Synthesis and evaluation of alkoxy-phenylamides and alkoxy-phenylimidazoles as potent sphingosine-1-phosphate receptor subtype-1 agonists

In the design of potent and selective sphingosine-1-phosphate receptor agonists, we were able to identify two series of molecules based on phenylamide and phenylimidazole analogs of FTY-720. Several designed molecules in these scaffolds have demonstrated selectivity for S1P receptor subtype 1 versus 3 and excellent in vivo activity in mouse. Two molecules PPI-4621 (4b) and PPI-4691 (10a), demonstrated dose responsive lymphopenia, when administered orally.     

Distribution and metabolism of corticotropin-releasing factor in the rat

To develop a mathematical model of the distribution and metabolism of rat corticotropin-releasing factor (rCRF), the time course of 125I-labelled rCRF in plasma was measured in male Sprague-Dawley rats (i) following a rapid injection of 24 ng rCRF/100 g body weight (BW), or (ii) following a rapid injection of 424 ng rCRF/100 g BW, or (iii) during an infusion at a rate ranging from 0.28 to 0.73 ng rCRF X min-1 X 100 g BW-1. The comparison of the one-, two-, and three-compartment models shows that the two-pool structure fits better to the dynamics of CRF in plasma as measured in each rat. Following a rapid injection the decay curve occurs in a biphasic manner; the early phase of disappearance is 25 times faster than the late one. There is no significant difference between the estimates of the metabolic clearance rate following both amplitudes of injection (0.40 +/- 0.06 and 0.48 +/- 0.05 mL X min-1 X 100 g BW-1). The volume of the first pool, 16.8 +/- 1.1 mL/100 g BW, is four times larger than the plasma volume. It would thus appear that CRF is rapidly distributed from plasma into several tissues which are represented in the first pool of the model. The mean residence time of every CRF molecule in the second compartment, from the moment of secretion to its elimination, is from three to four times longer than in the first one. It stays, on average, between 140 min and 3 h in the system before an irreversible exit.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparaisons des séquences d'ADN hautement répétées chez l'homme et diverses espèces de primates

Highly repeated DNA sequences from man, five other primate species and rat were compared using five restriction endonucleases. Calculations of a similarity index based on the mobility of various bands indicate that man, chimpanzee and baboons are very similar. The sequences of the genomes studied have apparently been reorganized during primate evolution.     

Getting western: biogeographical analysis of morphological variation,mitochondrial haplotypes and nuclear markers reveals cryptic species and hybrid zones in the Junonia butterflies of the American southwest and Mexico

The American southwest and northern Mexico has a great degree of endemic diversity compared with the rest of North America. The Pleistocene glaciations and the dispersal of species from glacial refuges in this region have been important engines for the production of biodiversity in the region. The New World Junonia are a recent radiation of butterflies that are thought to have spent time in these refuges during periods of glacial advancement. We have reconstructed the plausible movements and the contemporary geographic distributions of the five taxa (J. coenia, J. grisea, J. litoralis, J. nigrosuffusa and J. zonalis) that occur in the American southwest and northern Mexico using phenotypic and genotypic information primarily from specimens preserved in museum collections, supplemented with additional contemporary collections. Evidence of cryptic species and hybridization events were observed using mitochondrial haplotypes, genotypic variation at the nuclear wingless locus, multilocus DNA fingerprinting, patterns of larval host plant use, variation in life‐history traits and morphological characteristics. Based on these lines of evidence, and in spite of low levels of hybridization between them, we argue that all five Junonia taxa are independent evolutionary lineages. Junonia grisea and J. coenia are morphologically very similar, but differences in morphology, life‐history traits, nuclear genotypes and mitochondrial haplotypes suggest that they are a cryptic species pair, thus elevating J. grisea comb.n. to a full species when it had previously been considered to be a subspecies of J. coenia.     

Salt Content Impacts Food Preferences and Intake among Children

Decreasing dietary sodium intake, which can be achieved by reducing salt content in food, is recommended. Salt contributes to the taste of foods and makes them more enjoyable. Whether a food is liked or disliked is an important determinant of food intake, especially among children. However, the role of salt in children''s food acceptance has received little attention. The impact of salt content on children''s hedonic rating and intake of two foods was investigated in children. Using a within-subject crossover design, we recruited 75 children (8–11 years) to participate in five lunches in their school cafeteria. The target foods were green beans and pasta. The added salt content was 0, 0.6 or 1.2 g/100 g. The children''s intake (g) of all lunch items was measured. The children provided their hedonic rating of the food, a preference ranking and a saltiness ranking in the laboratory. Children could rank the foods according to salt content, and they preferred the two saltier options. A food-specific effect of salt content on intake was observed. Compared to the intermediate level (0.6 g salt/100 g), not adding salt decreased green bean intake (−21%; p = 0.002), and increasing the salt content increased pasta intake (+24%; p<0.0001). Structural Equation Modeling was used to model the relative weights of the determinants of intake. It showed that the primary driver of food intake was the child''s hunger; the second most important factor was the child''s hedonic rating of the food, regardless of its salt content, and the last factor was the child''s preference for the particular salt content of the food. In conclusion, salt content has a positive and food-specific effect on intake; it impacted food preferences and intake differently in children. Taking into account children''s preferences for salt instead of their intake may lead to excessive added salt.     

