On The Role of Higher-Order Terms in Local Piston Theory

The use of second- and third-order classical piston theory [1] (CPT) is commonplace, with the role of the higher-order terms being well understood [2]. The advantages of local piston theory (LPT) relative to CPT have been demonstrated previously [3]. Typically, LPT has been used to perturb a mean-steady solution obtained from the Euler equations, and recently, from the Navier-Stokes equations [4]. The applications of LPT in the literature have been limited to first-order LPT [5–7]. The reasoning behind this has been that the dynamic linearization used assumes small perturbations. The present note clarifies the role of higher-order terms in LPT. It is shown that second-order LPT makes a non-zero contribution to the normal-force prediction, in contrast to second-order CPT

Generalized formulation and review of piston theory for airfoils

The present work presents a brief review of some of the notable contributions to piston theory and of its theoretical basis. A generalized formulation of piston theory is given, applicable to both local and classical piston theory. A consistent generalized formulation of the downwash equation is given, accounting for arbitrary motion in the plane of the airfoil. The formulation reduces to established downwash equations through appropriate definition of the cylinder orientation. The theoretical range of validity of Lighthill’s classical piston theory is examined, and the relative accuracy of a number of approximate theories encapsulated by the formulation as applied to a planar wedge is considered. The relative importance of higher-order terms in piston theory is examined, with the significance of recent literature extending the fidelity of the firstorder term highlighted. It is subsequently suggested that current implementations of local piston theory may be improved through the use of a first-order term of suitable accuracy.Armaments Corporation of South Africa through the Fluxion grant.http://arc.aiaa.org/loi/aiaajhb2016Mechanical and Aeronautical Engineerin

A Practical Approach to New (5Z) 2-Alkylthio-5-arylmethylene- 1-methyl-1,5-dihydro-4H-imidazol-4-one Derivatives

International audienceA practical protocol for the preparation of (5Z)-2-alkylthio-5-arylmethylene-1-methyl-1,5-dihydro-4H-imidazol-4-one derivatives is reported. The new compounds were obtained in good yield and stereoselectivity in two steps, namely a solvent-free Knoevenagel condensation under microwave irradiation, followed by an S-alkylation reaction with various halogenoalkanes

Design and Synthesis of Thiazolo[5,4-f]quinazolines as DYRK1A Inhibitors, Part I

International audienc

Synthesis and biological activities of aminopyrimidyl-indoles structurally related to meridianins

International audienceThe synthesis of new meridianin derivatives substituted at the C-5 position of the 2-aminopyrimidine ring by various aryl groups and substituted or not by a methyl group on the indole nitrogen is described. These compounds were tested for their kinase inhibitory potencies toward five kinases (CDK5/p25, CK1δ/ε, GSK-3α/β, Dyrk1A and Erk2) as well as their in vitro antiproliferative activities toward a human fibroblast primary culture and two human solid cancer cell lines (MCF-7 and PA 1

New 5-ylidene rhodanine derivatives based on the dispacamide A model.

International audienceA practical approach for the preparation of ([Formula: see text]) 5-ylidene rhodanine derivatives bearing the (4,5-dihalogeno-pyrrol-2-yl)carbamoyl fragment of dispacamide A is reported. The new compounds were obtained in good yields (19-88 %) by Knoevenagel condensation according to a solution-phase microwave dielectric heating protocol in the presence of organic bases (piperidine, TEA, and AcONa) from a set of [Formula: see text]-substituted rhodanines 2(a-i). The ten synthetic products 3(a-j) have been synthesized with a [Formula: see text]-geometry about their exocyclic double bond and the structure of one of these compounds (3) was confirmed by a single X-ray diffraction analysis. The new ([Formula: see text]) 5-ylidene rhodanine derivatives 3(a-j) were tested against eight protein kinases

