Search PubMed⌕ Search

Biomedical subjects

M J Healy

Publications and source records attributed to M J Healy.

At least 37 records · Page 2Linked to original sources
PubMed1995

Survival data.

Explore the source record for details and available documents.

Aged↗
PubMed1994

Multilevel time series models with applications to repeated measures data.

The analysis of repeated measures data can be conducted efficiently using a two-level random coefficients model. A standard assumption is that the within-individual (level 1) residuals are uncorrelated. In some cases, especially where measurements are made close together in time, this may not be reasonable and this additional correlation structure should also be modelled. A time series model for such data is proposed which consists of a standard multilevel model for repeated measures data augmented by an autocorrelation model for the level 1 residuals. First- and second-order autoregressive models are considered in detail, together with a seasonal component. Both discrete and continuous time are considered and it is shown how the autocorrelation parameters can themselves be structured in terms of further explanatory variables. The models are fitted to a data set consisting of repeated height measurements on children.

Adolescent↗
PubMed1994

Associations of esterase 6 allozyme and activity variation with reproductive fitness in Drosophila melanogaster.

Previous studies have shown that the esterase 6 (EST6) enzyme of D. melanogaster is mainly produced in the sperm ejaculatory duct of the adult male and comparisons of wild-type males with laboratory null mutants have suggested that the enzyme plays a role in reproductive fitness. In this study we have compared 18 field-derived lines each isoallelic for Est6 for differences in five components of male reproductive fitness. No consistent fitness differences were found among lines differing in respect of the two major allozyme classes EST6-F and EST6-S, despite other evidence that these two classes are not selectively equivalent in the field. However, differences in reproductive fitness were found among lines differing in the minor mobility variants that segregate within EST6-F and EST6-S. A failure to distinguish among these minor forms may explain the discrepancies in previous studies on the effects of the major EST6 allozymes on reproductive fitness. The most significant associations we have found between EST6 and reproductive fitness were due to variation in EST6 activity levels. Male EST6 activity levels were found to be positively correlated with their time to first mating, negatively correlated with the numbers of eggs laid and progeny produced by their mates, and negatively correlated with the frequency with which their mates remate. We conclude that some EST6 variants differ in components of male reproductive fitness operative in laboratory cultures. However, the evidence for fitness differences is stronger for variants affecting the amount, rather than the structure of the enzyme, and the direction of the differences varies between some of the fitness components tested.

Alleles↗
PubMed1994

Causes and consequences of esterase 6 enzyme activity variation in pre-adult Drosophila melanogaster.

We report heritable threefold differences in both larval and pupal esterase 6 activity among 17 isoallelic lines of D. melanogaster extracted from a natural population. The activity differences in the two stages are only weakly correlated with each other or with previously determined values for esterase 6 activity in adults of these lines. The pre-adult activity variation is also unrelated to polymorphisms among the lines for six esterase 6 allozymes and six restriction sites in a region encompassing the esterase 6 coding DNA and the first kbp of 5' flanking DNA. However, two insertions, of 8.0 and 6.8 kbp, located about 1.4 kbp 5' of the esterase 6 coding region are associated with low activity in larvae and, to a lesser extent, in pupae, albeit not in adults. Restriction mapping reveals similarity between the 8.0 kbp insert and the 7.4 kbp retrotransposon 17.6. The differences in larval activity among lines are positively correlated with fitness as assessed from assays of pre-adult viability and development time but no significant associations between pupal esterase 6 activity and these measures are detected. Some effects of esterase 6 allozyme differences are also found for viability and development time but these effects could be explained by linkage disequilibrium between the 8.0 kbp insert and the EST6-9 allozyme.

Adaptation, Biological↗
PubMed1993

Evolutionary genetics of Drosophila esterases.

Over 30 carboxylester hydrolases have been identified in D. melanogaster. Most are classified as acetyl, carboxyl or cholinesterases. Sequence similarities among most of the carboxyl and all the cholinesterases so far characterised from D. melanogaster and other eukaryotes justify recognition of a carboxyl/cholinesterase multigene family. This family shows minimal sequence similarities with other esterases but crystallographic data for a few non-drosophilid enzymes show that the family shares a distinctive overall structure with some other carboxyl and aryl esterases, so they are all put in one superfamily of/beta hydrolases. Fifteen esterase genes have been mapped in D. melanogaster and twelve are clustered at two chromosomal sites. The constitution of each cluster varies across Drosophila species but two carboxyl esterases in one cluster are sufficiently conserved that their homologues can be identified among enzymes conferring insecticide resistance in other Diptera. Sequence differences between two other esterases, the EST6 carboxyl esterase and acetylcholinesterase, have been interpreted against the consensus super-secondary structure for the carboxyl/cholinesterase multigene family; their sequence differences are widely dispersed across the structure and include substantial divergence in substrate binding sites and the active site gorge. This also applies when EST6 is compared across species where differences in its expression indicate a difference in function. However, comparisons within and among species where EST6 expression is conserved show that many aspects of the predicted super-secondary structure are tightly conserved. Two notable exceptions are a pair of polymorphisms in the substrate binding site of the enzyme in D. melanogaster. These polymorphisms are associated with differences in substrate interactions in vitro and demographic data indicate that the alternative forms are not selectively equivalent in vivo.