Peroxisomes and peroxisomal enzymes along the crypt-villus axis of the rat intestine

Abstract. The development of peroxisomes and expression of their enzymes were investigated in differentiating intestinal epithelial cells during their migration along the crypt-villus axis. Sequential cell populations harvested by a low-temperature method were identified by microscopy, determination of alkaline phosphatase and sucrase activities and incorporation of [³H]-thymidine into DNA. Ultrastructural cytochemistry after staining for catalase activity, revealed the presence of peroxisomes in undifferentiated stem cells located in the crypt region. Morphometry indicated that the number of these organelles increased as intestinal epithelial cells differentiate. Catalase activity was higher in the crypt cells than in the mature enterocytes harvested from villus tips. On the other hand, an increasing gradient of activity was observed from crypts to villus tips for peroxisomal oxidases, i.e. fatty acyl coA oxidase, D-amino acid oxidase and polyamine oxidase. These findings indicate that biogenesis of peroxisomes occurs during migration of intestinal epithelial cells along the crypt-villus axis and that peroxisomal oxidases contribute substantially to the biochemical maturation of enterocytes.     

Mechanosensitive Adaptation of E-Cadherin Turnover across adherens Junctions

In the natural and technological world, multi-agent systems strongly depend on how the interactions are ruled between their individual components, and the proper control of time-scales and synchronization is a key issue. This certainly applies to living tissues when multicellular assemblies such as epithelial cells achieve complex morphogenetic processes. In epithelia, because cells are known to individually generate actomyosin contractile stress, each individual intercellular adhesive junction line is subjected to the opposed stresses independently generated by its two partner cells. Contact lines should thus move unless their two partner cells mechanically match. The geometric homeostasis of mature epithelia observed at short enough time-scale thus raises the problem to understand how cells, if considered as noisy individual actuators, do adapt across individual intercellular contacts to locally balance their time-average contractile stress. Structural components of adherens junctions, cytoskeleton (F-actin) and homophilic bonds (E-cadherin) are quickly renewed at steady-state. These turnovers, if they depend on forces exerted at contacts, may play a key role in the mechanical adaptation of epithelia. Here we focus on E-cadherin as a force transducer, and we study the local regulation and the mechanosensitivity of its turnover in junctions. We show that E-cadherin turnover rates match remarkably well on either side of mature intercellular contacts, despite the fact that they exhibit large fluctuations in time and variations from one junction to another. Using local mechanical and biochemical perturbations, we find faster turnover rates with increased tension, and asymmetric rates at unbalanced junctions. Together, the observations that E-cadherin turnover, and its local symmetry or asymmetry at each side of the junction, are mechanosensitive, support the hypothesis that E-cadherin turnover could be involved in mechanical homeostasis of epithelia.     

Poly-l -lysine-gold complexes used at different pH are probes for differential detection of glycosaminoglycans and phosphoproteins in the predentine and dentine of rat incisor

Summary At neutral pH, poly-l-lysine-gold complexes labelled the predentine extensively, whereas in dentine the number of gold complexes was reduced by half. Hyaluronidase pretreatment of the section at pH 6.8, prior to labelling, suppressed most of the staining in predentine and did not affect dentine. In contrast, alkaline phosphatase pretreatment at pH 9 enhanced the gold complex labelling in predentine and removed most of the labelling in dentine. This proves that at pH 7.2, the polyanions which are stained include a heterogeneous population of glycosaminoglycans, located in predentine, and phosphoproteins, visualized in dentine. At acidic pH levels (2.9 and 1.1), the number of scored gold complexes decreased, but the ratio between predentine and dentine labelling remained constant. Hyaluronidase pretreatment removed or firmly reduced the gold complex labelling both in predentine and dentine, whereas alkaline phosphatase pretreatment of the sections at pH 9 prior to labelling did not induce any change. This argues in favour of an increased specificity of polylysine-gold complex staining for glycosaminoglycans, stained at low pH in both predentine and dentine. Differential staining of glycosaminoglycans and phosphoproteins according to the pH provides a useful tool for studying the role played respectively by the two matrix components in dentine mineralization.