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At least 757 records · Page 42Linked to original sources
PubMed1993

Nucleotide sequence analysis of c-raf-1 cDNA and promoter from a radiation-resistant human squamous carcinoma cell line: deletion within exon 17.

The c-raf-1 proto-oncogene is the cellular homologue of v-raf, the oncogene of the acutely transforming retrovirus 3611-MSV. The product of c-raf-1 (raf-1) is a 74-kDa cytoplasmic serine/threonine protein kinase. We previously reported that antisense human c-raf-1 cDNA transfection results in reduction of the endogenous c-raf-1 transcript, decreased tumor growth rate, and enhanced radiation sensitivity of SQ-20B tumor cells established from a radiation-resistant laryngeal squamous cell carcinoma. In the study reported here, we used cDNA-linked polymerase chain reaction amplification and nucleotide sequencing to examine the structure of the 3233-bp SQ-20B c-raf-1 cDNA. The 812-bp c-raf-1 promoter region was analyzed by genomic DNA amplification followed by cloning and sequencing. Sequence comparison with a previously published c-raf-1 sequence indicated no structural changes within the coding region of SQ-20B c-raf-1. However, a 4-bp deletion was observed in the 3' untranslated region within exon 17. This deletion was also present in a c-raf-1 cDNA clone isolated from a SQ-20B cDNA library. While the possibility of a 3' transcriptional control mechanism cannot be ruled out, it appears that the raf-1 protein kinase may regulate the development of radioresistant malignancies via interaction with other molecules in the damage and repair-related signal transduction pathways.

Base Sequence↗
PubMed1990

Renal agenesis and dysgenesis: are they increasing?

Data from the Birth Defects Monitoring Program (BDMP) of the Centers for Disease Control (CDC) suggest that the birth prevalence of renal agenesis and dysgenesis combined is increasing. Medical records were reviewed for 1,404 of 1,669 (84%) infants in the BDMP with renal agenesis or dysgenesis noted on the newborn discharge summary to assess whether the observed trend reflects a true increase in one or both conditions or if it reflects changes in diagnostic, coding, or surveillance practices over time. For 1970-1982, the average rate per 100,000 live births and stillbirths was 3.5 for autopsy-confirmed bilateral renal agenesis and 1.7 for autopsy-confirmed bilateral renal dysgenesis. The birth prevalence of autopsy-confirmed bilateral renal agenesis fluctuated within this time period, peaking in 1975, while the rate of autopsy-confirmed bilateral renal dysgenesis increased steadily by 0.2 cases/100,000 births per year (P less than 0.001) with small peaks in 1976 and 1979. Unilateral renal agenesis or dysgenesis accounted for 17% of the confirmed cases, but most were detected by autopsy among infants who died shortly after birth rather than by diagnostic procedures such as ultrasound. Diagnostic information in the medical record suggested that the increase in the birth prevalence of renal agenesis and dysgenesis combined in the BDMF is due primary to the increasing prevalence of renal dysgenesis. Since medical records did not include sufficient information on risk factors, detailed analytic studies are needed to identify maternal risk factors that might account for the apparent increase in renal dysgenesis over time.

Congenital Abnormalities↗
PubMed1995

Cloning of rat obese cDNA and its expression in obese rats.

The mouse obese gene product, expressed specifically in adipose tissue, regulates energy balance in mice. Mutation of the obese gene results in marked obesity and type II diabetes as part of a syndrome that resembles morbid obesity in humans. Here we report the cloning and sequencing of rat obese cDNA. Neither alterations of nucleotide sequence in the coding region nor changes of the gene structure were found in two rat strains with obesity, Zucker (fa/fa) and Otsuka Long Evans Tokushima Fatty. The expression level of obese mRNA in adipose tissue of Zucker (fa/fa) rat was found to be about 4 times that in lean littermates, suggesting some mutation or abnormal expression of the receptor for the obese product in obese rats of this strain.

Animals↗
PubMed1994

SYNTAX: a rule-based stochastic simulation of the time-varying concentrations of positional isotopomers of metabolic intermediates.

