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At least 1,585 records · Page 88Linked to original sources
PubMed1994

The effect of background selection against deleterious mutations on weakly selected, linked variants.

This paper analyses the effects of selection against deleterious alleles maintained by mutation ('background selection') on rates of evolution and levels of genetic diversity at weakly selected, completely linked, loci. General formulae are derived for the expected rates of gene substitution and genetic diversity, relative to the neutral case, as a function of selection and dominance coefficients at the loci in question, and of the frequency of gametes that are free of deleterious mutations with respect to the loci responsible for background selection. As in the neutral case, most effects of background selection can be predicted by considering the effective size of the population to be multiplied by the frequency of mutation-free gametes. Levels of genetic diversity can be sharply reduced by background selection, with the result that values for sites under selection approach those for neutral variants subject to the same regime of background selection. Rates of fixation of slightly deleterious mutations are increased by background selection, and rates of fixation of advantageous mutations are reduced. The properties of sex-linked and autosomal loci in random-mating populations are compared, and the effects of background selection on asexual and self-fertilizing populations are considered. The implications of these results for the interpretation of studies of molecular evolution and variation are discussed.

Animals↗
PubMed2002

Comparisons of lung tumour mortality risk in the Japanese A-bomb survivors and in the Colorado Plateau uranium miners: support for the ICRP lung model.

PURPOSES: To estimate the ratio of risks for exposure to radon progeny relative to low-LET radiation based on human lung cancer data, taking account of possible time and age variations in radiation-induced lung cancer risk. MATERIALS AND METHODS: Fitting two sorts of time- and age-adjusted relative risk models to a case-control dataset nested within the Colorado Plateau uranium miner cohort and to the Japanese atomic (A)-bomb survivor mortality data. RESULTS: If all A-bomb survivors are compared with the Colorado data, there are statistically significant (two-sided p < 0.05) differences between the two datasets in the pattern of the variation of relative risk with time after exposure, age at exposure and attained age. The excess relative risk decreases much faster with time, age at exposure and attained age in the Colorado uranium miners than in the Japanese A-bomb survivors. If only male A-bomb survivors are compared with the Colorado data, there are no longer statistically significant differences between the two datasets in the pattern of variation of relative risk with time after exposure, age at exposure or attained age. There are no statistically significant differences between the male and female A-bomb survivors in the speed of reduction of relative risk with time after exposure, age at exposure or attained age, although there are indications of rather faster reduction of relative risk with time and age among male survivors than among female survivors. The implicit risk conversion factor for exposure to radon progeny relative to the A-bomb radiation in the male survivors is 1.8 x 10(-2) Sv WLM(-1) (95% CI 6.1 x10(-3), 1.1 x 10(-1)) using a model with exponential adjustments for the effects of radiation for time since exposure and age at exposure, and 1.9 x 10(-2) Sv WLM(-1) (95% CI 6.2 x 10(-3), 1.6 x 10(-1)) using a model with adjustments for the effects of radiation proportional to powers of time since exposure and attained age. Estimates of the risk conversion factor calculated using variant assumptions as to the definition of lung cancer in the Colorado data, or by excluding miners for whom exposure estimates may be less reliable, are very similar. The absence of information on cigarette smoking in the Japanese A-bomb survivors, and the possibility that this may confound the time trends in radiation-induced lung cancer risk in that cohort, imply that these findings should be interpreted with caution. CONCLUSIONS: There are no statistically significant differences between the male A-bomb survivors data and the Colorado miner data in the pattern of variation of relative risk with time after exposure and age at exposure. The risk conversion factor is very close to the value suggested by the latest ICRP lung model, albeit with substantial uncertainties.

Adult↗
PubMed2002

Pharmacogenomics as molecular autopsy for postmortem forensic toxicology: genotyping cytochrome P450 2D6 for oxycodone cases.

