Developmental regulation of p70 S6 kinase by a G protein-coupled receptor dynamically modelized in primary cells

The mechanisms whereby G protein-coupled receptors (GPCR) activate signalling pathways involved in mRNA translation are ill-defined, in contrast to tyrosine kinase receptors (TKR). We compared a GPCR and a TKR, both endogenously expressed, for their ability to mediate phosphorylation of 70-kDa ribosomal S6 kinase p70S6K in primary rat Sertoli cells at two developmental stages. In proliferating cells stimulated with follicle-stimulating hormone (FSH), active p70S6K was phosphorylated on T389 and T421/S424, through cAMP-dependent kinase (PKA) and phosphatidyl-inositide-3 kinase (PI3K) antagonizing actions. In FSH-stimulated differentiating cells, active p70S6K was phosphorylated solely on T389, PKA and PI3K independently enhancing its activity. At both developmental stages, insulin-induced p70S6K regulation was consistent with reported data. Therefore, TKR and GPCR trigger distinct p70S6K active conformations. p70S6K developmental regulation was formalized in a dynamic mathematical model fitting the data, which led to experimentally inaccessible predictions on p70S6K phosphorylation rate.     

Ethical principles and guidelines for scientific experiments on animals

Ethical principles and guidelines for scientific experiments on animals     

Effect of alkoxyglycerols on the serum ornithine carbamoyl transferase in connection with radiation treatment

Résumé L'ornithine carbamoyl transférase du sérum (S-OCT) augmente après un traitement aux rayons. L'augmentation la plus marquée a été observée le 4ème jour après le commencement de la radiothérapie. Nous n'avons toutefois observé qu'une petite augmentation de S-OCT lorsque des alcoxyglycérols ont été administrés prophylactiquement et pendant le traitement aux rayons.     

Sulindac sulfide suppresses 5-lipoxygenase at clinically relevant concentrations

Sulindac is a non-selective inhibitor of cyclooxygenases (COX) used to treat inflammation and pain. Additionally, non-COX targets may account for the drug’s chemo-preventive efficacy against colorectal cancer and reduced gastrointestinal toxicity. Here, we demonstrate that the pharmacologically active metabolite of sulindac, sulindac sulfide (SSi), targets 5-lipoxygenase (5-LO), the key enzyme in the biosynthesis of proinflammatory leukotrienes (LTs). SSi inhibited 5-LO in ionophore A23187- and LPS/fMLP-stimulated human polymorphonuclear leukocytes (IC₅₀ ≈ 8–10 μM). Importantly, SSi efficiently suppressed 5-LO in human whole blood at clinically relevant plasma levels (IC₅₀ = 18.7 μM). SSi was 5-LO-selective as no inhibition of related lipoxygenases (12-LO, 15-LO) was observed. The sulindac prodrug and the other metabolite, sulindac sulfone (SSo), failed to inhibit 5-LO. Mechanistic analysis demonstrated that SSi directly suppresses 5-LO with an IC₅₀ of 20 μM. Together, these findings may provide a novel molecular basis to explain the COX-independent pharmacological effects of sulindac under therapy.     

Participative Methodology for Local Development: The Contribution of Engineers Without Borders from Italy and Colombia: Towards the Improvement of Water Quality in Vulnerable Communities

This paper presents a systemic methodology by which engineering is put to use in vulnerable communities through applied technological research and the main results of its application. The methodology presented corresponds to one implemented and designed by two groups of Engineers without Borders in Europe and Latin America, to integrate technical know-how with local context in communities with water problems in Colombia and the Democratic Republic of Congo. The main results of this methodology are related to the improvement of the living conditions of vulnerable groups thanks to the integration of the communities?? knowledge with engineering know-how, leading to autonomous communities and engineering professors and students learning from real life problems to enrich applied sciences.     

High temperatures in the Late Cretaceous Arctic Ocean

To understand the climate dynamics of the warm, equable greenhouse world of the Late Cretaceous period, it is important to determine polar palaeotemperatures. The early palaeoceanographic history of the Arctic Ocean has, however, remained largely unknown, because the sea floor and underlying deposits are usually inaccessible beneath a cover of floating ice. A shallow piston core taken from a drifting ice island in 1970 fortuitously retrieved unconsolidated Upper Cretaceous organic-rich sediment from Alpha ridge, a submarine elevated feature of probable oceanic origin. A lack of carbonate in the sediments from this core has prevented the use of traditional oxygen-isotope palaeothermometry. Here we determine Arctic palaeotemperatures from these Upper Cretaceous deposits using TEX86, a new palaeothermometer that is based on the composition of membrane lipids derived from a ubiquitous component of marine plankton, Crenarchaeota. From these analyses we infer an average sea surface temperature of approximately 15 degrees C for the Arctic Ocean about 70 million years ago. This calibration point implies an Equator-to-pole gradient in sea surface temperatures of approximately 15 degrees C during this interval and, by extrapolation, we suggest that polar waters were generally warmer than 20 degrees C during the middle Cretaceous (approximately 90 million years ago).     

Alpha-neurexins couple Ca2+ channels to synaptic vesicle exocytosis

Synapses are specialized intercellular junctions in which cell adhesion molecules connect the presynaptic machinery for neurotransmitter release to the postsynaptic machinery for receptor signalling. Neurotransmitter release requires the presynaptic co-assembly of Ca2+ channels with the secretory apparatus, but little is known about how synaptic components are organized. Alpha-neurexins, a family of >1,000 presynaptic cell-surface proteins encoded by three genes, link the pre- and postsynaptic compartments of synapses by binding extracellularly to postsynaptic cell adhesion molecules and intracellularly to presynaptic PDZ domain proteins. Using triple-knockout mice, we show that alpha-neurexins are not required for synapse formation, but are essential for Ca2+-triggered neurotransmitter release. Neurotransmitter release is impaired because synaptic Ca2+ channel function is markedly reduced, although the number of cell-surface Ca2+ channels appears normal. These data suggest that alpha-neurexins organize presynaptic terminals by functionally coupling Ca2+ channels to the presynaptic machinery.