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41.
42.
alpha 1-Proteinase inhibitors (alpha 1-PIs) are members of the serpin
superfamily of proteinase inhibitors, and are important in the maintenance
of homeostasis in a wide variety of animal taxa. Previous studies have
shown that in mice (genus Mus), evolution of alpha 1-PIs is characterized
by gene amplification, region-specific concerted evolution, and rapid
accumulation of amino acid substitutions. The latter occurs primarily in
the reactive center, which is the region of the alpha 1-PI molecule that
determines the inhibitor's specificity for target proteinases. The P1
residue within the reactive center, which is methionine in so-called
orthodox alpha 1-PIs and an amino acid other than methionine in unorthodox
alpha 1-PIs, is a primary determinant of inhibitor specificity. In the
present study, we find that the expression of mRNAs encoding unorthodox
alpha 1-PIs is polymorphic within Mus species, i.e., among individuals or
inbred strains. This is in striking contrast to mRNAs that encode orthodox
alpha 1-PIs, whose concentrations are relatively invariant. The
intraspecies variations in mRNA expression represent polymorphisms in the
structure of the alpha 1- PI gene family. The results, taken together with
previously described aspects of alpha 1-PI evolution, indicate that the
dissimilar levels of polymorphism exhibited by orthodox and unorthodox
alpha 1-PIs, which likely have distinct physiological functions, may
reflect different levels of selective constraint. The significance of this
finding to the evolution of gene families is discussed.
相似文献
43.
Antigen/antibody complexes can efficiently target antigen presenting cells to allow stimulation of the cellular immune response. Due to the difficulty of manufacture and their inherent instability complexes have proved inefficient cancer vaccines. However, anti-idiotypic antibodies mimicking antigens have been shown to stimulate both antibody and T cell responses. The latter are due to T cell mimotopes expressed within the complementarity-determining regions (CDRs) of antibodies that are efficiently presented to dendritic cells in vivo. Based on this observation we have designed a DNA vaccine platform called ImmunoBody™, where cytotoxic T lymphocyte (CTL) and helper T cell epitopes replace CDR regions within the framework of a human IgG1 antibody. The ImmunoBody™ expression system has a number of design features which allow for rapid production of a wide range of vaccines. The CDR regions of the heavy and light chain have been engineered to contain unique restriction endonuclease sites, which can be easily opened, and oligonucleotides encoding the T cell epitopes inserted. The variable and constant regions of the ImmunoBody™ are also flanked by restriction sites, which permit easy exchange of other IgG subtypes. Here we show a range of T cell epitopes can be inserted into the ImmunoBody™ vector and upon immunization these T cell epitopes are efficiently processed and presented to stimulate high frequency helper and CTL responses capable of anti-tumor activity.Key words: DNA vaccines, cancer vaccines, melanoma, CTL, helper T cells 相似文献
44.
45.
E?BaptesteEmail author E?Susko J?Leigh D?MacLeod RL?Charlebois WF?Doolittle 《BMC evolutionary biology》2005,5(1):33
Background
Since Darwin's Origin of Species, reconstructing the Tree of Life has been a goal of evolutionists, and tree-thinking has become a major concept of evolutionary biology. Practically, building the Tree of Life has proven to be tedious. Too few morphological characters are useful for conducting conclusive phylogenetic analyses at the highest taxonomic level. Consequently, molecular sequences (genes, proteins, and genomes) likely constitute the only useful characters for constructing a phylogeny of all life. For this reason, tree-makers expect a lot from gene comparisons. The simultaneous study of the largest number of molecular markers possible is sometimes considered to be one of the best solutions in reconstructing the genealogy of organisms. This conclusion is a direct consequence of tree-thinking: if gene inheritance conforms to a tree-like model of evolution, sampling more of these molecules will provide enough phylogenetic signal to build the Tree of Life. The selection of congruent markers is thus a fundamental step in simultaneous analysis of many genes. 相似文献46.
Electrophysiological and biochemical responses of mouse vomeronasal receptor cells to urine-derived compounds: possible mechanism of action 总被引:1,自引:1,他引:0
Receptor cells of the vomeronasal organ (VNO) are thought to detect
pheromone-like molecules important for reproductive physiology. Several
compounds derived from male mouse urine have been demonstrated to affect
endocrine events in female mice. In the present study, the ability of these
compounds to affect VNO activity was tested. In dissociated VNO cells held
under voltage clamp conditions, application of dehydro-exo-brevicomin (DHB)
evoked an outward current at negative holding potentials and an inward
current at positive holding potentials. Under current clamp, DHB reduced
action potential firing. Since DHB application caused a decrease in
membrane conductance, this compound appeared to act by reducing inward
current through closing an ion channel. Biochemical experiments tested the
effects of DHB and 2- (sec-butyl)-4,5-dihydrothiazole (SBT) on cAMP levels
in the VNO. A mixture of DHB and SBT decreased cAMP levels in VNO sensory
tissue and had no effect on VNO non-sensory tissue. The results suggest
that pheromones have an inhibitory influence on action potential generation
and on cAMP levels in receptor cells of the VNO.
