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961.
Xue Y Moore LB Orans J Peng L Bencharit S Kliewer SA Redinbo MR 《Molecular endocrinology (Baltimore, Md.)》2007,21(5):1028-1038
The human nuclear pregnane X receptor (PXR) responds to a wide variety of xenobiotic and endobiotic compounds, including pregnanes, progesterones, corticosterones, lithocholic acids, and 17beta-estradiol. In response to these ligands, the receptor controls the expression of genes central to the metabolism and excretion of potentially harmful chemicals from both exogenous and endogenous sources. Although the structural basis of PXR's interaction with small and large xenobiotics has been examined, the detailed nature of its binding to endobiotics, including steroid-like ligands, remains unclear. We report the crystal structure of the human PXR ligand-binding domain (LBD) in complex with 17beta-estradiol, a representative steroid ligand, at 2.65 A resolution. Estradiol is found to occupy only one region of PXR's expansive ligand-binding pocket, leaving a notable 1000 A3 of space unoccupied, and to bridge between the key polar residues Ser-247 and Arg-410 in the PXR LBD. Positioning the steroid scaffold in this way allows it to make several direct contacts to alphaAF of the receptor's AF-2 region. The PXR-estradiol complex was compared with that of other nuclear receptors, including the estrogen receptor, in complexes with analogous ligands. It was found that PXR's placement of the steroid is remarkably distinct relative to other members of the nuclear receptor superfamily. Using the PXR-estradiol complex as a guide, the binding of other steroid- and cholesterol-like molecules was then considered. The results provide detailed insights into the manner in which human PXR responds to a wide range of endobiotic compounds. 相似文献
962.
963.
Yero D Pajón R Caballero E González S Cobas K Fariñas M Lopez Y Acosta A 《FEMS immunology and medical microbiology》2007,50(3):430-433
We employed a prime-boost regimen in combination with the expression library immunization protocol to improve the protective effectiveness of a genomic library used as immunogen. To demonstrate the feasibility of this novel strategy, we used as a prime a serogroup B Neisseria meningitidis random genomic library constructed in a eukaryotic expression vector. Mice immunized with different fractions of this library and boosted with a single dose of meningococcal outer membrane vesicles elicited higher bactericidal antibody titers compared with mice primed with the empty vector. After the boost, passive administration of sera from mice primed with two of these fractions significantly reduced the number of viable bacteria in the blood of infant rats challenged with live N. meningitidis. The method proposed could be applied to the identification of subimmunogenic antigens during vaccine candidate screening by employing expression library immunization. 相似文献
964.
Elizabeth D. Hughes Yun Yan Qu Suzanne J. Genik Robert H. Lyons Christopher D. Pacheco Andrew P. Lieberman Linda C. Samuelson Igor O. Nasonkin Sally A. Camper Margaret L. Van Keuren Thomas L. Saunders 《Mammalian genome》2007,18(8):549-558
Genetically modified mouse strains derived from embryonic stem (ES) cells are powerful tools for gene function analysis. ES
cells from the C57BL/6 mouse strain are not widely used to generate mouse models despite the advantage of a defined genetic
background. We assessed genetic variation in six such ES cell lines with 275 SSLP markers. Compared to C57BL/6, Bruce4 differed
at 34 SSLP markers and had significant heterozygosity on three chromosomes. BL/6#3 and Dale1 ES cell lines differed at only
3 SSLP makers. The C2 and WB6d ES cell lines differed at 6 SSLP markers. It is important to compare the efficiency of producing
mouse models with available C57BL/6 ES cells relative to standard 129 mouse strain ES cells. We assessed genetic stability
(the tendency of cells to become aneuploid) in 110 gene-targeted ES cell clones from the most widely used C57BL/6 ES cell
line, Bruce4, and 710 targeted 129 ES cell clones. Bruce4 clones were more likely to be aneuploid and unsuitable for ES cell-mouse
chimera production. Despite their tendency to aneuploidy and consequent inefficiency, use of Bruce4 ES cells can be valuable
for models requiring behavioral studies and other mouse models that benefit from a defined C57BL/6 background.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
965.
Tony I. Venelinov John H. Beattie Jack R. Dainty Wendy J. Hollands Susan J. Fairweather-Tait Linda J. Harvey 《Journal of trace elements in medicine and biology》2007,21(2):138-140
To develop further our understanding of initial dietary copper metabolism, a method has been developed to separate plasma copper that is bound to albumin, from that bound to ceruloplasmin. This method has been tested using plasma samples from a pilot study involving six human volunteers who consumed 3mg oral doses of the stable isotope (65)Cu and gave blood samples at timed intervals up to 7 days. The results suggest that this method can be used to monitor dynamic fluctuations in newly absorbed copper over a short time frame. 相似文献
966.