Une histoire de la recherche de substances naturelles à activités thérapeutiques

L identification d une substance naturelle, produite par un organisme vivant n est que l une des toutes premières étapes du développement d un nouveau médicament. Beaucoup de molécules à visée thérapeutique développées par des sociétés pharmaceutiques ont en fait été découvertes dans des laboratoires académiques. C est toujours un continuum de la recherche fondamentale vers la recherche appliquée, souvent de la recherche publique vers la recherche privée, qui aboutit à la mise au point d un médicament. Leur fabrication, directement à partir de substances naturelles, pose fréquemment le problème de l approvisionnement en matière première. De nombreuses équipes du monde entier se heurtent aux difficultés de synthèse de ces molécules naturelles complexes. Ce travail de thèse retrace l histoire des travaux majeurs sur la recherche de molécules naturelles d intérêt médical à travers les succès et les échecs de chercheurs ayant mis leur énergie, leur imagination, leur ténacité et leur patience au service de la science pour surmonter les obstacles et découvrir de nouvelles molécules de grand intérêt thérapeutique. Elle présente également un travail complémentaire de mise au point d une base de données regroupant un certain nombre de plantes utiles dans la lutte contre le cancer dans le cadre d un projet de vulgarisation scientifique. La discussion est consacrée à la question de la place du hasard dans les découvertes scientifiques à travers l'exemple de Pierre Potier.Identifying a natural substance produced by a living organism is only one of the very first steps towards the development of a new drug. Many molecules which were aimed at therapeutic goals and developed by pharmaceutical companies have in fact been discovered in academic research laboratories. The elaboration of a new drug is always a continuum from basic research toward applied research, and often from public research toward private research. Making these drugs straight from natural substances frequently confronts us with the problem of finding the raw materials. Numerous teams all over the world are facing the difficulties linked to the synthesis of these complex natural molecules.This PhD thesis relates the story of the milestones in the research of natural molecules for medicine through the successes and failures of scientists who put their energy, imagination, tenacity and patience into Science in order to overcome obstacles and discover new molecules for therapeutic use.It also presents a complementary work which consists in developing a database of useful plants in cancer fighting as part of a project of scientific vulgarisation. The discussion is about the part of chance in scientific discovery through the example of Pierre Potier.BORDEAUX1-Bib.electronique (335229901) / SudocSudocFranceF

Inhibition of NF-κB-mediated signaling by the cyclin-dependent kinase inhibitor CR8 overcomes pro-survival stimuli to induce apoptosis in chronic lymphocytic leukemia cells

Purpose: Chronic lymphocytic leukemia (CLL) is currently incurable with standard chemotherapeutic agents, highlighting the need for novel therapies. Overcoming proliferative and cytoprotective signals generated within the microenvironment of lymphoid organs is essential for limiting CLL progression and ultimately developing a cure. Experimental Design: We assessed the potency of cyclin-dependent kinase (CDK) inhibitor CR8, a roscovitine analog, to induce apoptosis in primary CLL from distinct prognostic subsets using flow cytometry–based assays. CLL cells were cultured in in vitro prosurvival and proproliferative conditions to mimic microenvironmental signals in the lymphoid organs, to elucidate the mechanism of action of CR8 in quiescent and proliferating CLL cells using flow cytometry, Western blotting, and quantitative real-time PCR. Results: CR8 was 100-fold more potent at inducing apoptosis in primary CLL cells than roscovitine, both in isolated culture and stromal-coculture conditions. Importantly, CR8 induced apoptosis in CD40-ligated CLL cells and preferentially targeted actively proliferating cells within these cultures. CR8 treatment induced downregulation of the antiapoptotic proteins Mcl-1 and XIAP, through inhibition of RNA polymerase II, and inhibition of NF-κB signaling at the transcriptional level and through inhibition of the inhibitor of IκB kinase (IKK) complex, resulting in stabilization of IκBα expression. Conclusions: CR8 is a potent CDK inhibitor that subverts pivotal prosurvival and proproliferative signals present in the tumor microenvironment of CLL patient lymphoid organs. Our data support the clinical development of selective CDK inhibitors as novel therapies for CLL

Synthesis of new pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs as DYRK1A inhibitors

International audienceNew pyridazino[4,5-b]indol-4-ones and pyridazin-3(2H)-one analogs were synthesized and their inhibitory activities against DYRK1A, CDK5/p25, GSK3α/β and p110-α isoform of PI3K evaluated using harmine as reference. Both furan-2-yl 10 and pyridin-4-yl 19 from the two different series, exhibited submicromolar IC50 against DYRK1A with no activities against the three other kinases. In addition, compound 10 exhibited antiproliferative activities in the Huh-7, Caco2 and MDA-MB-231 cell lines