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

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Phosphorylation of CLEC-2 is dependent on lipid rafts, actin polymerization,secondary mediators, and Rac

The C-type lectin-like receptor 2 (CLEC-2)activates platelets through Src and Syk tyrosine kinases via a single cytoplasmic YxxL motif known as a hem immunoreceptor tyrosine-based activation motif (hemITAM).Here, we demonstrate using sucrose gradient ultracentrifugation and methyl--cyclodextrin treatment that CLEC-2 translocates to lipid rafts upon ligand engagement and that translocation is essential for hemITAM phosphorylation and signal initiation. HemITAM phosphorylation, but not translocation, is also critically dependent on actin polymerization,Rac1 activation, and release of ADP and thromboxane A2 (TxA2). The role of ADP and TxA2 in mediating hosphorylation is dependent on ligand engagement and rac activation but is independent of platelet aggregation. In contrast,tyrosine phosphorylation of the GPVIFcR -chain ITAM, which has 2 YxxL motifs,is independent of actin polymerization and secondary mediators. These results reveal a unique series of proximal events in CLEC-2 phosphorylation involving actin polymerization, secondary mediators,and Rac activation

Observation of Hybrid Earthquakes at Nyamulagira Volcano in the Democratic Republic of the Congo

The Nyamulagira volcano is located in the western branch of the East African rift (bordered by a many faults) and is often characterized by fissural eruptions of very potassic fluid lavas. These eruptions are preceded by a variety of pre-eruptive low-frequency seismic signals. Hybrid earthquakes are one of these signals. In this short communication, we collected seismic data over a four-year period from 2011 to 2014 (a period during which two eruptions Were observed at Nyamulagira: one in November 2011, another in June 2014) at the station of Rusayo and Kibumba which are very close to this volcano (about 10 km), with the aim of analyzing the characteristics of hybrid earthquakes as well as the volcanic activity that they accompany. We found that these earthquakes are characterized by a high frequency  occurrence ranged between 3 and 10 Hz, they often occur  in swarms and located at shallow depths between 0 and 5 km. They are interpreted as being related to a movement of breakage of rocks by fluids and generally in weakness areas that are the emplacement of cracks and faults of the East African Rift. They therefore accompany magmatic intrusions and precede most of the fissural eruptions observed at Nyamulagira volcano. These hybrid earthquakes are used as indicators of imminent eruptions and their observation is an effective tool for monitoring the Nyamulagira volcano

Rheological and textural properties of lafun, a stiff dough, from improved cassava varieties

We studied the textural and rheological (viscoelastic) properties of fresh lafun dough, a fermented cassava product, and their changes during storage at 45 °C for 5 and 24 h, in order to determine after‐cooking storability. Lafun flours were produced from three types of cassava varieties: seven improved white‐fleshed varieties, seven improved provitamin A carotenoids (pVAC) varieties and two local white‐fleshed varieties; and processed into lafun doughs. Pasting properties of the flours were assessed. Flours from local varieties had pasting profiles with highest viscosities, while pVAC flours had the lowest. The three types of cassava varieties varied significantly in most of their pasting properties. Four promising improved varieties were identified, based on high peak viscosity (55.8–61.5 P) and stiffer texture than local varieties during storage. Undesirable varieties were also found, which softened during storage instead of hardening. Optimum texture of lafun dough was obtained after 5 h of storage

Role of Gas6 Receptors in Platelet Signaling during Thrombus Stabilization and Implications for Antithrombotic Therapy

Mechanisms regulating thrombus stabilization remain largely unknown. Here, we report that loss of any 1 of the Gas6 receptors (Gas6-Rs), i.e., Tyro3, Axl, or Mer, or delivery of a soluble extracellular domain of Axl that traps Gas6 protects mice against life-threatening thrombosis. Loss of a Gas6-R does not prevent initial platelet aggregation but impairs subsequent stabilization of platelet aggregates, at least in part by reducing “outside-in” signaling and platelet granule secretion. Gas6, through its receptors, activates PI3K and Akt and stimulates tyrosine phosphorylation of the β3 integrin, thereby amplifying outside-in signaling via αIIbβ3. Blocking the Gas6-R–αIIbβ3 integrin cross-talk might be a novel approach to the reduction of thrombosis

