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31.
Roel GW Verhaak Frank JT Staal Peter JM Valk Bob Lowenberg Marcel JT Reinders Dick de Ridder 《BMC bioinformatics》2006,7(1):105-15
Background
Intensity values measured by Affymetrix microarrays have to be both normalized, to be able to compare different microarrays by removing non-biological variation, and summarized, generating the final probe set expression values. Various pre-processing techniques, such as dChip, GCRMA, RMA and MAS have been developed for this purpose. This study assesses the effect of applying different pre-processing methods on the results of analyses of large Affymetrix datasets. By focusing on practical applications of microarray-based research, this study provides insight into the relevance of pre-processing procedures to biology-oriented researchers. 相似文献32.
Erythroid differentiation sensitizes K562 leukemia cells to TRAIL-induced apoptosis by downregulation of c-FLIP 总被引:6,自引:0,他引:6
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Hietakangas V Poukkula M Heiskanen KM Karvinen JT Sistonen L Eriksson JE 《Molecular and cellular biology》2003,23(4):1278-1291
Regulation of the apoptotic threshold is of great importance in the homeostasis of both differentiating and fully developed organ systems. Triggering differentiation has been employed as a strategy to inhibit cell proliferation and accelerate apoptosis in malignant cells, in which the apoptotic threshold is often characteristically elevated. To better understand the mechanisms underlying differentiation-mediated regulation of apoptosis, we have studied death receptor responses during erythroid differentiation of K562 erythroleukemia cells, which normally are highly resistant to tumor necrosis factor (TNF) alpha-, FasL-, and TRAIL-induced apoptosis. However, upon hemin-mediated erythroid differentiation, K562 cells specifically lost their resistance to TNF-related apoptosis-inducing ligand (TRAIL), which efficiently killed the differentiating cells independently of mitochondrial apoptotic signaling. Concomitantly with the increased sensitivity, the expression of both c-FLIP splicing variants, c-FLIP(L) and c-FLIP(S), was downregulated, resulting in an altered caspase 8 recruitment and cleavage in the death-inducing signaling complex (DISC). Stable overexpression of both c-FLIP(L) and c-FLIP(S) rescued the cells from TRAIL-mediated apoptosis with isoform-specific effects on DISC-recruited caspase 8. Our results show that c-FLIP(L) and c-FLIP(S) potently control TRAIL responses, both by distinct regulatory features, and further imply that the differentiation state of malignant cells determines their sensitivity to death receptor signals. 相似文献
33.
DNA-protein cross-links are generated by both endogenous and exogenous DNA damaging agents, as intermediates during normal DNA metabolism, and during abortive base excision repair. Cross-links are relatively common lesions that are lethal when they block progression of DNA polymerases. DNA-protein cross-links may be broadly categorized into four groups by the DNA and protein chemistries near the cross-link and by the source of the cross-link: DNA-protein cross-links may be found (1) in nicked DNA at the 3' end of one strand (topo I), (2) in nicked DNA at the 5' end of one strand (pol beta), (3) at the 5' ends of both strands adjacent to nicks in close proximity (topo II; Spo 11), and (4) in one strand of duplex DNA (UV irradiation; bifunctional carcinogens and chemotherapeutic agents). Repair mechanisms are reasonably well-defined for groups 1 and 3, and suggested for groups 2 and 4. Our work is focused on the recognition and removal of DNA-protein cross-links in duplex DNA (group 4). 相似文献
34.