相似文献
47.
48.
Walter RB; Rolig RL; Kozak KA; McEntire B; Morizot DC; Nairn RS 《Molecular biology and evolution》1993,10(6):1227-1238
Fishes represent the stem vertebrate condition and have maintained several
gene arrangements common to mammalian genomes throughout the 450 Myr of
divergence from a common ancestor. One such syntenic arrangement includes
the GPI-PEPD enzyme association on Xiphophorus linkage group IV and human
chromosome 19. Previously we assigned the Xiphophorus homologue of the
human ERCC2 gene to linkage group U5 in tight association with the CKM
locus. CKM is also tightly linked to the ERCC2 locus on human chromosome
19, leading to speculation that human chromosome 19 may have arisen by
fusion of two ancestral linkage groups which have been maintained in
fishes. To investigate this hypothesis further, we isolated and sequenced
Xiphophorus fish genomic regions exhibiting considerable sequence
similarity to the human DNA ligase 1 amino acid sequence. Comparison of the
fish DNA ligase sequence with those of other species suggests several modes
of amino acid conservation in this gene. A 2.2-kb restriction fragment
containing part of an X. maculatus DNA ligase 1 exon was used in backcross
hybrid mapping with 12 enzyme or RFLP loci. Significant linkage was
observed between the nucleoside phosphorylase (NP2) and the DNA ligase
(LIG1) loci on Xiphophorus linkage group VI. This assignment suggests that
the association of four DNA repair-related genes on human chromosome 19 may
be the result of chance chromosomal rearrangements.
相似文献
49.
Four derivatives of the ergot dopamine (DA) agonist lisuride (LIS), namely 6-n-propyl-lisuride (6-n-propyl-LIS), transdihydrolisuride (TDHL), 6-n-propyl-transdi-hydrolisuride (6-n-propyl-TDHL) and 2-bromolisuride (2-Br-LIS) were investigated in female rats with regard to their influence on hyperprolactinaemia induced by pretreatment with reserpine (2 mg/kg i.p., 24 h) at various intervals following their subcutaneous or oral administration (0.05 mg/kg). Two hours after administration, LIS, 6-n-propyl-LIS, and 6-n-propyl-TDHL caused a statistically significant inhibition of reserpine-induced hyperprolactinaemia of about the same extent. Eight hours after administration 6-n-propyl-LIS and 6-n-propyl-TDHL were as active as after 2 h in inhibiting prolactin (PRL) secretion whereas LIS was almost ineffective in this respect. TDHL caused a statistically significant inhibition of PRL secretion at 2 and 8 h after oral administration; this effect was less pronounced after s.c. administration. In contrast to the aforementioned derivatives 2-Br-LIS further increased the reserpine-induced hyperprolactinaemia. In normal male rats pretreatment with 2-Br-LIS (0.025-6.25 mg/kg s.c., 2 h) dose-dependently stimulated PRL secretion. The present data support the assumption of the longlasting DA agonistic action of 6-n-propyl-LIS and 6-n-propyl-TDHL and of the antidopaminergic properties of 2-Br-LIS recently derived from behavioural studies. 相似文献
50.
Seegmiller A; Williams KR; Hammersmith RL; Doak TG; Witherspoon D; Messick T; Storjohann LL; Herrick G 《Molecular biology and evolution》1996,13(10):1351-1362
Internal eliminated sequences (IESs) often interrupt ciliate genes in the
silent germline nucleus but are exactly excised and eliminated from the
developing somatic nucleus from which genes are then expressed. Some long
IESs are transposons, supporting the hypothesis that short IESs are ancient
transposon relics. In light of that hypothesis and to explore the
evolutionary history of a collection of IESs, we have compared various
alleles of a particular locus (the 81 locus) of the ciliated protozoa
Oxytricha trifallax and O. fallax. Three short IESs that interrupt two
genes of the locus are found in alleles from both species, and thus must be
relatively ancient, consistent with the hypothesis that short IESs are
transposon relics. In contrast, TBE1 transposon interruptions of the locus
are allele-specific and probably the results of recent transpositions.
These IESs (and the TBE1s) are precisely excised from the DNA of the
developing somatic macronucleus. Each IES interrupts a highly conserved
sequence. A few nucleotides at the ends of each IES are also conserved,
suggesting that they interact critically with IES excision machinery.
However, most IES nucleotide positions have evolved at high rates, showing
little or no selective constraint for function. Nonetheless, the length of
each IES has been maintained (+/- 3 bp). While one IES is approximately 33
bp long, three other IESs have very similar sizes, approximately 70 bp
long. Two IESs are surrounded by direct repeats of the sequence TTCTT. No
other sequence similarities were found between any of the four IESs.
However, the ends of one IES do match the inverted terminal repeat
consensus sequence of the "TA" IESs of Paramecium. Three O. trifallax
alleles appear to have been recipients in recent conversion events that
could have been provoked by double-strand breaks associated with IES ends
subsequent to IES transposition. Our findings support the hypothesis that
short IESs evolved from ancient transposons that have lost most of their
sequences, except those necessary for precise excision during macronuclear
development.
相似文献