Pharmacogenomics, the study of the impact of heritable traits on pharmacology and toxicology, may serve as an adjunct for certifying opioid fatalities. Oxycodone, frequently prescribed for the relief of moderate to severe pain, is metabolized by cytochrome P450 (CYP) 2D6, encoded by a polymorphic gene with three mutations (*3, *4, and *5) with a combined 95% allelic frequency and about 10% prevalence. Individuals with variant alleles are more susceptible to oxycodone toxicity. By assessing the prevalence of CYP2D6 polymorphisms and covariables, we hypothesized that oxycodone fatality may be partially due to poor drug metabolism caused by CYP2D6 variant alleles. From the Milwaukee County Medical Examiner's Office (MCMEO), a retrospective analysis of 15 oxycodone cases was followed by genotyping blood samples for the variant alleles by conventional and real-time PCRs. Institutional Review Board approval was obtained. Oxycodone, extracted from blood and/or urine, was quantitated by GC-MS. The results show two homozygous for 2D6*4 and four heterozygous for 2D6*4. The MCMEO was not significantly different from those in the control group (n = 26) (p > 0.05, Fisher's Exact Test). However, genotyping CYP2D6 provided a more definitive interpretation of the oxycodone toxicity in four cases. Therefore, pharmacogenomics may serve as an adjunct in the determination of the cause and manner of death in forensic toxicology and a pharmacogenomic algorithm for genotyping has been proposed.

Adolescent↗
PubMed2001

Intergenic transcripts containing a novel human cytochrome P450 2C exon 1 spliced to sequences from the CYP2C9 gene.

The cytochrome P450 2C (CYP2C) gene locus was found to include a novel exon 1 sequence with high similarity to the canonical exon 1 of CYP2C18. Rapid amplification of cDNA ends (RACE) and PCR amplifications of human liver cDNA revealed the presence of several intergenic species containing the CYP2C18 exon 1-like sequence spliced to different combinations of exonic and intronic sequences from the CYP2C9 gene. One splice variant was found to have an open reading frame starting at the canonical translation initiation codon of the CYP2C18 exon 1-like sequence. Another variant consisted of the nine typical CYP2C9 exons spliced after the CYP2C18 exon 1-like sequence through a segment of CYP2C9 5' flanking sequences. Moreover, analysis of bacterial artificial chromosome (BAC) clones revealed that the CYP2C18 exon 1-like sequence was located in the intergenic region between the CYP2C19 and CYP2C9 genes. The finding that a solitary exon is spliced with sequences from a neighboring gene may be interpreted as representing a general evolutionary mechanism aimed at using the full expression potential of a cell's genomic informational content.

5' Flanking Region↗
PubMed2003

Polymorphisms past and present.

Polymorphisms, particularly genetic variants of the red blood cell, have served as a major focus for the research of Frank B. Livingstone over the course of a long and productive career. Recent investigations confirm the value of key insights that he contributed to this area more than four decades ago. As Livingstone recognized, the same underlying evolutionary model that guides genetic studies in present populations also provides a productive framework for interpreting patterns of variation in the skeleton and dentition throughout past human evolution. Examples explored in detail here include polymorphisms in hominoid nasal bone shapes and fourth lower premolar roots. This work provides both empirical and theoretical contexts for investigating patterns of human variation over the last 6 to 8 million years.

Genetic Variation↗
PubMed1993

Adequacy of continuous ambulatory peritoneal dialysis.

Adequacy of continuous ambulatory peritoneal dialysis (CAPD) and its variants is assessed by clinical outcomes, biochemical parameters and clearance parameters. Clinical outcomes lack specificity and probably sensitivity. Nevertheless, they constitute the "gold standard" to which any other method assessing dialysis adequacy must be compared. Biochemical parameters are both non-sensitive and non-specific and cannot be used to assess dialysis adequacy. Clearance of small molecular weight azotemic substances (urea, creatinine) presents considerable computational problems and interpretative difficulties. In preliminary studies, clearance studies have been able to differentiate between peritoneal dialysis patients having symptoms of inadequate dialysis and those clinically adequately dialyzed. Among population outcomes (morbidity, maintenance of peritoneal dialysis for long periods, hospitalization rate, mortality), only mortality seems to be associated with low clearances in retrospective studies. Prospective multicenter studies comparing clearance values to clinical outcomes are needed to evaluate clearance studies as methods of assessing peritoneal dialysis adequacy.