We present a new approach to simulation of metabolic pathways. The syntactic approach combines a rule-based description of biochemical reactions with a stochastic model of chemical kinetics. Each syntactic rule describes the location in a product molecule to which a particular carbon of a reactant molecule will be transferred. Using specifically labeled substrates and known rates of chemical reactions, our simulation predicts the time-dependent changes in concentration of positional isotopomers of metabolic intermediates. (A positional isotopomer of a compound is an isomer that is determined by the positions of isotopes within the molecule, e.g., [1,2-13C]glucose and [1,3,5-13C]glucose). For the simulation of the 13C-positional isotopomers of the citric acid cycle in heart cells we require only 39 syntactic rules, compared to the 176 ordinary differential equations required by the traditional approach. Addition of chemical reactions to the simulation does not require changing the program code for the existing reactions. In comparison, addition of a reaction to a system described by differential equations requires altering the equations for all isotopomers of all reactants and products of the new chemical reaction.

Carbon Isotopes↗
PubMed1995

Experiments in coding clinical information: an analysis of clinicians using a computerized coding tool.

We present data from a controlled experiment with computerized browsing and encoding tool. Eighteen practicing clinicians were asked to extract medical concepts from narrative exercise cases using two approaches--traditional and computer-assisted use of ICD-9. Our results indicate that completeness of coding can be improved by up to 55% using a computerized coding tool; enforcing mandatory as opposed to optional modifier codes results in lower rates of incomplete coding (0 vs 55%), higher rates of correct coding (41 to 92%), and no change in the number of incorrect codings; and manual coding takes 100% longer than coding with the help of the computerized coding tool. Furthermore, clinicians need 59% more time for processing the whole set of codes than is suggested by the sum of individual codes. We conclude that use of a computerized coding tool can save time and result in higher quality coding However, de facto time spent on coding may be underestimated when looking at individual coding times instead of looking at the whole task of processing a clinical scenario.

Computers↗
PubMed2001

Analysis of the Ser786Pro interleukin-4 receptor alpha allelic variant in allergic and nonallergic asthma and its functional consequences.

Asthma and other atopic disorders affect a large percentage of the population. While many factors contribute to the phenotype of asthma, there is a strong genetic predisposition. IL-4 is a central mediator of allergic inflammation. Along with IL-13, it is the major cytokine responsible for the induction of IgE synthesis. Furthermore, IL-4 acts on Th0 cells and promotes their differentiation into Th2 cells resulting in the production of more IL-4 and IL-13, thereby propagating the allergic cascade. Both IL-4 and IL-13 utilize IL-4Ralpha as a component of their cognate receptor complexes. Eight polymorphisms of the IL-4Ralpha gene resulting in amino acid changes in the coding sequence have been described, and several have been associated with asthma. The central objective of this study was to elucidate the role of the Ser786Pro polymorphism in asthma and its impact on IL-4R function. One-hundred ninety-six individuals with asthma and 53 controls were genotyped for Pro786. Pro786 occurred infrequently in the general population with an allele frequency of 1.8% and, thus, is unlikely to play a major role in atopy or asthma. The Pro786 allele frequency was 1.5% in the asthma group and 2.8% in the control group. The asthma group was subdivided into allergic and nonallergic asthma, and the Pro786 allele frequencies were 1.7 and 1.0%, respectively. The data suggested linkage disequilibrium between Ser786Pro and the Gln576Arg allele, which is associated with atopy. In order to study the impact of the polymorphism on receptor signaling function, we transfected a mouse B lymphoma cell line with the wild-type and Pro786 variants of human IL-4Ralpha. The Ser786Pro polymorphism in isolation did not affect IL-4R function.

Adult↗
PubMed1995

Production of a chimeric fibroin light-chain polypeptide in a fibroin secretion-deficient naked pupa mutant of the silkworm Bombyx mori.

