ether phospho-glyco-lipids are indeed efficient to modulate SK3 ion channel that consequently reduced cancer cell migration (in vitro assays) and abolished the formation of bone metastases in a murine model of breast cancer

Thio-ether functionalized glycolipid amphiphilic compounds reveal a potent activator of SK3 channel with vasorelaxation effect

International audienceThe modulation of SK3 ion channels can be efficiently and selectively achieved by using the amphiphilic compound Ohmline (a glyco-glycero-ether-lipid). We report herein a series of Ohmline analogues featuring the replacement of one ether function by a thioether function located at the same position or shifted close to its initial position. The variation of the lipid chain length and the preparation of two analogues featuring either one sulfoxide or one sulfone moiety complete this series. Patch clamp measurements indicate that the presence of the thioether function (compounds 7 and 17a) produces strong activators of SK3 channels, whereas the introduction of a sulfoxide or a sulfone function at the same place produces amphiphiles devoid of an effect on SK3 channels. Compounds 7 and 17a are the first amphiphilic compounds featuring strong activation of SK3 channels (close to 200% activation). The cytosolic calcium concentration determined from fluorescence at 3 different times for compound 7b (13 min, 1 h, 24 h) revealed that the effect is different suggesting that the compound could be metabolized over time. This compound could be used as a strong SK3 activator for a short time. The capacity of 7b to activate SK3 was then used to induce vasorelaxation via an endothelium-derived hyperpolarization (EDH) pathway. For the first time, we report that an amphiphilic compound can affect the endothelium dependent vasorelaxation.Des analogues de l’Ohmline, contenant une fonction soufrée, sont décrits et testés comme modulateur des canaux ioniques SK3. Deux puissants activateurs sont identifiés. Néanmoins leur effet est limité dans le temps. Il est suggéré que ces composés, dotés d’une fonction thioéther, soient oxydés en sulfoxide et sulfone au cours du temps conduisant à une modification de leur activité. Un compose inhibiteur est également identifié mais son manque de sélectivité pourrait expliquer l’absence d’effet sur les entrées calciques associé à l’inhibition des canaux SK3. Finalement, il est montré pour la première fois qu’un composé amphiphile (l’un des activateurs des canaux SK3) présente un effet de vasorelaxation

Layered Simple Hydroxides Functionalized by Fluorene-Phosphonic Acids: Synthesis, Interface Theoretical Insights, and Magnetoelectric Effect

International audienceCopper- and cobalt-based layered simple hydroxides (LSH) are successfully functionalized by a series of fluorene mono- and diphosphonic acids, using anionic exchange reactions and a preintercalation strategy. The lateral functionalization of the fluorene moieties has only little impact on the overall structure of the obtained layered hybrid materials but it influences the organization of the molecules within the interlamellar spacing. For bulky fluorene (9,9-dioctyl derivative), luminescence is preserved when inserted into copper and cobalt hydroxydes, whereas it is completely quenched for the other fluorenes. Detailed characterization of the internal structure and chemical bonding properties for copper- and cobalt-based hybrids is performed via ancillary experimental techniques. For the copper-based LSH class, for which more elusive findings are found, first-principles molecular dynamics simulations unravel the fundamental stabilizing role of the H-bonding network promoted within the local environments of the fluorene mono- and diphosphonic acids. The cobalt series of compounds constitute a new class of hybrid magnets, with ordering temperatures ranging from 11.8 to 17.8 K and show a clear magnetoelectric effect. This effect appears above a threshold magnetic field, which is null below the magnetic ordering temperature, and it persists in the paramagnetic regime till about 110 K

Layered Simple Hydroxides Functionalized by Fluorene-Phosphonic Acids: Synthesis, Interface Theoretical Insights, and Magnetoelectric Effect

International audienceCopper- and cobalt-based layered simple hydroxides (LSH) are successfully functionalized by a series of fluorene mono- and diphosphonic acids, using anionic exchange reactions and a preintercalation strategy. The lateral functionalization of the fluorene moieties has only little impact on the overall structure of the obtained layered hybrid materials but it influences the organization of the molecules within the interlamellar spacing. For bulky fluorene (9,9-dioctyl derivative), luminescence is preserved when inserted into copper and cobalt hydroxydes, whereas it is completely quenched for the other fluorenes. Detailed characterization of the internal structure and chemical bonding properties for copper- and cobalt-based hybrids is performed via ancillary experimental techniques. For the copper-based LSH class, for which more elusive findings are found, first-principles molecular dynamics simulations unravel the fundamental stabilizing role of the H-bonding network promoted within the local environments of the fluorene mono- and diphosphonic acids. The cobalt series of compounds constitute a new class of hybrid magnets, with ordering temperatures ranging from 11.8 to 17.8 K and show a clear magnetoelectric effect. This effect appears above a threshold magnetic field, which is null below the magnetic ordering temperature, and it persists in the paramagnetic regime till about 110 K

Prevalence of undiagnosed psoriatic arthritis among psoriasis patients: Systematic review and meta-analysis

International audienceSkin psoriasis precedes the onset of psoriatic arthritis (PsA) in 84% of patients with psoriasis. Dermatologists have an important role to screen psoriasis patients for PsA. The efficiency of PsA screening remains unknown