High affinity retinoic acid receptor antagonists: analogs of AGN 193109

A series of high affinity retinoic acid receptor (RAR) antagonists were prepared based upon the known antagonist AGN 193109 (2). Introduction of various phenyl groups revealed a preference for substitution at the para-position relative to the meta-site. Antagonists with the highest affinities for the RARs possessed hydrophobic groups, however, the presence of polar functionality was also well tolerated.     

Complete genome sequence of the genetically tractable hydrogenotrophic methanogen Methanococcus maripaludis

The genome sequence of the genetically tractable, mesophilic, hydrogenotrophic methanogen Methanococcus maripaludis contains 1,722 protein-coding genes in a single circular chromosome of 1,661,137 bp. Of the protein-coding genes (open reading frames [ORFs]), 44% were assigned a function, 48% were conserved but had unknown or uncertain functions, and 7.5% (129 ORFs) were unique to M. maripaludis. Of the unique ORFs, 27 were confirmed to encode proteins by the mass spectrometric identification of unique peptides. Genes for most known functions and pathways were identified. For example, a full complement of hydrogenases and methanogenesis enzymes was identified, including eight selenocysteine-containing proteins, with each being paralogous to a cysteine-containing counterpart. At least 59 proteins were predicted to contain iron-sulfur centers, including ferredoxins, polyferredoxins, and subunits of enzymes with various redox functions. Unusual features included the absence of a Cdc6 homolog, implying a variation in replication initiation, and the presence of a bacterial-like RNase HI as well as an RNase HII typical of the Archaea. The presence of alanine dehydrogenase and alanine racemase, which are uniquely present among the Archaea, explained the ability of the organism to use L- and D-alanine as nitrogen sources. Features that contrasted with the related organism Methanocaldococcus jannaschii included the absence of inteins, even though close homologs of most intein-containing proteins were encoded. Although two-thirds of the ORFs had their highest Blastp hits in Methanocaldococcus jannaschii, lateral gene transfer or gene loss has apparently resulted in genes, which are often clustered, with top Blastp hits in more distantly related groups.     

Effect of maternal serum on viability and function of early human placental explants

Summary Fetal bovine serum (FBS) is frequently used to supplement chemically defined media such as Ham’s F10 when studying placental explant cultures. However in vitro production of hormones is usually declining by the 2nd or 3rd day and is short-lived (7 to 10 days). In this study we explored the use of human maternal serum (HMS) from early gestation as the medium supplement to Ham’s F10. Early placental hormone production was compared using two concentrations of FBS and HMS. On Day 3 of incubation, progesterone production in 10% HMS was 12-fold increased over that in 10% FBS, estradiol production was increased 10-fold, and βhCG production more than 3-fold. When the serum concentrations were increased to 40%, the results in all cases were similar to those at 10%. Preliminary characterization studies revealed that the stimulatory activity of HMS is heat-labile, neither extractable into organic solvent (diethyl ether) nor dialyzable, suggesting that it is protein in nature. In a long-term incubation, compared with FBS (7 days), HMS permitted survival of culture up to 30 days, judged both histologically and biochemically. We conclude that HMS provides substance(s), probably protein in nature, not present in FBS or non-pregnant human serum, which are important for human placental viability and function in vivo.     

Killing, letting die and moral perception

There are a number of arguments that purport to show, in general terms, that there is no difference between killing and letting die. These are used to justify active euthanasia on the basis of the reasons given for allowing patients to die. I argue that the general and abstract arguments fail to take account of the complex and particular situations which are found in the care of those with terminal illness. When in such situations, there are perceptions and intuitions available that do not easily find propositional form but lead most of those whose practice is in the care of the dying to resist active euthanasia. I make a plea for their intuitions to be heeded above the sterile voice of abstract premises and arguments by examining the completeness of the outline form of the pro-euthanasia argument. In doing so, I make use of Nussbaum's discussion of moral perception and general claims to be found in the literature of moral particularism.     

Schistosoma mansoni: a comparative study of plasma and erythrocyte lipid alterations in the experimentally infected mouse and in selected human patients

Alterations of plasma and erythrocyte lipids associated with hepatosplenic schistosomiasis mansoni were studied in the mouse and in human patients. Qualitative and quantitative differences were observed between the two species which indicated that the experimentally infected mouse should not be used as a model for altered lipid metabolism associated with Schistosoma mansoni infections in man. Also blood lipid values should not be used as prophylactic indicators for experimental therapeutical studies in the infected mouse, although lipid determinations could have clinical value in studies of human patients. In infected mice plasma cholesterol and phospholipid were significantly reduced (40 and 25%, respectively), but proportions of individual plasma phospholipids were unchanged. In contrast, only plasma cholesterol was reduced in human patients with compensated or decompensated hepatosplenic schistosomiasis (16 and 29%, respectively); of the individual phospholipids, lecithin was significantly increased and lysolecithin was decreased. The percentage of plasma total cholesterol was reduced in infected mice and patients suggesting that hypocholesterolemia is due mainly to decreased cholesteryl ester. Lipid changes also occurred in erythrocytes. Those of infected mice had significantly elevated membrane phospholipid content and no changes in cholesterol or in the proportions of the individual phospholipid fractions. In marked contrast, the erythrocytes of two groups of human patients had significantly higher levels of cholesterol without a raised total phospholipid concentration. Moreover, decreased proportions of lysolecithin and increased proportions of lecithin were apparent although only the increased membrane lecithin associated with compensated patients was statistically significant.     

Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein

Sclerosteosis is an autosomal recessive sclerosing bone dysplasia characterized by progressive skeletal overgrowth. The majority of affected individuals have been reported in the Afrikaner population of South Africa, where a high incidence of the disorder occurs as a result of a founder effect. Homozygosity mapping in Afrikaner families along with analysis of historical recombinants localized sclerosteosis to an interval of approximately 2 cM between the loci D17S1787 and D17S930 on chromosome 17q12-q21. Here we report two independent mutations in a novel gene, termed "SOST." Affected Afrikaners carry a nonsense mutation near the amino terminus of the encoded protein, whereas an unrelated affected person of Senegalese origin carries a splicing mutation within the single intron of the gene. The SOST gene encodes a protein that shares similarity with a class of cystine knot-containing factors including dan, cerberus, gremlin, prdc, and caronte. The specific and progressive effect on bone formation observed in individuals affected with sclerosteosis, along with the data presented in this study, together suggest that the SOST gene encodes an important new regulator of bone homeostasis.