The allelic Nd-s and Nd-sD mutations of the silkworm Bombyx mori are mapped to the same locus as that of the fibroin light (L)-chain gene (Fib-L). The silkworm carrying the homozygous Nd-s or Nd-sD mutation secretes less than 0.3% of the normal level of fibroin and produces a thin cocoon (naked pupa). In this study, cDNA sequences of the Nd-s and Nd-sD L-chains were compared with the cDNA and genomic sequences of the L-chain of the B. mori J-139 strain, a normal-level producer of fibroin. The two mutant cDNA sequences are almost identical except for one base change in the coding region. The N-terminal half of the L-chain encoded by exons I to III is identical between the mutants and J-139, but the rest of the molecule is completely different. The C-terminal half of the Nd-sD mutant L-chain is encoded by two exons, IV' and V', which are brought into proximity with the exon III by recombination between sequences in the third intron and in the far downstream region with concomitant loss of a region containing exons IV to VII. Sequences corresponding to exons IV' and V' are present about 10 kb downstream of the L-chain gene in the J-139 genome. Their homologous sequences have not been found in the DNA and protein databases. The chimeric L-chain molecule of about 27 kDa is present in posterior silk glands of Nd-s and Nd-sD strains without disulfide-bonding to the fibroin heavy (H-) chain, as revealed by Western blotting with the antibody specific to the C-terminal half of the mutant L-chain.

Amino Acid Sequence↗
PubMed2000

Transcriptome analysis of fibroblast cells immediate-early after human cytomegalovirus infection.

Human cytomegalovirus (HCMV) has been shown to have the potential to alter cellular gene expression early after infection. However, one-gene approaches and the use of closed system gene expression technologies have identified only few cellular genes whose activity changed immediate-early. We therefore used serial analysis of gene expression (SAGE) to investigate the transcriptional program of human fibroblasts in response to HCMV in the immediate-early phase of infection. Differential expression of various cellular genes was monitored. Transcriptional expression changes of genes coding for ribosomal proteins reflected a general cellular response to starvation and stress. But differential regulation of genes coding for transcription factors and proteins associated with cellular metabolism, homeostasis and cell structure may represent transcriptional alterations in response to HCMV infection. Expression kinetics by 5' nuclease fluorigenic real-time PCR of selected genes revealed partial protection of infected cells against initial stress-associated alterations of gene expression and indicated fluctuations of transcriptional levels over time. Additionally, agreement with the quantitative results obtained by SAGE was observed only for genes up-regulated in HCMV-infected cells. This finding pointed to various technical and statistical parameters that all may be critical for quantitative transcriptome studies using global approaches, especially when exploring biological systems in a critical phase of cellular physiology.

Cell Cycle↗
PubMed2000

Molecular evolution of the histone 3 multigene family in the Drosophila melanogaster species subgroup.

Molecular evolution of the histone multigene family was studied by cloning and sequencing regions of the histone 3 gene in the Drosophila melanogaster species subgroup. Analysis of the nucleotide substitution pattern showed that in the coding region synonymous changes occurred more frequently to A or T in contrast to the GC-rich base composition, while in the 3' region the nucleotide substitutions were most likely in equilibrium. These results suggested that the base composition at the third codon position of the H3 gene, i.e., codon usage, has been changing to A or T in the Drosophila melanogaster species subgroup.

Animals↗
PubMed2006

Genome-wide analysis of DNA methylation changes in human malignancies.

DNA methylation is an epigenetic modification of the DNA sequence and thus does not change the genetic code but affects chromosomal stability and gene expression. DNA methylation patterns are heritable and can be passed on to the daughter cell. In this review, we briefly summarize our current knowledge on normal DNA methylation patterns and move on to discuss the current state of the field with respect to altered DNA methylation in cancer. We make a special attempt to address current questions relating to genome-wide DNA methylation patterns. Since DNA methylation is used as a therapeutic target in clinical studies, it is of utmost importance to define potential target sequences that could be used as diagnostic or prognostic markers. We conclude the review by outlining possible scenarios that may explain tumor type-specific DNA methylation patterns described by assays evaluating genome-wide levels of DNA methylation.

CpG Islands↗
PubMed1994

Temperature-sensitive mutants of hsp82 of the budding yeast Saccharomyces cerevisiae.

The budding yeast Saccharomyces cerevisiae has two HSP90-related genes per haploid genome, HSP82 and HSC82. Random mutations were induced in vitro in the HSP82 gene by treatment of the plasmid with hydroxylamine. Four temperature-sensitive (ts) mutants and one simultaneously ts and cold-sensitive (cs) mutant were then selected in a yeast strain in which HSC82 had previously been disrupted. The mutants were found to have single base changes in the coding region, which caused single amino acid substitutions in the HSP82 protein. All of these mutations occurred in amino acid residues that are well conserved among HSP90-related proteins of various species from Escherichia coli to human. Various properties including cell morphology, macromolecular syntheses and thermosensitivity were examined in each mutant at both the permissive and nonpermissive temperatures. The mutations in HSP82 caused pleiotropic effects on these properties although the phenotypes exhibited at the nonpermissive temperature varied among the mutants.

