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Frequency of ischaemic exercise E.C.G. Changes in symptom-free men with various forms of primary hyperlipaemia.

Serum cholesterol and triglycerides were measured in approximately 12,000 men attending a screening centre. 130 symptom-free men (aged thirty-five to sixty-five) were selected from the top 2% with the highest lipid values. They, and 59 normolipaemic controls, were studied by recording electrocardiograms (E.C.G.) before and during exercise. The frequency of so-called ischaemic E.C.G. changes (ST-segment depressions Minnesota code 4.1-4.4) increased with age both in controls and in the hyperlipaemic group. Ischaemic E.C.G. changes were significantly more common in all types of hyperlipaemia (types IIA, IIB, III, and IV) than in controls. The high frequency of the exercise E.C.G. changes in symptom-free hyperlipaemic men reinforces the argument for early treatment of hyperlipaemia to prevent ischaemic heart-disease.

Adult↗

Single amino acid substitution defines a naturally occurring genetic variant of human thymidylate synthase.

Previously, we identified an altered structural form of thymidylate synthase (TS) in a human colonic tumor cell line. This form, which is encoded by a variant structural gene, renders cells relatively resistant to 5-fluoro-2'-deoxyuridine as a result of the reduced affinity of the enzyme for the active metabolite 5-fluoro-2'-deoxyuridylic acid. We have isolated a cDNA clone specific to the altered TS and have determined its sequence. Two point mutations distinguish the normal from the altered TS mRNAs. One, a (A----G) change, is located within the 3'-untranslated region; the other, a T----C change within the amino acid-coding region, predicts replacement of tyrosine by histidine at residue 33 of the polypeptide. This sequence change was confirmed by direct analysis of cDNA amplified by the polymerase chain reaction and was further verified using allele-specific oligonucleotides as probes in Northern blots. These results, along with studies by other laboratories showing Tyr33 to be evolutionarily conserved, suggest that this residue plays an important role in TS function.

Amino Acid Sequence↗

The role of mitochondria in aging.

Aging is a process drawing attention of many researchers, and at present many theories exists, which try to explain this chain of inevitable events leading to death of organism. In this article we focused our attention on a theory explaining the degenerative changes occurring during aging by the effect of oxygen free radicals. These highly reactive radicals are produced during oxidative phosphorylation in mitochondria. All cellular components appear to be sensitive to oxygen-radical damage. Lipids, proteins and nucleic acids are probably the most susceptible to this injury. Lipoperoxidation of lipids together with cross-linking of proteins with phospholipids and nucleic acids caused changes in membrane fluidity. Mitochondrial DNA coding several subunits of respiratory chain enzymes can be also damaged by these radicals. All these changes together have negative impact on mitochondrial metabolism resulting progressive decrease of the efficiency of oxidative phosphorylation and thus of the whole organism.

Aging↗

Molecular characterization of familial hypercholesterolemia in Spain: identification of 39 novel and 77 recurrent mutations in LDLR.

Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolemia (FH), an autosomal dominant inherited disorder associated with an increased risk of premature atherosclerosis. The aim of this study was to characterize the LDLR mutations in a group of 476 apparently non-related Spanish FH patients. The promoter region and the 18 exons with their flanking intron sequences of the LDLR gene were screened by PCR-SSCP analysis and DNA sequencing. In addition, we tested for the presence of the mutation p.R3500Q in the gene coding for apolipoprotein B-100 (apo B-100). We found 77 mutations previously described, and 39 novel mutations affecting the LDLR gene: 8 missense, 5 nonsense, 15 frameshift, 5 splicing, 4 in frame, one nucleotide change in the non-coding sequence of exon 1, and one silent variant. We have identified al least one of these LDLR gene mutations in 329 subjects (69%). Four patients were homozygous, 4 patients were compound heterozygous, 48 patients were found to carry two different sequence variants in the same allele and 4 patients carried three different sequence variants in the same allele. Additionally, 4 subjects were carriers of the p.R3500Q mutation in the apo B gene. All of these findings indicate that there is a broad spectrum of mutations and sequence variants in the LDLR gene causing FH in Spain.

Codon, Nonsense↗

Infectious cDNA clones of porcine reproductive and respiratory syndrome virus and their potential as vaccine vectors.

Full-length infectious cDNA clones have recently become available for both European and North American genotypes of porcine reproductive and respiratory syndrome virus (PRRSV), and it is now possible to alter the PRRSV genome and create genetically defined mutant viruses. Among many possible applications of the PRRSV infectious cDNA clones, development of genetically modified vaccines is of particular interest. Using infectious clones, the PRRSV genome has been manipulated by changing individual amino acids, deleting coding regions, inserting foreign sequences, and generating arterivirus chimeras. The limited available data suggest that all structural proteins of PRRSV are essential for replication of the virus, and that PRRSV infectivity is relatively intolerant of subtle changes within the structural proteins. The major tasks in PRRSV research are to identify virulence factors and pathogenic mechanisms, and to understand the structure-function relationships of individual viral proteins. Utilizing these infectious clones as tools, a new generation of safe and efficacious PRRS vaccines may be constructed.

