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51.
Reduced natural selection associated with low recombination in Drosophila melanogaster 总被引:7,自引:1,他引:7
Synonymous codons are not used equally in many organisms, and the extent of
codon bias varies among loci. Earlier studies have suggested that more
highly expressed loci in Drosophila melanogaster are more biased,
consistent with findings from several prokaryotes and unicellular
eukaryotes that codon bias is partly due to natural selection for
translational efficiency. We link this model of varying selection intensity
to the population-genetics prediction that the effectiveness of natural
selection is decreased under reduced recombination. In analyses of 385 D.
melanogaster loci, we find that codon bias is reduced in regions of low
recombination (i.e., near centromeres and telomeres and on the fourth
chromosome). The effect does not appear to be a linear function of
recombination rate; rather, it seems limited to regions with the very
lowest levels of recombination. The large majority of the genome apparently
experiences recombination at a sufficiently high rate for effective natural
selection against suboptimal codons. These findings support models of the
Hill-Robertson effect and genetic hitchhiking and are largely consistent
with multiple reports of low levels of DNA sequence variation in regions of
low recombination.
相似文献
52.
Exposure of rat liver mitochondria to inorganic arsenate followed by reisolation and washing to remove the added arsenate results in uncoupled respiration with succinate and ascorbate (), but and values of 1.3 to 1.6 with 3-hydroxybutyrate or glutamate. and values greater than 1.0 with NAD+-linked substrates arise as a result of partial reactivation of coupling at sites 2 and 3 by these substrates. In the presence of rotenone, NAD+-linked substrates can still reactivate coupling with succinate or ascorbate at these sites. The extent of reactivation in the presence of rotenone by 3-hydroxybutyrate is decreased by simultaneous addition of acetoacetate. The results suggest that the coupling at sites 2 and 3 is amenable to control through changes in the reduction state of some specific components of the respiratory chain located remotely from these sites. 相似文献
53.
da Silva FH Pereira VG Yasumura EG Tenório LZ de Carvalho LP Lisboa BC Matsumoto PK Stilhano RS Samoto VY Calegare BF Brandão Lde C D'Almeida V Filippo TR Porcionatto M Toma L Nader HB Valero VB Camassola M Nardi NB Han SW 《Genetic vaccines and therapy》2012,10(1):2-11
Background
Mucopolysaccharidosis type I (MPSI) is caused by a deficiency in alpha-L iduronidase (IDUA), which leads to lysosomal accumulation of the glycosaminoglycans (GAGs) dermatan and heparan sulfate. While the currently available therapies have good systemic effects, they only minimally affect the neurodegenerative process. Based on the neuroprotective and tissue regenerative properties of mesenchymal stem cells (MSCs), we hypothesized that the administration of MSCs transduced with a murine leukemia virus (MLV) vector expressing IDUA to IDUA KO mouse brains could reduce GAG deposition in the brain and, as a result, improve neurofunctionality, as measured by exploratory activity.Methods
MSCs infected with an MLV vector encoding IDUA were injected into the left ventricle of the brain of 12- or 25-month-old IDUA KO mice. The behavior of the treated mice in the elevated plus maze and open field tests was observed for 1 to 2 months. Following these observations, the brains were removed for biochemical and histological analyses.Results
After 1 or 2 months of observation, the presence of the transgene in the brain tissue of almost all of the treated mice was confirmed using PCR, and a significant reduction in GAG deposition was observed. This reduction was directly reflected in an improvement in exploratory activity in the open field and the elevated plus maze tests. Despite these behavioral improvements and the reduction in GAG deposition, IDUA activity was undetectable in these samples. Overall, these results indicate that while the initial level of IDUA was not sustainable for a month, it was enough to reduce and maintain low GAG deposition and improve the exploratory activity for months.Conclusions
These data show that gene therapy, via the direct injection of IDUA-expressing MSCs into the brain, is an effective way to treat neurodegeneration in MPSI mice. 相似文献54.
Bongkrekic acid and atractyloside, inhibitors of adenine nucleotide translocase, do not inhibit Ca2+ uptake and H+ production by pig heart mitochondria. However, bongkrekic acid, but not atractyloside, inhibits dinitrophenol-induced Ca2+ efflux and H+ uptake. Conversely, ruthenium red blocks Ca2+ uptake and H+ production but does not prevent dinitrophenol-induced Ca2+ efflux and H+ uptake by mitochondria. These results suggest that mitochondrial Ca2+ uptake and release exist as two independent pathways. The efflux of Ca2+ from mitochondria is mediated by a bongkrekic acid sensitive component which is apparently not identical to the ruthenium red sensitive Ca2+ uptake carrier. 相似文献
55.
Kappa-chain constant-region gene sequences in genus Rattus: coding regions are diverging more rapidly than noncoding regions 总被引:2,自引:0,他引:2
We have determined the nucleotide sequence of a 1,200-base pair (bp)
genomic fragment that includes the kappa-chain constant-region gene (C
kappa) from two species of native Australian rodents, Rattus leucopus
cooktownensis and Rattus colletti. Comparison of these sequences with each
other and with other rodent C kappa genes shows three surprising features.