Base Sequence↗
PubMed1988

Deletion mutagenesis of the ice nucleation gene from Pseudomonas syringae S203.

The ice nucleation gene inaZ, from Pseudomonas syringae S203, was manipulated to produce a series of defined rearrangements in its coding sequence without changing the reading frame. The effects of these mutations on the ice nucleation phenotype were determined in a heterologous host, Escherichia coli K12. Deletions which disrupted the periodicity of 16 codons, in a repetitive region of inaZ, caused the frequencies of ice nuclei in the bacterial population to be significantly depressed; the nuclei with thresholds at warmer temperatures were most affected. In contrast, when the periodicity was left intact, deletions and duplications in the same region had only slight effects on nucleation activity. Deletions removing part or all of one of the nonrepetitive regions (that encoding the amino-terminal domain of the InaZ protein) did not abolish nucleation activity, but caused it to be limited to cooler threshold temperatures. In contrast, the non-repetitive carboxy-terminal domain of the InaZ protein was shown to be essential for ice nucleation at all temperatures. The differential requirements (for periodicity, and for the amino-terminus) in forming nuclei with different thresholds may be significant for understanding what determines the threshold temperature of an ice nucleus.

Amino Acid Sequence↗
PubMed1988

The repressor gene (c) of the Streptomyces temperate phage phi c31: nucleotide sequence, analysis and functional cloning.

The nucleotide sequence of the 3.4 kb SphI-G fragment that contained the repressor gene (c) of the temperate Streptomyces phage phi c31 was determined. Analysis of this sequence revealed a large open reading frame with protein coding character and sequence changes in c gene point and deletion mutants identified this as the coding region of the repressor. Two of the mutants studied had undergone deletions of 1.1 kb and 1.4 kb that had occurred across short direct repeats of 6 bp and 11 bp, respectively. Coupled in vitro transcription-translation experiments using the cloned SphI-G fragment and Streptomyces lividans cell free extracts identified a protein product of approximately 72 kDa, in close agreement with that predicted from the nucleotide sequence. A strongly predicted helix-turn-helix motif that may be involved in DNA binding occurred towards the carboxy-terminus of the amino acid sequence. Initial attempts to clone the SphI-G fragment in Streptomyces failed; using information gained from the sequence analysis a smaller segment of this DNA fragment was cloned in S. lividans and conferred immunity to a clear plaque mutant (c1) of phi c31.

Bacteriophages↗
PubMed1996

Acquisition of the ts phenotype by a chemically mutagenized cold-passaged human respiratory syncytial virus vaccine candidate results from the acquisition of a single mutation in the polymerase (L) gene.

A cold-passaged (cp) temperature-sensitive (ts) mutant of human respiratory syncytial virus designated RSV cpts-248 was previously derived by random chemical mutagenesis of the non-ts mutant cp-RSV that possesses one or more host range mutations. We previously demonstrated in rodents and seronegative chimpanzees that the cpts-248 virus is more attenuated than cp-RSV and is more stable genetically than previously isolated RSV ts mutants. In the present study, we determined that the acquisition of the ts phenotype and the increased attenuation of the cpts-248 virus are associated with a single nucleotide substitution at nucleotide 10,989 that results in a change in the coding region (amino acid position 831) of the polymerase gene. The identification of this attenuating ts mutation is important because cpts-248 was used as the parent virus for the generation of a number of further attenuated mutants that are currently being evaluated as candidate vaccine strains in clinical trials in infants. Furthermore, technology now exists to rationally design new vaccine candidates by incorporating multiple attenuating mutations, such as the one identified here, into infectious viruses that are genetically stable and appropriately attenuated.

Animals↗
PubMed1986

Genetic variation for superoxide dismutase level in Drosophila melanogaster.