Animals↗

Complex allotypes of the rabbit immunoglobulin kappa light chains are encoded by structural alleles.

We have isolated the rabbit immunoglobulin b9 Ck light chain gene and compared its nucleotide sequence with the b4, b4var , b5 and bas Ck sequences. In spite of the high number of substitutions found between the different rabbit Ck coding regions, only very few changes are silent. Furthermore, the nucleotide changes are clustered in segments which correlate with the bends and helical regions found in the tertiary structure of the Ck domain of the protein. The flanking regions present a higher degree of conservation than the coding regions. The two genomic EcoRI fragments hybridizing to a b4cDNA probe have been correlated with the two distinct loci, Ck1 and Ck2 : one encodes for the nominal b9 Ck allotype and the other contains the information for the bas Ck region. The b allotypes are true alleles which could have evolved by intergenic conversion.

Alleles↗

A comparison of MMPI profile types across standard and contemporary norms.

Changes in mean elevation, dispersion, overall configuration, and code type of well-defined MMPI profiles derived from diagnostic groups with known clinical correlates were examined after transformation using contemporary norms developed by Colligan, Osborne, Swenson, and Offord (1983). A total of 34 MMPI profiles from both Gilberstadt and Duker (1965) and Marks, Seeman, and Haller (1974) were analyzed using contemporary normalized T scores. Results yielded the expected reduction in mean elevation and dispersion about the mean upon transformation to contemporary norms. Linear and contemporary normalized T-score profiles correlated highly with each other and manifested a similar pattern of correlation with Skinner and Jackson's (1978) three modal MMPI types. Similarity in the code types of 94% of the profiles was found. However, the substantial number of order changes in the scales that comprise the code type evident upon transformation highlights the caution and care necessary when one is interpreting MMPI profiles based on contemporary norms. Continued use of original norms together with contemporary norms appears indicated until the full implications of profile and code type differences upon transformation to contemporary norms are understood.

Humans↗

Changes in PC12 cell morphology induced by transfection with 42C cDNA, coding for a member of the S-100 protein family.

The cloned DNA coding for 42C protein (light chain of calpactin I), whose mRNA is induced in PC12 cells by treatment with nerve growth factor (NGF), was reintroduced into these cells. A cell line was obtained in which the outgrowth of processes in the absence of added NGF, similar to that induced in the parental PC12 cells by the factor, was accompanied by high levels of 42C RNA. The apparent reason for this constitutive overexpression of 42C is the stable integration of multiple copies of the 42C DNA into the cell genome. These results further support the notion that S-100 protein family, of which 42C is a member, may play an important role in development.

Adrenal Gland Neoplasms↗

Genetic recombination at different points in the Npro-coding region of bovine viral diarrhea viruses and the potentials to change their antigenicities and pathogenicities.

Cytopathogenic (cp) bovine viral diarrhea virus (BVDV) strain KS86-1 cp was isolated from a cow persistently infected with non-cytopathogenic (ncp) BVDV strain KS86-ncp after development of mucosal disease by superinfection with cp BVDV strain Nose. cp BVDV strains 799cp and 839cp were also isolated from independent cattle that developed mucosal disease by superinfection with cp BVDV KS86-1cp. In the present study, genetic analysis revealed that the genes of cp BVDV strains 799cp and 839cp were chimeras between the genes of the persisting ncp BVDVs and that of superinfecting KS86-1cp. The genetic recombination that generates 799cp occurred between the identical points in the N(pro) gene region, whereas genetic recombination that generates 839cp occurred between different points in the N(pro) gene region. Both 799cp and 839cp were inherited Jiv gene of KS86-1cp strain and envelope protein genes of the persisting viruses. In addition, neutralization test disclosed that antigenicities of 799cp, 839cp, and KS86-1cp were also similar to each persisting virus. These findings indicate that exogenous cp BVDV containing insertion of Jiv gene in the 5 terminal region can induce genetic recombination with the original ncp BVDV at different points in the N(pro) gene region, and those viruses have high potential to change those antigenicities and pathogenicities by RNA recombination.

Animals↗

Effect of two different syringes on syringe driver function.