Effects of nucleotide sequence alignment on phylogeny estimation: a case study of 18S rDNAs of apicomplexa 总被引:13,自引:5,他引:8
The reconstruction of phylogenetic history is predicated on being able to
accurately establish hypotheses of character homology, which involves
sequence alignment for studies based on molecular sequence data. In an
empirical study investigating nucleotide sequence alignment, we inferred
phylogenetic trees for 43 species of the Apicomplexa and 3 of Dinozoa based
on complete small-subunit rDNA sequences, using six different
multiple-alignment procedures: manual alignment based on the secondary
structure of the 18S rRNA molecule, and automated similarity-based
alignment algorithms using the PileUp, ClustalW, TreeAlign, MALIGN, and SAM
computer programs. Trees were constructed using neighboring-joining,
weighted-parsimony, and maximum- likelihood methods. All of the multiple
sequence alignment procedures yielded the same basic structure for the
estimate of the phylogenetic relationship among the taxa, which presumably
represents the underlying phylogenetic signal. However, the placement of
many of the taxa was sensitive to the alignment procedure used; and the
different alignments produced trees that were on average more dissimilar
from each other than did the different tree-building methods used. The
multiple alignments from the different procedures varied greatly in length,
but aligned sequence length was not a good predictor of the similarity of
the resulting phylogenetic trees. We also systematically varied the gap
weights (the relative cost of inserting a new gap into a sequence or
extending an already-existing gap) for the ClustalW program, and this
produced alignments that were at least as different from each other as
those produced by the different alignment algorithms. Furthermore, there
was no combination of gap weights that produced the same tree as that from
the structure alignment, in spite of the fact that many of the alignments
were similar in length to the structure alignment. We also investigated the
phylogenetic information content of the helical and nonhelical regions of
the rDNA, and conclude that the helical regions are the most informative.
We therefore conclude that many of the literature disagreements concerning
the phylogeny of the Apicomplexa are probably based on differences in
sequence alignment strategies rather than differences in data or
tree-building methods.
相似文献
35.
Cross-hybridizing snake satellite, Drosophila, and mouse DNA sequences may have arisen independently 总被引:2,自引:0,他引:2
Previous reports have interpreted hybridization between snake satellite DNA
and DNA clones from a variety of distant taxonomic groups as evidence for
evolutionary conservation, which implies common ancestry (homology) and/or
convergence (analogy) to produce the cross- hybridizing sequences. We have
isolated 11 clones from a genomic library of Drosophila melanogaster, using
a cloned 2.5-kb snake satellite probe of known nucleotide sequence. We have
also analysed published sequence data from snakes, mice, and Drosophila.
These data show that (1) all of the cross-hybridization between the snake,
fly, and mouse clones can be accounted for by the presence of either of two
tandem repeats, [GATA]n and [GACA]n and (2) these tandem repeats are
organized differently among the different species. We find no evidence that
these sequences are homologous apart from the existence of the simple
repeat itself, although their divergence from a common ancestral sequence
cannot be ruled out. The sequences contain a variety of homogeneous
clusters of tandem repeats of CATA, GA, TA, and CA, as well as GATA and
GACA. We suggest that these motifs may have arisen by a self-accelerating
process involving slipped-strand mispairing of DNA. Homogeneity of the
clusters might simply be the result of a rate of accumulation of tandem
repeats that exceeds that of other mutations.
相似文献
36.
Structural comparison of fibroblast growth factor-specific heparan sulfates derived from a growing or differentiating neuroepithelial cell line 总被引:3,自引:1,他引:2
Brickman YG; Nurcombe V; Ford MD; Gallagher JT; Bartlett PF; Turnbull JE 《Glycobiology》1998,8(5):463-471
Heparan sulfate (HS) glycosaminoglycans are essential modulators of
fibroblast growth factor (FGF) activity both in vivo and in vitro, and
appear to act by cross-linking particular forms of FGF to appropriate FGF
receptors. We have recently isolated and characterized two separate HS
pools derived from immortalized embryonic day 10 mouse neuroepithelial 2.3D
cells: one from cells in log growth phase, which greatly potentiates the
activity of FGF-2, and the other from cells undergoing contact-inhibition
and differentiation, which preferentially activates FGF-1. These two pools
of HS have very similar functional activities to those species isolated
from primary neuroepithelial cells at corresponding stages of active
proliferation or differentiation. We present here a structural comparison
between these cell line HS species to establish the nature of the changes
that occur in the biosynthesis of HS. A combination of chemical and
enzymatic cleavage, low pressure chromatography and strong anion-exchange
HPLC were used to generate full chain models of each species. Overall, the
HS pools synthesized in the dividing cell line pools possessed less complex
sulfation than those derived from more differentiated, growth arrested
cells.
相似文献
37.