Insect Chemical defense

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Enantioselective syntheses and absolute configuration of the ladybird defence alkaloids (+)-calvine and (+)-2-epicalvine

Enantiomerically pure (+)-calvine (1a) and (+)-2-epicalvine (1b), two piperidine alkaloids isolated from ladybird beetles of the genus Calvia (Coccinellidae), were synthesized by two different strategies starting from (−)-2,3,6,7,8,8a-hexahydro-3-phenyl-5H-[1,3]oxazolo[3,2-a]pyridine-5-carbonitrile (2). The key steps of these syntheses are the stereocontrolled formation of an asymmetric centre α to the nitrogen atom of 2 and the subsequent introduction of the methoxycarbonylmethyl substituent at the α′-position. Comparison of the optical rotations of the synthetic benzoates (12a) and (12b) with those of the corresponding benzoates derived from the natural compounds has revealed the absolute configuration of (+)-calvine to be (2S,6S) and that of (+)-2-epicalvine to be (2R,6S).SCOPUS: ar.jFLWINinfo:eu-repo/semantics/publishe

Biosynthèse d'alcaloïdes défensifs de Coccinellidae

info:eu-repo/semantics/nonPublishe

Synthèse asymétrique et configuration absolue des alcaloïdes défensifs de coccinelles du genre Calvia

La famille des Coccinellidae est divisée en six sous-familles et comprend plus de 5200 espèces répandues dans le monde entier. En général, les coccinelles souffrent peu des prédateurs, ce qui peut être attribué a une vaste gamme de défenses (capacité d'envois brusques, camouflage, mimétismes, aposématisme, etc.). Ces insectes disposent également de défenses chimiques: en cas de danger, 1'adulte s'immobilise dans une attitude imitant celle d'un individu mort (thanatose) et secrète des gouttelettes d'hémolymphe au niveau des articulations tibiofémorales de ses pattes par un mécanisme appelé « saignée réflexe ». Chez de nombreuses coccinelles, cet exsudat contient un ou plusieurs alcaloïdes dont l’amertume et la toxicité sont considérées, dans une large mesure, comme une protection vis-à-vis de prédateurs potentiels. Le compose majoritaire contenu dans la sécrétion émise lors de la saignée réflexe de deux coccinelles du genre Calvia est la calvine, l’isomère cis de la lactone. On trouve également dans l’hémolymphe des coccinelles Calvia 14-guttata de petites quantités de 2-epicalvine ainsi que des traces d'adaline. La sécrétion défensive de Calvia 10-guttata contient, en plus de ces trois alcaloïdes, de la propyléine, un alcaloïde déjà isole de Propylaea 14-punctata. Afin de déterminer la configuration absolue de la calvine et de la 2-epicalvine, nous avons entrepris la synthèse asymétrique de ces alcaloïdes. Deux voies de synthèse ont été étudiées, partant toutes les deux de (-)-3-phenyloxazolo[3,2-a]piperidine-5-carbonitrile. Les étapes clé de ces synthèses sont. i) 1'introduction régio- et hautement stéréosélective (ee > 99 %) d'une chaîne pentyle en alpha de 1'atome d'azote; ii) le greffage d'un groupement méthoxycarbonylméthyle en position alpha' par une séquence oxydation anodique - substitution nucléophile ou en utilisant la méthode « CN(R,S)» développée par Husson et ses collaborateurs; iii) l’hydroxyethylation de l’atome d'azote suivie de lactonisation, ce qui nous a permis d'obtenir les deux épimeres, calvine et 2-épicalvine dans un rapport 1/1.La configuration absolue (2S,6S) de la (+)-calvine et celle (2R,6S) de la (+)-2-epicalvine ont été déterminées par comparaison des pouvoirs rotatoires des benzoates de synthèse avec ceux des benzoates dérivant des alcaloïdes naturels

An ecdysteroid (22-acetyl-20-hydroxyecdysone) from the defense gland secretion of an insect: Chrysolina carnifex (Coleoptera: Chrysomelidae)

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