A laboratory investigation into the effect of two different syringes on the performance of a syringe driver was undertaken in order to assess accuracy of delivery, occlusion-alarm delay time and the effect of incorrectly coding the device for the syringe in use. Results indicated that accuracy of delivery was of the order of -1%/h for both syringe types at an infusion rate of 5 ml/h. Clinically and statistically significant differences in the occlusion-to-alarm time were found between syringes and between infusion rates. At 99.9 ml/h lag time was about 30 seconds for both syringes, whereas at 5 ml/h this was 667 seconds for one syringe and 903 seconds for the other. Incorrect coding of the driver for the syringe in use, resulted in a significant change in the accuracy of delivery at an infusion rate of 5 ml/h. Similarly, incorrect coding resulted in changes in the occlusion-alarm time. These results carry significant pharmacological implications for the clinical situation.

Humans↗

Doing well by doing good? A supermarket shuttle feasibility study.

OBJECTIVE: Creating a more healthful food environment requires a new line of research that examines the impact of healthful changes on business's bottom line. This study investigates whether supermarket-sponsored shuttles can be self-supporting or make a profit in low-income urban areas. DESIGN: 2000 Census data were used to identify zip codes in California with low income, low vehicle ownership, and high population density to identify potential markets for shuttle programs. The breakeven point was calculated for a hypothetical shuttle program operating in these zip codes. MAIN OUTCOME MEASURES: Breakeven point in the number of months of shuttle operation. ANALYSIS: Breakeven analysis. RESULTS: Sixty-seven zip codes met the criteria for inclusion in the study. A supermarket shuttle program would break even in most zip codes if 10% of households without a car used the shuttle. If 15% used the shuttle, shuttle programs in all zip codes would make a profit. CONCLUSIONS: A shuttle program could be self-supporting in all 67 zip codes. IMPLICATIONS: Those interested in changing the food environment to support a healthful diet could use this information to share with supermarket executives and other key decision makers.

California↗

Sequence fossils, triplet expansion, and reconstruction of earliest codons.

mRNA sequences are known to carry a hidden periodical pattern (GCU)n, which may be considered a remnant of sequence organization of mRNA early in its evolution, dominated by codons for alanine and their point mutation derivatives. A similar pattern is characteristic of the master (consensus) tRNA sequence derived in 1981 by Eigen and Winkler-Oswatitsch. The master tRNA sequence is thought to represent one of the earliest mRNA. From analysis of literature and from our own calculations presented in this work, the (GCU)n pattern appears to be the most expandable in the norm and in disease. The speculation is put forward that (GCU)n and polyalanine have been key players at the beginning of the triplet code, and the first codons, apart from the GCU triplet, were point change derivatives of the generic triplet GCU, coding for amino acids present in the early prebiotic-biotic environment. The set of the earliest amino acids is derived on the basis of structural simplicity, presence in imitated prebiotic conditions and involvement with class II aminoacyl-tRNA synthetases. The set consists of six amino acids: Ala, Asp, Gly, Pro, Ser and Thr. All these amino acids are, indeed, encoded by the GCU triplet and its derivatives, as predicted. Thus, the pairs GCN (Ala), GAU (Asp), GGU (Gly), CCU (Pro), UCU (Ser) and ACU (Thr) can be viewed as an early triplet code.

Codon↗

Sequence relationships among the hemagglutinin genes of 12 subtypes of influenza A virus.

Nucleotide sequences of the 3' 20% of the hemagglutinin gene of 32 influenza A virus strains from the 12 known hemagglutinin subtypes have been determined. Although the sequences of hemagglutinin genes and proteins of different subtypes differ greatly, cysteine and some other amino acid residues are totally conserved, presumably reflecting evolution of the 12 different hemagglutinins from a single gene. When viruses of one subtype, isolated over a period of time, are compared, the hemagglutinin gene and protein sequences show a slow accumulation of nucleotide changes and some amino acid changes. Since sequence data from the genes coding for the matrix and nonstructural proteins also show an accumulation of changes with time, it seems that antigenic selection (of the surface antigens) does not contribute significantly to the rate of change on influenza gene sequences. Although the rate of nucleotide change during drift is more than sufficient to account for the amino acid sequence differences observed in the 12 subtypes, there is a clear distinction, by antigenic as well as sequence analyses, between viruses of one subtype (0-9% amino acid variation) and viruses of other subtypes (20-74% amino acid variation). No virus has yet been found that is intermediate between subtypes.

Amino Acid Sequence↗

Replication capacities of natural and artificial precore stop codon mutants of hepatitis B virus: relevance of pregenome encapsidation signal.