Creatinine↗
PubMed2007

A FISH comparison of variant derivatives of the recurrent dic(17;20) of myelodysplastic syndromes and acute myeloid leukemia: Obligatory retention of genes on 17p and 20q may explain the formation of dicentric chromosomes.

The dic(17;20) is a recurrent unbalanced translocation occurring rarely in myelodysplastic syndromes and acute myeloid leukemia. We have studied eleven cases with the dic(17;20) or a more complex derivative, all of which showed deletion of 17p and 20q material. The tumor suppressor gene TP53 was not always lost, supporting a more distal gene as the target of these 17p deletions. All derivatives could be interpreted as having initially been formed as a dicentric chromosome, those with a larger amount of material between the centromeres having undergone further rearrangement to stabilize the chromosome while retaining proximal 17p and proximal 20q material. We propose that critical sequences on both 17p and 20q proximal to the sites of deletion must be retained during the critical 17p and 20q deletions. This would explain the excess of dicentric chromosomes resulting from 17;20 translocation, and the apparent stabilization of the unstable derivatives by further rearrangements which preserve 17p and 20q material.

Acute Disease↗
PubMed1996

A new method of STR interpretation using inferential logic--development of a criminal intelligence database.

A short tandem repeat (STR) system consisting of seven multiplexed loci has recently been introduced in the UK to support a National strategy to create large DNA databases for criminal intelligence purposes. The process uses automated sequencers, employing dye-labelled primers. Identification of tetrameric loci such as HUMTH01 are straightforward. Sizing windows are estimated by running a series of control allelic ladders on several gels and 'unknown' samples are designated if they fall within a defined window. However, utilisation of complex STRs (eg. D21S11) characteristically have common variants which differ by just 2 bp. In addition, rare alleles are encountered which may differ by just 1 bp from a common variant. To assist with the identification of alleles, we have introduced a series of allelic ladders, so that direct comparisons with 'unknown' samples can be made on the same gel. To designate an allele, it should be within 0.5 bp of an allelic ladder marker. Not all alleles (in particular rare alleles) can be included within an allelic ladder, however their expected positions can be easily calculated by reference to existing alleles in the ladder. Measurement of band shift is also a useful diagnostic tool. A series of guidelines are described to enable reliable allelic identification. These guidelines can be converted into computer programmes which form the basis of an expert system.

Alleles↗
PubMed2006

How we can interpret the T1 dispersion of MC, HPMC and HPC polymers above glass temperature?

The chain dynamics in methyl cellulose (MC), hydroxypropylmethyl cellulose (HPMC) and hydroxypropyl cellulose (HPC) were studied with the aid of field-cycling NMR relaxometry technique in the temperature range from 300 to 480 K that is above the glass transition, but below thermal degradation. The frequency dependence of proton spin-lattice relaxation time was determined between 24 kHz and 40 MHz for selected temperatures. The experimental spin-lattice relaxation dispersion data were fitted with the power law relations of T(1) proportional variant omega(gamma) predicted by the tube/reptation model. The exponent's values found from the fitting procedure for MC, HPMC and HPC almost exactly match the ones predicted in tube/reptation model for limit II (gamma=0.75) and in MC also for limit III (gamma=0.50). Remarkably, this finding concerns the polymers in networks formed of the same polymer species.

Cellulose↗
PubMedDate not supplied

[Variant of quantitative evaluation of the mechanisms of orthostatic response of central hemodynamics].