First, the coding regions are diverging at a rate severalfold higher than
that of the nearby noncoding regions. Second, replacement changes within
the coding region are accumulating at a rate at least as great as that of
silent changes. Third, most of the amino acid replacements are localized in
one region of the C kappa domain--namely, the carboxy-terminal "bends" in
the alpha-carbon backbone. These three features have previously been
described from comparisons of the two allelic forms of C kappa genes in R.
norvegicus. These data imply the existence of considerable evolutionary
constraints on the noncoding regions (based on as yet undetermined
functions) or powerful positive selection to diversify a portion of the
constant-region domain (whose physiological significance is not known).
These surprising features of C kappa evolution appear to be characteristic
only of closely related C kappa genes, since comparison of rodent with
human sequences shows the expected greater conservation of coding regions,
as well as a predominance of silent nucleotide substitutions within the
coding regions.
相似文献
56.
Becca Asquith Angelina J Mosley Adrian Heaps Yuetsu Tanaka Graham P Taylor Angela R McLean Charles RM Bangham 《Retrovirology》2005,2(1):1-9
Background
Cellular infection with human immunodeficiency virus (HIV) both in vitro and in vivo requires a member of the chemokine receptor family to act as a co-receptor for viral entry. However, it is presently unclear to what extent the interaction of HIV proteins with chemokine receptors generates intracellular signals that are important for productive infection.Results
In this study we have used a recently described family of chemokine inhibitors, termed BSCIs, which specifically block chemokine-induced chemotaxis without affecting chemokine ligands binding to their receptors. The BSCI termed Peptide 3 strongly inhibited CCR5 mediated HIV infection of THP-1 cells (83 ± 7% inhibition assayed by immunofluoresence staining), but had no effect on gp120 binding to CCR5. Peptide 3 did not affect CXCR4-dependent infection of Jurkat T cells.Conclusion
These observations suggest that, in some cases, intracellular signals generated by the chemokine coreceptor may be required for a productive HIV infection. 相似文献57.
Fortunato Ferrara Sara D’Angelo Tiziano Gaiotto Leslie Naranjo Hongzhao Tian Susanne Gr?slund Elena Dobrovetsky Peter Hraber Fridtjof Lund-Johansen Silvia Saragozza Daniele Sblattero Csaba Kiss Andrew RM Bradbury 《MABS-AUSTIN》2015,7(1):32-41
Only a small fraction of the antibodies in a traditional polyclonal antibody mixture recognize the target of interest, frequently resulting in undesirable polyreactivity. Here, we show that high-quality recombinant polyclonals, in which hundreds of different antibodies are all directed toward a target of interest, can be easily generated in vitro by combining phage and yeast display. We show that, unlike traditional polyclonals, which are limited resources, recombinant polyclonal antibodies can be amplified over one hundred million-fold without losing representation or functionality. Our protocol was tested on 9 different targets to demonstrate how the strategy allows the selective amplification of antibodies directed toward desirable target specific epitopes, such as those found in one protein but not a closely related one, and the elimination of antibodies recognizing common epitopes, without significant loss of diversity. These recombinant renewable polyclonal antibodies are usable in different assays, and can be generated in high throughput. This approach could potentially be used to develop highly specific recombinant renewable antibodies against all human gene products. 相似文献
58.
59.
60.
A molecular and evolutionary study of the beta-globin gene family of the Australian marsupial Sminthopsis crassicaudata 总被引:1,自引:0,他引:1
Cooper SJ; Murphy R; Dolman G; Hussey D; Hope RM 《Molecular biology and evolution》1996,13(7):1012-1022
Beta-globin gene families in eutherians (placental mammals) consist of a
set of four or more developmentally regulated genes which are closely
linked and, in general, arranged in the order 5'-embryonic/fetal genes-
adult genes-3'. This cluster of genes is proposed to have arisen by tandem
duplication of ancestral beta-globin genes, with the first duplication
occurring 200 to 155 MYBP just prior to a period in mammalian evolution
when eutherians and marsupials diverged from a common ancestor. In this
paper we trace the evolutionary history of the beta-globin gene family back
to the origins of these mammals by molecular characterization of the
beta-globin gene family of the Australian marsupial Sminthopsis
crassicaudata. Using Southern and restriction analysis of total genomic DNA
and bacteriophage clones of beta-like globin genes, we provide evidence
that just two functional beta-like globin genes exist in this marsupial,
including one embryonic- expressed gene (S.c-epsilon) and one
adult-expressed gene (S.c-beta), linked in the order 5'-epsilon-beta-3'.
The entire DNA sequence of the adult beta-globin gene is reported and shown
to be orthologous to the adult beta-globin genes of the North American
marsupial Didelphis virginiana and eutherian mammals. These results,
together with results from a phylogenetic analysis of mammalian beta-like
globin genes, confirm the hypothesis that a two-gene cluster, containing an
embryonic- and an adult-expressed beta-like globin gene, existed in the
most recent common ancester of marsupials and eutherians. Northern analysis
of total RNA isolated from embryos and neonatals indicates that a switch
from embryonic to adult gene expression occurs at the time of birth,
coinciding with the transfer of the marsupial from a uterus to a pouch
environment.
相似文献