The emergence of hepatitis B virus variants unable to express HBe protein during late stage of viral infection may represent an important mechanism of viral persistence. The molecular mechanisms responsible for the elimination of HBe expression are nonsense or frameshift mutations or initiation codon mutations in part of its coding sequence, the precore region. So far only 2 of the 29 precore amino acid codons have been found mutated to stop codons in nature, although a total of 10 codons are convertible to stop codons by single nucleotide changes. Since the HBe-coding sequence is largely overlapped by the pregenome encapsidation signal (epsilon signal), a recently found cis-acting element required for the packaging of pregenomic RNA, the absence of other potential nonsense mutants could result from their impairment of the epsilon signal. Seven such potential stop codon mutants were constructed and tested for replication capacities by transfection into a hepatoma cell line. Five mutants were replication competent, but at levels lower than that of a prevalent natural stop codon mutant. The remaining two mutants were completely defective in DNA replication, which clearly explained why these two mutants are not found in nature. Northern blot analysis revealed wild-type levels of RNA transcription by these two mutants but complete lack of packaged pregenomic RNA. Additional studies lent further support to the importance of the epsilon signal in pregenome encapsidation and suggested relaxed sequence requirements for the computer-predicted hexanucleotide bulge region as compared to the hexanucleotide loop of the signal.

Base Sequence↗

Patterns of use and changes in diagnosis during first admission. National Case Register Study.

The goal of this study was to describe patterns of diagnosis and to explore the extent to which diagnosis changes during first-in-life psychiatric admissions. All 2,998 first admissions to Israeli psychiatric wards in 1989 were studied. Diagnosis did not change in at least 60% of the cases. Diagnoses in order of stability were: mental retardation (84%), substance abuse (82%), organic conditions (77.5%), neurotic (75%), schizophrenia (74%), personality disorders (73%), affective (68%), childhood (55%), paranoid (45%) and V-codes (22%). There was less change in diagnosis for patients over 45 (37.5%), than for patients aged 19-44 (43.2%) and 15-18 (57.8%). Diagnoses assigned at admission to first hospitalization are not likely to change during that hospitalization.

Adolescent↗

Temperature sensitivity of the cdc9-1 allele of Saccharomyces cerevisiae DNA ligase is dependent on specific combinations of amino acids in the primary structure of the expressed protein.

In this study we present the characterization of the temperature-sensitive mutant allele cdc9-1 encoding DNA ligase, of Saccharomyces cerevisiae strain A364A by DNA sequencing. Comparison with the published wild-type sequence from strain SK1 revealed 13 nucleotide exchanges between these two sequences, which are derived from non-isogenic genetic backgrounds. Only four of these changes, distributed over the whole coding region, lead to amino acid exchanges in the protein chain. Our analysis of the sequence of the wild-type CDC9 allele from strain A364A revealed differences from the isogenic cdc9-1 allele in only two nucleotides: one silent change and one leading to a single amino acid exchange. The latter is therefore responsible for the temperature-sensitive phenotype. A mosaic protein, in which a region carrying this amino acid exchange has been inserted in place of the corresponding part of CDC9 from the non-isogenic strain SK1, is not temperature sensitive. The exchange of a longer stretch of DNA leading to atteration of three amino acids of the protein compared with the original sequence of SK1 is required to obtain a temperature-sensitive DNA ligase in this strain, while in strain A364A a single amino acid change is sufficient for expression of a temperature-sensitive protein.

Amino Acid Sequence↗

Decoherence by correlated noise and quantum error correction.

We study the decoherence of a quantum computer in an environment which is inherently correlated in time and space. We first derive the nonunitary time evolution of the computer and environment in the presence of a stabilizer error correction code, providing a general way to quantify decoherence for a quantum computer. The general theory is then applied to the spin-boson model. Our results demonstrate that effects of long-range correlations can be systematically reduced by small changes in the error correction codes.

Journal Article↗

[Trends in incidence of cancer in southeast North Brabant and North Limburg during 1975-1986; report from the IKZ/SOOZ cancer registration (Integrated Cancer Center South/Cooperative Organization Oncology Hospitals)].

Trends in the incidence of cancer have been determined in the Southeast of the Netherlands from 1975 to 1986 inclusive by means of the regional SOOZ cancer registry. Age-adjusted registration rates of cancer in males rose rather steeply from more than 371 per 10(5) men-years to 424 in 1982-3 and fell thereafter to 407 per 10(5) in 1986. A similar changing pattern was seen in cancer of the lung, larynx, prostate and kidney and possibly also in cancer of the head and neck. The incidence of colorectal cancer had skin melanoma increased while that of cancer of the stomach fell. Age-adjusted incidence of cancer in females rose steadily from 266 to 290 per 10(5) woman-years. A steady increase was observed for cancer of the lung, breast, bladder and melanoma and temporarily for cancer of the kidney. The incidence of cancer of the stomach and gallbladder fell continuously. These changes in incidence generally corresponded with trends in cancer mortality as registered with the Central Bureau of Statistics. Bias from changes in data collection and coding appears to be negligible, but a certain influence on the registration rates from the markedly increased number of consultants managing cancer patients is likely. Contrasting trends in male and female rates of cancer of the airways illustrate the marked changes in smoking patterns since the sixties.

Female↗