RECENT ADVANCES IN METAL-CATALYZED C-H FUNCTIONALIZATION OF PYRIMIDINONES, QUINAZOLINONES AND FUSED QUINAZOLINONES

International audienceThis review emphasises the recent developments in metal-catalyzed functionalization using direct C-H bond activation of pyrimidinones (uracils), quinazolinones and quinazolinone-based fused poly-N-heterocycles as well as metal-catalyzed C-H functionalization of high valuable 2-arylquinazolinones

Synthesis of Thiazolo[5,4-f]quinazolin-9(8H)-ones as Multi-Target Directed Ligands of Ser/Thr Kinases

International audienceA library of thirty novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives belonging to four series designated as 12, 13, 14 and 15 was efficiently prepared, helped by microwave-assisted technology when required. The efficient multistep synthesis of methyl 6-amino-2-cyano- benzo[d]thiazole-7-carboxylate (1) has been reinvestigated and performed on a multigram scale. The inhibitory potency of the final products against five kinases involved in Alzheimer’s disease was evaluated. This study demonstrates that some molecules of the 12 and 13 series described in this paper are particularly promising for the development of new multi-target inhibitors of kinase

Synthesis of bioactive 2-(arylamino)thiazolo[5,4-f]-quinazolin-9-ones via the Hügershoff reaction or Cu- catalyzed intramolecular C-S bond formation

International audienceA library of thirty eight novel thiazolo[5,4-f]quinazolin-9(8H)-one derivatives (series 8, 10, 14 and 17) was prepared via the Hügershoff reaction and a Cu catalyzed intramolecular C-S bond formation, helped by microwave-assisted technology when required. The efficient multistep synthesis of the key 6-amino-3-cyclopropylquinazolin-4(3H)-one (3) has been reinvestigated and performed on a multigram scale from the starting 5-nitroanthranilic acid. The inhibitory potency of the final products was evaluated against five kinases involved in Alzheimer’s disease and showed that some molecules of the 17 series described in this paper are particularly promising for the development of novel multi-target inhibitors of kinases

Short-term effects on heart rate variability of occipito-mastoid suture normalization in healthy subjects

Occipito-mastoid structure normalization (OMSN) is an osteopathic manipulative treatment aimed at reducing tension around the jugular foramen, where cranial nerves IX, X, and XI exit the skull. The purpose of this study was to observe how heart rate variability (HRV), a marker of autonomic cardiac regulation, was modulated after an OMSN vs. a sham technique (SHAM). Pre- and post-intervention HRV was analyzed in two randomly chosen groups of 15 participants (OMSN vs. SHAM group). HRV was collected in the supine position 5 min before and 5 min after a 10-min application of either OMSN or SHAM. The time and group effect was analyzed using a two-way ANOVA. Independently from group intervention, a significant time effect induced increased HRV. No group effect differences were observed. Multiple comparisons for time and group interaction showed that the root mean square of successive differences (RMSSD), a vagally mediated HRV variable, increased to a greater extent for the OMSN group (p = 0.03) than for the SHAM group. However, both OMSN and SHAM techniques had a significant effect on HRV. Compared to a SHAM technique, OMSN had a significant effect on HRV vagally related metric RMSSD in the short term. We conclude that 10 min of OMSN may be used to induce a short-term influence on parasympathetic autonomic nervous system modulations

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

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Measures de vent 3D avec le lidar Doppler coherent Live à bord d'un avion

International audienceA three-dimensional (3D) wind profiling Lidar, based on the latest high power 1.5 µm fiber laser development at Onera, has been successfully flown on-board a SAFIRE (Service des Avions Français Instrumentés pour la Recherche en Environnement) ATR42 aircraft. The Lidar called LIVE (LIdar VEnt) is designed to measure wind profiles from the aircraft down to ground level, with a horizontal resolution of 3 km, a vertical resolution of 100 m and a designed accuracy on each three wind vector components better than 0.5 m.s −1. To achieve the required performance, LIVE Lidar emits 410 µJ laser pulses repeating at 14 KHz with a duration of 700 ns and uses a conical scanner of 30 • total opening angle and a full scan time of 17 s.Un lidar vent 3D, basé sur le dernier développement de laser à fibre de 1,5 µm à haute puissance de l’ONERA a été testé avec succès à bord d’un avion SAFIRE ATR42. Le lidar appelé LIVE est conçu pour mesurer les profils de vent de l’avion jusqu'au sol, avec une résolution horizontale de 3 km, une résolution verticale de 100 m et une précision calculée supérieure à 0,5 m / s pour chaque composante du vecteur du vent

Polymeric nanocapsules prevent oxidation of core-loaded molecules: evidence based on the effects of docosahexaenoic acid and neuroprostane on breast cancer cells proliferation