This paper describes an approach that can help clarify mechanisms of central circulation of orthostatic men using a mathematical model and noninvasive methods of examinations. Circulation parameters such as peripheral resistance (PR), arterial compliance (Ca), and ratio of vein compliance (Cv) to the pump coefficient of the heart (beta) were determined by the "partial identification" method of the two-component circulation model with the aid of cardiac output and arterial blood pressure measured by tetrapolar thoracic rheography and tachooscillography. The paper also contains physiological interpretation of the above parameters as related to the upright posture of man. Peripheral resistance in the head-up position characterizes both the degree of arterial vasoconstriction and the state of the so-called muscle pump. Blood displacement to the lower body results in an increase of the ratio Cv . beta. The orthostatic reaction of circulation of 28 healthy male subjects was investigated. Blood pooling in the lower body, with venous and cardiac reactions being manifest, led to the fall of arterial pressure and cardiac output to 67% when compared with the pretest level. The change in the properties of resistance vessels (Ca and PR) accelerated the recovery of the arterial pressure value.

Adolescent↗
PubMed1995

The tempo and mode of SIV quasispecies development in vivo calls for massive viral replication and clearance.

Simian immunodeficiency virus (SIV) quasispecies development was followed in four monkeys (Macacca fascicularis) infected by intramuscular inoculation of phage lambda-SIVmac239 DNA. Rooted phylogenetic trees were reconstructed and used to interpret the data. The rate of fixation of base substitutions varied within and between animals reaching 3.3 x 10(-2) per site per year. These data suggest that the tempo of quasispecies development requires both massive viral replication and efficient clearance of SIV. Despite this, no significant difference was found between the observed and expected ratio of synonymous/nonsynonymous substitutions, suggesting that there was little or no selection of antigenic variants in the V1 and V2 hypervariable regions of envelope.

Amino Acid Sequence↗
PubMed1986

Pseudofractures of the cervical vertebral body.

A lucency traversing obliquely across the inferior-posterior aspect of cervical vertebral bodies may be a normal variant due to osteophytes of the uncinate processes or transverse processes with a resultant Mach band phenomenon. This could be misinterpreted as a fracture of the vertebral body in a patient with a history of cervical injury. A review of normal lateral cervical vertebral films obtained on patients with no traumatic history showed this phenomenon to occur in 27% of adults. It was not observed in children. The proper interpretation is easily made when one considers the location and the fact that a cervical fracture does not occur in such a location as an isolated event.

Adolescent↗
PubMed1999

Measuring the perceptual magnet effect in the perception of /i/ by German listeners.

In a study of the internal category structure of the vowel /i/, Kuhl found a "perceptual magnet effect": Discrimination sensitivity was poorer for category instances that were acoustically similar to the category prototype than it was for category instances that were not. The typicality of category exemplars was determined by goodness judgments and was found to correlate with the acoustics of average production. Analysis and interpretation of discrimination performance relied on two important assumptions: that listeners perceived all stimuli presented as exemplars of the same vowel category and that, apart from the influence of phonetic coding, discrimination sensitivity was the same across the investigated part of the vowel space. In the present study, it is shown that production and perception estimates of the category prototype may diverge, possibly because listeners seem to prefer hyperarticulated variants of vowel categories. An approach towards measurement of intra-category discrimination minima is put forward and tested that protects against intercategory confounds and avoids the isosensitivity assumption.

Germany↗
PubMed1989

Enlargement of the pancreatic head in patients with pancreas divisum.

Pancreas divisum (PD) is a congenital anomaly present in 6-10% of the population. Computed tomography (CT) examinations in eight of 15 patients (53%) with endoscopic retrograde pancreatography (ERCP)-proven PD were interpreted as showing enlargement of the pancreatic head. Two of these had carcinoma, three had pancreatitis limited to the ventral pancreas, and three were normal. Criteria to distinguish nonpathologic enlargement of the pancreatic head due to PD alone from pathologic causes may include homogeneous parenchyma and an absence of other abnormal signs on CT. Because PD may simulate a pancreatic head mass, the radiologist should be familiar with this variant, and ERCP should precede biopsy unless other evidence of malignancy is present.