Broad Complex (BRC) is an essential ecdysone-pathway gene required for entry into and progression through metamorphosis in Drosophila melanogaster. Mutations of three BRC complementation groups cause numerous phenotypes, including a common suite of morphogenesis defects involving central nervous
system (CNS), adult salivary glands (aSG), and male genitalia. These defects are phenocopied by the juvenile hormone mimic
methoprene. Four BRC isoforms are produced by alternative splicing of a protein-binding BTB/POZ-encoding exon (BTB
BRC
) to one of four tandemly duplicated, DNA-binding zinc-finger-encoding exons (Z1
BRC
, Z2
BRC
, Z3
BRC
, Z4
BRC
). Highly conserved orthologs of BTB
BRC
and all four Z
BRC
were found among published cDNA sequences or genome databases from Diptera, Lepidoptera, Hymenoptera, and Coleoptera, indicating
that BRC arose and underwent internal exon duplication before the split of holometabolous orders. Tramtrack subfamily members, abrupt, tramtrack, fruitless, longitudinals lacking (lola), and CG31666 were characterized throughout Holometabola and used to root phylogenetic analyses of Z
BRC
exons, which revealed that the Z
BRC
clade includes Z
abrupt
. All four Z
BRC
domains, including Z4
BRC
, which has no known essential function, are evolving in a manner consistent with selective constraint. We used transgenic
rescue to explore how different BRC isoforms contribute to shared tissue-morphogenesis functions. As predicted from earlier
studies, the common CNS and aSG phenotypes were rescued by BRC-Z1 in rbp mutants, BRC-Z2 in br mutants, and BRC-Z3 in 2Bc mutants. However, the isoforms are required at two different developmental stages, with BRC-Z2 and -Z3 required earlier than
BRC-Z1. The sequential action of BRC isoforms indicates subfunctionalization of duplicated Z
BRC
exons even when they contribute to common developmental processes.
Electronic supplementary material The online version of this article (doi:) contains supplementary material, which is available to authorized users. 相似文献
967.
Borrelia burgdorferi, a causative agent of Lyme disease, has a highly unusual segmented genome composed of both circular molecules and linear DNA replicons terminated by covalently closed hairpin ends or telomeres. Replication intermediates of the linear molecules are processed into hairpin telomeres via the activity of ResT, a telomere resolvase. We report here the results of limited proteolysis and mass spectroscopy to identify two main structural domains in ResT, separated by a chymotrypsin cleavage site between residues 163 and 164 of the 449 amino acid protein. The two domains have been overexpressed and purified. DNA electrophoretic mobility shift assays revealed that the C-terminal domain (ResT(164-449)) displays sequence-specific DNA binding to the box 3,4,5 region of the telomere, while the N-terminal domain (ResT(1-163)) exhibits sequence-independent DNA binding activity. Further analysis by DNase I footprinting supports a model for telomere resolution in which the hairpin binding module of the N-terminal domain is delivered to the box 1,2 region of the telomere through its tethering to ResT(164-449). Conversely, ResT(1-164) may play an important regulatory role by modulating both sequence-specific DNA binding activity and catalysis by the C-terminal domain. 相似文献
968.
Notch signalling is needed to maintain, but not to initiate, the formation of prosensory patches in the chick inner ear 总被引:4,自引:0,他引:4
Notch signalling is well-known to mediate lateral inhibition in inner ear sensory patches, so as to generate a balanced mixture of sensory hair cells and supporting cells. Recently, however, we have found that ectopic Notch activity at an early stage can induce the formation of ectopic sensory patches. This suggests that Notch activity may have two different functions in normal ear development, acting first to promote the formation of the prosensory patches, and then later to regulate hair-cell production within the patches. The Notch ligand Serrate1 (Jag1 in mouse and humans) is expressed in the patches from an early stage and may provide Notch activation during the prosensory phase. Here, we test whether Notch signalling is actually required for prosensory patch development. When we block Notch activation in the chick embryo using the gamma-secretase inhibitor DAPT, we see a complete loss of prosensory epithelial cells in the anterior otocyst, where they are diverted into a neuroblast fate via failure of Delta1-dependent lateral inhibition. The cells of the posterior prosensory patch remain epithelial, but expression of Sox2 and Bmp4 is drastically reduced. Expression of Serrate1 here is initially almost normal, but subsequently regresses. The patches of sensory hair cells that eventually develop are few and small. We suggest that, in normal development, factors other than Notch activity initiate Serrate1 expression. Serrate1, by activating Notch, then drives the expression of Sox2 and Bmp4, as well as expression of the Serrate1 gene itself. The positive feedback maintains Notch activation and thereby preserves and perhaps extends the prosensory state, leading eventually to the development of normal sensory patches. 相似文献
969.
970.
Deciphering the molecular machinery of stem cells: a look at the neoblast gene expression profile
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Rossi L Salvetti A Marincola FM Lena A Deri P Mannini L Batistoni R Wang E Gremigni V 《Genome biology》2007,8(4):R62