International audienceBackground:Nanocapsules, as a delivery system, are able to target drugs and other biologically sensitive moleculesto specific cells or organs. This system has been intensively investigated as a way to protect bioactives drugs frominactivation upon interaction with the body and to ensure the release to the target. However, the mechanism ofimproved activity of the nanoencapsulated molecules is far from being understood at the cellular and subcellularlevels. Epidemiological studies suggest that dietary polyunsaturated fatty acids (PUFA) can reduce the morbidityand mortality from breast cancer. This influence could be modulated by the oxidative status of the diet and it hasbeen suggested that the anti-proliferative properties of docosahexaenoic acid (DHA) are enhanced by pro-oxidantagents Methods:The effect of encapsulation of PUFA on breast cancer cell proliferation in different oxidative mediumwas evaluated in vitro. We compared the proliferation of the human breast cancer cell line MDA-MB-231 and ofthe non-cancer human mammary epithelial cell line MCF-10A in different experimental conditions. Results:DHA possessed anti-proliferative properties that were prevented by alpha-tocopherol (an antioxidant) andenhanced by the pro-oxidant hydrogen peroxide that confirmsthat DHA has to be oxidized to exert its anti-proliferativeproperties. We also evaluated the anti-proliferative effects of the 4(RS)-4-F4t-neuroprostane, a bioactive, non-enzymaticoxygenated metabolite of DHA known to play a major role inthe prevention of cardiovascular diseases. DHA-loadednanocapsules was less potent than non-encapsulated DHA while co-encapsulation of DHA with H2O2maintainedthe inhibition of proliferation. The nanocapsules slightly improves the anti-proliferative effect in the case of4(RS)-4-F4t-neuroprostane that is more hydrophilic than DHA. Conclusion:Overall, our findings suggest that the sensitivity of tumor cell lines to DHA involves oxidized metabolites.They also indicate that neuroprostane is a metabolite participating in the growth reducing effect of DHA, but it is not thesole. These results also suggest that NC seek to enhance the stability against degradation, enhance cellular availability,and control the release of bioactive fatty acids following their lipophilicities

Herpes-Virus Infection in Patients with Langerhans Cell Histiocytosis: A Case-Controlled Sero-Epidemiological Study, and In Situ Analysis

BACKGROUND: Langerhans cell histiocytosis (LCH) is a rare disease that affects mainly young children, and which features granulomas containing Langerhans-type dendritic cells. The role of several human herpesviruses (HHV) in the pathogenesis of LCH was suggested by numerous reports but remains debated. Epstein-barr virus (EBV, HHV-4), & Cytomegalovirus (CMV, HHV-5) can infect Langerhans cells, and EBV, CMV and HHV-6 have been proposed to be associated with LCH based on the detection of these viruses in clinical samples. METHODOLOGY: We have investigated the prevalence of EBV, CMV and HHV-6 infection, the characters of antibody response and the plasma viral load in a cohort of 83 patients and 236 age-matched controls, and the presence and cellular localization of the viruses in LCH tissue samples from 19 patients. PRINCIPAL FINDINGS: The results show that prevalence, serological titers, and viral load for EBV, CMV and HHV-6 did not differ between patients and controls. EBV was found by PCR in tumoral sample from 3/19 patients, however, EBV small RNAs EBERs -when positive-, were detected by in situ double staining in bystander B CD20+ CD79a+ lymphocytes and not in CD1a+ LC. HHV-6 genome was detected in the biopsies of 5/19 patients with low copy number and viral Ag could not be detected in biopsies. CMV was not detected by PCR in this series. CONCLUSIONS/SIGNIFICANCE: Therefore, our findings do not support the hypothesis of a role of EBV, CMV, or HHV-6 in the pathogenesis of LCH, and indicate that the frequent detection of Epstein-barr virus (EBV) in Langerhans cell histiocytosis is accounted for by the infection of bystander B lymphocytes in LCH granuloma. The latter observation can be attributed to the immunosuppressive micro environment found in LCH granuloma

Multi-messenger observations of a binary neutron star merger

On 2017 August 17 a binary neutron star coalescence candidate (later designated GW170817) with merger time 12:41:04 UTC was observed through gravitational waves by the Advanced LIGO and Advanced Virgo detectors. The Fermi Gamma-ray Burst Monitor independently detected a gamma-ray burst (GRB 170817A) with a time delay of ~1.7 s with respect to the merger time. From the gravitational-wave signal, the source was initially localized to a sky region of 31 deg2 at a luminosity distance of 40+8-8 Mpc and with component masses consistent with neutron stars. The component masses were later measured to be in the range 0.86 to 2.26 Mo. An extensive observing campaign was launched across the electromagnetic spectrum leading to the discovery of a bright optical transient (SSS17a, now with the IAU identification of AT 2017gfo) in NGC 4993 (at ~40 Mpc) less than 11 hours after the merger by the One- Meter, Two Hemisphere (1M2H) team using the 1 m Swope Telescope. The optical transient was independently detected by multiple teams within an hour. Subsequent observations targeted the object and its environment. Early ultraviolet observations revealed a blue transient that faded within 48 hours. Optical and infrared observations showed a redward evolution over ~10 days. Following early non-detections, X-ray and radio emission were discovered at the transient’s position ~9 and ~16 days, respectively, after the merger. Both the X-ray and radio emission likely arise from a physical process that is distinct from the one that generates the UV/optical/near-infrared emission. No ultra-high-energy gamma-rays and no neutrino candidates consistent with the source were found in follow-up searches. These observations support the hypothesis that GW170817 was produced by the merger of two neutron stars in NGC4993 followed by a short gamma-ray burst (GRB 170817A) and a kilonova/macronova powered by the radioactive decay of r-process nuclei synthesized in the ejecta