lation with anti-CD28 enhanced NFATc nuclear accumulation (Fig. 4B), in keeping with the finding that T H 2 cytokine induction in wildtype T H cells requires costimulation (Fig. 2C). In contrast, anti-CD3 treatment alone led to an increase in nuclear NFATc in Jnk1-/-T H cells and a decrease in cytoplasmic NFATc (Fig. 4, A and B), consistent with the high T H 2 cytokine production by CD3-activated Jnk1-/cells (Fig. 2C). The enhanced accumulation of nuclear NFATc in Jnk1-/-T H cells was observed in cells 8, 24, and 48 hours after stimulation, but was not observed in nonactivated cells (10). NFATc accumulation was specific because the amount of nuclear NFATp, a proposed negative regulator of T H 2 cytokine genes (21), was the same in wild-type and Jnk1-/cells (Fig. 4A). Enhanced nuclear accumulation of NFATc in Jnk1-/-T cells was not blocked by anti-IL-4 (Fig. 4A); hence, increased IL-4 production and NFATc nuclear localization is intrinsic to T cell receptor signaling and is not secondary to IL-4 production. Because NFATc can bind to the IL-4 promoter and is required for IL-4 production and T H 2 differentiation (20, 22), the greatly enhanced amount of nuclear NFATc could account for the increased IL-4 production in CD3activated Jnk1-deficient mice. The mechanism by which JNK1 negatively regulates NFATc nuclear accumulation remains to be resolved. The isoform NFAT4 is phosphorylated and negatively regulated by JNK, leading to nuclear exclusion (23). This regulation appears to be specific to the NFAT4 isoform; evidence for JNK regulation of NFATc was not reported (23). An indirect mechanism may therefore account for the altered regulation of NFATc in Jnk1-/-T H cells. NFATc and NFATp can bind to the IL-4 promoter NFAT sites (22). Both Jnk1 and NFATp knockout mice have enhanced T cell proliferation and T H 2 cytokine production (21, 24), precisely the opposite of the NFATc knockout. It is therefore possible that these two NFAT factors antagonize each other in the regulation of the IL-4 gene. The apparent similarity between NFATp-/and Jnk1-/phenotypes supports a functional linkage between JNK1 and NFAT. Our results further reveal a novel mechanism by which TCR signaling negatively regulates T H 2 cytokines through JNK1. Positive and negative regulation of JNK1 activity may affect the decision of T H cells to differentiate into T H 1 or T H 2 effectors, and therefore may affect the type of immune response that is initiated. The function of JNK1 demonstrated in this study is distinct from that of JNK2, which is required for IFN-␥ production in T H 1 cells (14). Moreover, the related p38 mitogen-activated protein kinase pathway is T H 1 specific and drives IFN-␥ transcription (25). Together, these pathways potentiate the T H 1 response and provide a potential target for pharmaceutical intervention.
The origin of whales and their transition from terrestrial life to a fully aquatic existence has been studied in depth. Palaeontological, morphological and molecular studies suggest that the order Cetacea (whales, dolphins and porpoises) is more closely related to the order Artiodactyla (even-toed ungulates, including cows, camels and pigs) than to other ungulate orders. The traditional view that the order Artiodactyla is monophyletic has been challenged by molecular analyses of variations in mitochondrial and nuclear DNA. We have characterized two families of short interspersed elements (SINEs) that were present exclusively in the genomes of whales, ruminants and hippopotamuses, but not in those of camels and pigs. We made an extensive survey of retropositional events that might have occurred during the divergence of whales and even-toed ungulates. We have characterized nine retropositional events of a SINE unit, each of which provides phylogenetic resolution of the relationships among whales, ruminants, hippopotamuses and pigs. Our data provide evidence that whales, ruminants and hippopotamuses form a monophyletic group.
A phylogenetic tree for fowl including chicken in the genus Gallus and based on mitochondrial D-loop analysis further supports the hypothesis developed from morphology and progeny production that red junglefowl (RJF) is the direct ancestor of the chicken. The phylogenetic positions of the chicken and the other fowl species in the genus Gallus are of great importance when considering maintenance and improvement of chicken breeds through introgression of genetic variation from wild-type genomes. However, because the phylogenetic analysis based on the DNA sequences is not sufficient to conclude the phylogenetic positions of the fowls in the genus, in the present study, we have determined sequences of whole mitochondrial DNA (mtDNA) and two segments of the nuclear genome (intron 9 of ornithine carbamoyltransferase, and four chicken repeat 1 elements) for the species in the genus Gallus. The phylogenetic analyses based on mtDNA sequences revealed that two grey junglefowls (GyJF) were clustered in a clade with RJFs and chicken, and that one GyJF was located in a remote position close to Ceylon junglefowl (CJF). The analyses based on the nuclear sequences revealed that alleles of GyJFs were alternatively clustered with those of CJF and with those of RJFs and chicken. Alternative clustering of RJF and chicken alleles were also observed. These findings taken together strongly indicate that inter-species hybridizations have occurred between GyJF and RJF/chicken and between GyJF and CJF.
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