Mireille B Johnson Stephen L Clifford Benoît Goossens Silvester Nyakaana Bryan Curran Lee JT White E Jean Wickings Michael W Bruford 《BMC evolutionary biology》2007,7(1):1-14
Background
The mitochondrial genomes of snakes are characterized by an overall evolutionary rate that appears to be one of the most accelerated among vertebrates. They also possess other unusual features, including short tRNAs and other genes, and a duplicated control region that has been stably maintained since it originated more than 70 million years ago. Here, we provide a detailed analysis of evolutionary dynamics in snake mitochondrial genomes to better understand the basis of these extreme characteristics, and to explore the relationship between mitochondrial genome molecular evolution, genome architecture, and molecular function. We sequenced complete mitochondrial genomes from Slowinski's corn snake (Pantherophis slowinskii) and two cottonmouths (Agkistrodon piscivorus) to complement previously existing mitochondrial genomes, and to provide an improved comparative view of how genome architecture affects molecular evolution at contrasting levels of divergence.Results
We present a Bayesian genetic approach that suggests that the duplicated control region can function as an additional origin of heavy strand replication. The two control regions also appear to have different intra-specific versus inter-specific evolutionary dynamics that may be associated with complex modes of concerted evolution. We find that different genomic regions have experienced substantial accelerated evolution along early branches in snakes, with different genes having experienced dramatic accelerations along specific branches. Some of these accelerations appear to coincide with, or subsequent to, the shortening of various mitochondrial genes and the duplication of the control region and flanking tRNAs.Conclusion
Fluctuations in the strength and pattern of selection during snake evolution have had widely varying gene-specific effects on substitution rates, and these rate accelerations may have been functionally related to unusual changes in genomic architecture. The among-lineage and among-gene variation in rate dynamics observed in snakes is the most extreme thus far observed in animal genomes, and provides an important study system for further evaluating the biochemical and physiological basis of evolutionary pressures in vertebrate mitochondria. 相似文献38.
U Lamminm?ki S Paupério A Westerlund-Karlsson J Karvinen P L Virtanen T L?vgren P Saviranta 《Journal of molecular biology》1999,291(3):589-602
The length of the heavy chain complementarity-determining region 2 (CDRH2) was extended beyond what is found in germline genes to improve the binding properties of an anti-estradiol antibody. The previous immunochemical characterization and the molecular modeling of the high affinity (Ka=3.9x10(8)) murine anti-estradiol antibody 57-2 suggested that a part of the antigen was loosely recognized by the antibody. The CDRH2, because of its close location but scarce contacts with the hapten, was considered as a conceivable target for mutagenesis. Libraries with either two, three or four random amino acid insertions in the tip of the CDRH2 loop were constructed and displayed on the M13 filamentous phage as Fab fragments. Mutations were introduced also into the rest of the VHdomain by error-prone polymerase chain reaction to allow the surrounding structures to adapt to the extended CDRH2. After the panning of the libraries with an antigen off-rate-based selection, a number of active clones, most of which showed significantly improved affinity and specificity, were isolated, characterized and sequenced. The results indicate that the structure of the antibody can tolerate a number of different insertions in the CDRH2 region. They also suggest that the repertoire of antibody libraries can be expanded by extending the length of the CDR loops beyond that naturally provided by the given set of germline genes. This kind of mutagenesis can be generally useful for the engineering of hapten-binding antibodies. 相似文献
39.
40.
To understand why cross-species infection of prion disease often results in inefficient transmission and reduced protein conversion, most research has focused on defining the effect of variations in PrP primary structures, including sequence compatibility of substrate and seed. By contrast, little research has been aimed at investigating structural differences between different variants of PrPC and secondary structural requirements for efficient conversion. This is despite a clear role for molecular chaperones in formation of prions in non-mammalian systems, indicating the importance of secondary/tertiary structure during the conversion process. Recent data from our laboratory on the cellular location of disease-specific prion cofactors supports the critical role of specific secondary structural motifs and the stability of these motifs in determining the efficiency of disease-specific prion protein conversion. In this paper we summarize our recent results and build on the hypothesis previously suggested by Wuthrich and colleagues, that stability of certain regions of the prion protein is crucial for protein conversion to abnormal isoforms in vivo. It is suggested that one role for molecular cofactors in the conversion process is to stabilize PrPC structure in a form that is amenable for conversion to PrPSc.Key words: cofactor, structure, cell-free conversion assay, fibrillization, stability, loop region 相似文献