Adolescent↗
PubMed1986

Phenotyping of human complement component C4, a class-III HLA antigen.

The plasma complement protein C4 is encoded at two highly polymorphic loci, A and B, within the class-III region of the major histocompatibility complex. At least 34 different polymorphic variants of human C4 have been identified, including non-expressed or 'null' alleles. The main method of identification of C4 polymorphic allotypes is separation on the basis of charge by agarose-gel electrophoresis of plasma. On staining by immunofixation with anti-C4 antibodies, each C4 type gives three major bands, but, since individuals can have up to five allotypes, the overlapping banding pattern is difficult to interpret. We show that digestion of plasma samples with carboxypeptidase B, which removes C-terminal basic amino acids, before electrophoresis, produces a single, sharp, distinct band for each allotype and allows identification of the biochemical basis of the multiple banding pattern previously observed in C4 phenotype determination.

Carboxypeptidase B↗
PubMed1976

Fate of mismatched base-pair regions in polyoma heteroduplex DNA during infection of mouse cells.

Heteroduplex DNA has been constructed from two variants of polyoma virus that differ genotypically at four distinct sites. The genotypes of the progeny virus derived from infections of mouse cells with single heteroduplexes have been analyzed to determine how the genotypic markers of the parental heteroduplex segregate. Markers that are separated by a length of DNA greater than 600 nucleotides segregate independently. Segregation was not detected between two markers separated by only approximately 90 nucleotides. We interpret these results on the basis of the correction of mismatched base-pair regions in the heteroduplex before the completion of DNA replication. We suggest that this technique provides valuable information concerning gene conversion in mamalian cells and permits the transfer of genotypic markers from one virus strain to another.

Base Sequence↗
PubMed2002

Quantifying physiological data with Lempel-Ziv complexity--certain issues.

The oscillations observed in physiological data can be attributed largely to the presence of either a nonlinear deterministic or a nondeterministic component. The Lempel-Ziv complexity and its variants have been used successfully to quantify the regularity of these oscillations. The decrease in the complexity can be observed in the case of nontrivial deterministic patterns as well as correlated noise. Thus, any conclusion on the nature of the pattern based solely on the value of the Lempel-Ziv complexity is incomplete. In this paper, the use of the surrogate data technique is suggested to avoid spurious interpretation of this measure of complexity. The data sets considered include the uterine contraction obtained during active labor. The surrogates are generated using the amplitude adjusted fourier transform and the iterated amplitude adjusted fourier transform. The approximate entropy is used as an alternate measure to verify the results obtained.

Cluster Analysis↗
PubMed1995

Fluorescence overlay antigen mapping of the epidermal basement membrane zone: II. Color fidelity.

In this second report on the fluorescence overlay antigen mapping (FOAM) technique, we highlight some of the errors that may influence faithful color rendition of slide preparations using triple antigen immunofluorescence staining. Reliable interpretation of multicolor fluorescence images requires that the observer can unambiguously assign each color in these images to the presence of a specific combination of the labeled antigens. This is possible only when the image fidelity meets certain standards. The present study concentrates on color fidelity which is easily undermined by spectral matching errors, image contrast errors, and exposure time errors. Evaluation of these errors, using the photomicrographic overlay variant of FOAM, showed the potential unreliability of the simultaneous use of multiple fluorophores for immunofluorescence microscopy. The procedures described here may serve as a solid starting point in formulating technical conditions that allow reliable color rendition in multicolor immunofluorescence microscopy. Furthermore, these procedures can be adapted to studies other than the analysis of basement membrane zone antigens, to which they have been first applied.

Basement Membrane↗