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Preeclampsia is a placenta-dependent disorder with both local and systemic anomalies with neonatal and maternal morbidity. It is manifested late in pregnancy, but the onset is during early stages of gestation. The current hypothesis regarding the aetiology of preeclampsia is focused on maladaptation of immune responses and defective trophoblast invasion. Thus, an excessive maternal inflammatory response, perhaps directed against foreign fetal antigens, results in a chain of events including shallow trophoblast invasion, defective spiral artery remodelling, placental infarction and release of pro-inflammatory cytokines and placental fragments in the systemic circulation. During normal pregnancy, trophoblasts interact in the decidua with the unique uterine NK cells, modifying their cytokine repertoire, regulating adhesion molecules and matrix metalloproteinases. The inability of trophoblasts to accomplish these changes might be a critical factor for the onset of preeclampsia. Several cytokines, produced at the maternal-fetal interface, have an impact on trophoblast invasion. It is suggested that deficiency of interleukin-10 may contribute to enhanced inflammatory responses towards the trophoblasts elicited by e.g. tumour necrosis factor-alpha and interferon-gamma. Consequently, trophoblasts subjected to a high rate of apoptosis are hampered in their invasive capacity resulting in defective transformation of spiral arteries, hypoxia, thrombosis and infarction of the placenta. The ensuing infarction of placenta leads to leakage of increasing amounts of placental fragments and cytokines in the maternal circulation and an exaggerated systemic endothelial activation as identified in preeclampsia. So far, treatment of preeclampsia is focused on signs like hypertension, whereas attempts of modifying immune responses may be a possibility in the future.
The prfB gene encodes peptide-chain-release factor 2 of Escherichia cofi, which catalyzes translation termination at UGA and UAA codons. The gene, identified by sequencing, is located at the 62-min region of the E. coli chromosome. The pra gene is followed by an open reading frame encoding a 57,603-Da protein. This downstream open reading frame was identified as herC, a gene defined by a suppressor mutation that restores replication of a ColEl plasmid mutant. RNA blot hybridization and S1 nuclease protection analyses of in vivo transcripts showed thatprjB and herC are cotranscribed into a 2800-base transcript in the counterclockwise direction with respect to the E. coli genetic map. Thus, we refer to the two genes as the prfB-herC operon. Data are presented that suggest that supK, a mutation in Salmonella typhimurium that suppresses UGA termination, is the structural gene for Salmonella release factor 2. Translation control within the prJB-herC operon and the relationship of these genes to a tRNA methyltransferase are discussed.Polypeptide chain termination requires participation of two peptide-chain-release factors that recognize specific termination codons. Release factor 1 (RF1) catalyzes termination at UAA and UAG codons, and release factor 2 (RF2) catalyzes termination at UGA and UAA codons (1).The RF1 gene has been cloned on the basis of competition between a nonsense suppressor tRNA and a translation release factor. The increased RF1 concentration due to the increased RF1 gene dosage reduces the efficiency of suppression by a glutamine-inserting UAG suppressor, supE (2). The gene encoding RF1 has been named prfA and is located at 27 min on the Escherichia coli genome. Near 27 min on the genetic map, uar and sueB mutations have also been located.The uar mutant is temperature-sensitive for growth, misreads UAA codons, and increases the efficiency of UAA and UAG nonsense suppression (3). The sueB mutation enhances the efficiency of UAG nonsense suppression (4, 5). Complementation analysis has disclosed that these mutations occur in the prfA gene. The data have been interpreted as direct genetic evidence that RF1 catalyzes translation termination at the UAA and UAG codons in E. coli (6).The RF2 gene has been isolated from the Carbon and Clarke E. coli plasmid bank (7) on the basis of RF2 overproduction detected by an anti-RF2 antibody. The RF2 plasmid also reduces the efficiency oftRNA UGA suppressors in vivo (7). The deduced amino acid sequences of RF1 and RF2 are similar (8). However, the chromosomal location of the RF2 gene had not been reported.The present study was initiated in an effort to explain a mutation designated herC180, which was isolated as a host suppressor of a replication-deficient ColEl plasmid (ref. 9 and K.K., unpublished work). This herC mutation was mapped at 62 min on the E. coli chromosome. Cloning and sequencing analyses with the herC region of the chromosome revealed that the RF2 gene is located immediately upstream of herC in the same transcriptional unit.l MATERIALS AND ME...
Chorismic acid is the common precursor for the biosynthesis of the three aromatic amino acids as well as for four vitamins. Mutants of Escherichia coli defective in any of the genes involved in the synthesis of chorismic acid are also unable to synthesize uridine 5-oxyacetic acid (cmo5U) and its methyl ester (mcmo5U). Both modified nucleosides are normally present in the wobble position of some tRNA species. Mutants defective in any of the specific pathways leading to phenylalanine, tyrosine, tryptophan, folate, enterochelin, ubiquinone, and menaquinone have normal levels of cmo5U and mcmo5U in their tRNA. The presence of shikimic acid in the growth medium restores the ability of an aroD mutant to synthesize cmo5U, while O-succinylbenzoate, which is an early intermediate in the synthesis of menaquinone, does not. Thus, chorismic acid is a key metabolite in the synthesis of these two modified nucleosides in tRNA. The absence of chorismic acid blocks the formation of cmo5U and mcmo5U at the first step, which might be the formation of 5-hydroxyuridine. This results in an unmodified U in the wobble position of tRNA(1Val) and in most of the tRNAs normally containing cmo5U and mcmo5U. Since cmo5U and mcmo5U are synthesized under anaerobic conditions, the formation of these nucleosides does not require molecular oxygen. One of the carbon atoms of the side chain, --O--CH2--COOH, originates from the methyl group of methionine. The other carbon atom does not originate directly from the C-1 pool, from the carboxyl group methionine, or from bicarbonate. This metabolic link between intermediary metabolism and translation also exists for another member of the family Enterobacteriaceae, Salmonella typhimurium, as well as for the distantly related gram-positive organism Bacillus subtilis.
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