A Saccharomyces cerevisiae sterol auxotroph, FY3 (a hem] erg7 ura), was used to probe the characteristics of sterol uptake in S. cerevisiae. The steady-state cellular concentration of free sterol at the late exponential phase of growth could be adjusted within a 10-fold range by varying the concentration of exogenously supplied sterol. When cultured on 1 ,ug of sterol ml-', the cells contained a minimal cellular free-cholesterol concentration of 0.85 nmol/mg (dry weight) and were termed sterol depleted. When cultured on 11 ,ug of sterol ml-' or more, the cells contained a maximal cellular free-cholesterol concentration of 6.8 nmol/mg (dry weight) and were termed free sterol saturated. Cells with free-sterol concentrations below the maximal level were capable of accumulating free sterol from the medium. The capacity of the cells for cholesterol uptake was inversely proportional to the initial intracellular concentration. The uptake of sterol was shown to be a nonactive process that is independent of cellular energy sources or viability. The intracellular transport of sterol for esterification is not sensitive to anti-microtubule agents.

The 5-HTR agonist lorcaserin, clinically approved for the treatment of obesity, causes important side effects mainly related to subtype selectivity. In the search for 5-HTR allosteric modulators as safer antiobesity drugs, a chemical library from Vivia Biotech was screened using ExviTech platform. Structural modifications of identified hit VA240 in synthesized analogues 6-41 afforded compound 11 (N-[(1-benzyl-1H-indol-3-yl)methyl]pyridin-3-amine, VA012), which exhibited dose-dependent enhancement of serotonin efficacy, no significant off-target activities, and low binding competition with serotonin or other orthosteric ligands. PAM 11 was very active in feeding inhibition in rodents, an effect that was not related to the activation of 5-HTR. A combination of 11 with the SSRI sertraline increased the anorectic effect. Subchronic administration of 11 reduced food intake and body weight gain without causing CNS-related malaise. The behavior of compound 11 identified in this work supports the interest of a serotonin 5-HTR PAM as a promising therapeutic approach for obesity.

Background: Podocalyxin (podxl) is a heavily glycosylated transmembrane protein mainly found on the apical membrane of rat podocytes and also in endothelial, hematopoietic, and tumor cells. Despite of its interest no much is known about the transcriptional regulation of podxl in different cells. Thus, we aimed at studying the functional features of the 5'-regulatory region of the human Podxl gene.

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A group of wild broodstock of Senegalese sole Solea senegalensis was introduced into a culture facility in southwest Spain for endocrinological studies, and fish were kept under standard culture conditions . External signs of disease (dark coloration, hyperactivity, uncoordinated swimming and behavior) appeared suddenly, and the group experienced almost 100% mortality thereafter. The few survivors from this group, kept in a different facility, developed similar signs the next year. The cause of the disease was unclear, although viruslike structures were observed in ultrathin sections of kidney from one diseased fish, and it was possible to isolate a birnavirus from all the visceral and skin homogenates from this and other specimens inoculated onto samples of the CHSE-214 (chinook salmon embryo) cell line . Further serologic, phenotypic, and biochemical characterizations of the agent indicated its similarity to infectious pancreatic necrosis virus (IPNV) . Western blot assays using the anti-IPNV monoclonal antibody AS 1 reacted positively with the VP2 protein of the new agent . A complementary DNA fragment was amplified from each of the IPNV reference strains tested and from the virus isolated from S. senegalensis . In all cases, the fragments amplified were of 339 base pairs, as expected . The results show that the new isolate is an aquatic birnavirus .