We have studied genetic variation for levels of activity of the enzyme superoxide dismutase (SOD) in Drosophila melanogaster. We have constructed 34 lines homozygous for a given second and a given third chromosome derived from eight original lines; all lines were homozygous for the "fast" (F) allele of Sod. The variation in the relative levels of SOD CRM ranges from 1 to 1.6. The second chromosomes modify the SOD level, even though the structural Sod locus is in the third chromosome, and the specific effect of a given second chromosome depends on the particular third chromosome with which it is combined. This indicates that the variation in SOD content is controlled by polygenic modifiers present in the second (and in the third) chromosome. In addition to these trans-acting modifiers, we have isolated a cis-acting element (SodCA1) that reduces SOD CRM levels to 3.5% of a typical F/F homozygote. SodCA1 is either a mutation in a regulatory site closely linked to the structural locus or a change in the coding sequence affecting the rate of degradation of the enzyme.

Alleles↗
PubMed1995

A single amino acid substitution in the capsid protein VP1 of coxsackievirus B3 (CVB3) alters plaque phenotype in Vero cells but not cardiovirulence in a mouse model.

We previously described a large plaque attenuant (p14V-1) derived from a cardiovirulent Coxsackievirus B3 (CVB3) and showed that there were no major determinants of either attenuation or plaque phenotype in the 5' nontranslated region (5'NTR). Part of the region encoding the last 124 amino acids of VP3 and the first 106 amino acids of VP1 of the attenuant was then sequenced and compared to the wild-type. Three nucleotide changes were found in the VP1 coding region: a silent single base change at nucleotide position 2467 (C to U) and a double-base change at position 2690-1 (AA to GT), which leads to a change from lysine to serine at amino acid position 80. This mutation maps to the begining of B-C loop of the three-dimensional structure of VP1 of CVB3, where a distinct surface projection is formed. Two infectious chimeric cDNA clones were constructed, based on a cardiovirulent cDNA construct. In one construct, the 5'NTR and the VP3-VP1 region were from p14V-1 and in the other, only the VP3-VP1 region was from this attenuant. Both chimeric viruses produced large plaques on Vero cell monolayers, similar to p14V-1 but larger than the prototypic cardiovirulent virus. In vivo experiments showed that both chimeric viruses induced myocarditis in a murine model, similar to wild-type virus. We conclude that mutation serine-80 in capsid protein VP1 of p14V-1 is a determinant of the large plaque phenotype but is not responsible for attenuation.

Amino Acid Sequence↗
PubMed1990

Identification of the mutations in the parents of a patient with a putative compound heterozygosity for acute intermittent porphyria.

The molecular abnormalities responsible for acute intermittent porphyria were investigated in both parents of a girl who was retrospectively diagnosed as having a homozygous form of the disease. The mutations in the parents are different from each other and both of them correspond to previously identified G to A changes in the coding part of the porphobilinogen deaminase mRNA. These point mutations lead to the presence of a catalytically-defective but immunologically-reactive enzyme. Our results support the conclusion that the propositus girl may represent the first case of compound heterozygosity for acute intermittent porphyria alleles.

Acute Disease↗
PubMed1988

Functional neuroarchitecture of the retina: hypothesis on the dysfunction of retinal dopaminergic circuitry in Parkinson's disease.

Recent morphologic and functional techniques for the study of nerve cells, such as intracellular injection and neurotransmitter immunohistochemistry, allow a new approach to the functional architecture of the retinal circuitry. Two types of dopaminergic cells are described: amacrine cells and interplexiform cells. These latter cells, which send processes to both the inner and outer plexiform layers, form a feedback loop acting at the level of horizontal cell coupling. Two molecules localized in such cells, dopamine and GABA, have antagonistic effects on horizontal cell coupling and regulate the diameter of their receptive fields which code for contrast. Changes in the ERG, VEPs and contrast sensitivity occur in Parkinsonian patients and are identical to those observed in animal models whose dopaminergic retinal system has been destroyed, thus suggesting a degenerative process of this system in Parkinson's disease. The observation of dopamine neurons, labelled by their tyrosine hydroxylase immunoreactivity, in the retina of 5 patients, led to the observation of reduced dopamine innervation in the central retina of Parkinsonian patients.

Dopamine↗