Amino Acid Sequence↗
PubMed1993

Counted data (1).

Explore the source record for details and available documents.

Analysis of Variance↗
PubMed1993

Data transformations.

Explore the source record for details and available documents.

Data Interpretation, Statistical↗
PubMed1993

Effects of the residue adjacent to the reactive serine on the substrate interactions of Drosophila esterase 6.

Esterase 6 from Drosophila melanogaster is a carboxylesterase that belongs to the serine esterase multigene family. It has a basic histidine (His) at residue 187, adjacent to the reactive serine (Ser) at residue 188, whereas most other characterized members of the family have an acidic glutamate (Glu) in the equivalent position. We have used site-directed in vitro mutagenesis to replace the His codon of the esterase 6 gene with either Gln or Glu codons. The enzymes encoded by these active-site mutants and a wild-type control have been expressed, purified, and characterized. Substitution of Gln for His at position 187 has little effect on the biochemical properties of esterase 6, but the presence of Glu at this position is associated with three major differences. First, the pH optimum is increased from 7 to 9. Second, the mutant enzyme shows decreased activity for beta-naphthyl esters and p-nitrophenyl acetate but has gained the ability to hydrolyze acetylthiocholine. Finally, the Gibb's free energy of activation for the enzyme is increased. These results suggest that residue 187 interacts directly with the substrate alkyl group and that this interaction is fully realized in the transition state. We further propose that the presence of His rather than Glu at position 187 in esterase 6 contributes significantly to its functional divergence from the cholinesterases and that this divergence is due to different interactions between residue 187 and the substrate alkyl group.

Acetylthiocholine↗
PubMed1993

Standards for ovarian volume in childhood and puberty.

OBJECTIVE: To examine the growth of the ovary and the prevalence of polycystic ovaries in childhood and to compare the ovarian volumes of girls with growth disorders. DESIGN: A retrospective study of ovarian volume measurements made with ultrasound. SETTING: Paediatric Endocrine Outpatient service at The Middlesex Hospital. PATIENTS: The control group consisted of girls with no endocrine defect. The study group consisted of girls with GH insufficiency, treated and untreated; skeletal dysplasia (and no endocrine defect) on a trial of recombinant human GH; and tall stature. METHODS: The prevalence of polycystic appearance ovaries in the control group was noted. Centiles were calculated for the volumes of normal appearance ovaries in the control group (428 scans from 358 girls). Standard deviation scores were calculated for the ovarian volumes in the study groups. RESULTS: There was continuous growth of the ovaries throughout childhood. There was an increase in the prevalence of polycystic ovaries from 6% at 6 years of age, until 26% of the scans showed polycystic ovaries at 15 years of age. The ovarian volume SD score of untreated GH insufficient girls was less than controls but did not achieve statistical significance. It was significantly less than that of GH-insufficient girls on GH, girls with skeletal dysplasia on GH, and girls with tall stature. Tall girls had significantly greater ovarian volume than either of the GH-treated groups. CONCLUSIONS: Growth hormone appears to influence ovarian growth. Most women who have polycystic ovarian appearance develop this appearance during childhood and puberty.

Body Height↗
PubMed1992

Molecular analysis of the lethal(1)B214 region at the base of the X chromosome of Drosophila melanogaster.

Approximately 50 kb of genomic DNA was isolated from polytene chromosome bands 19F1 and 2 of Drosophila melanogaster. Bands 19F1 and 2 are in the immediate vicinity of the beta-heterochromatin at the base of the X chromosome and encompass the little fly-like and lethal(1)B214 complementation groups. The cloned DNA consists of an approximately 21 kb stretch of unique or low copy number sequence that is bounded by repetitive elements interspersed with further unique sequences. The presence of repeated sequences is characteristic of regions within and adjacent to beta-heterochromatin. At least part of a tRNA gene cluster is present within the 50 kb of cloned DNA. The cloned region also produces at least 18 discrete size classes of developmentally regulated poly(A)+ RNA species. A 2 kb EcoRI fragment (E10), which lies in the 21 kb stretch of unique sequence, generates seven of these transcripts (of sizes 3.5, 3.35, 2.1, 2.0, 1.5, 1.2 and 1.0 kb) in wild-type flies. However, a small deletion of approximately 75 bp in E10 in a lethal(1)B214 mutant allele is associated with alterations in the production or processing of all seven of these transcripts. These data identify E10 sequences as belonging to the lethal(1)B214 gene and suggest that the wild-type lethal(1)B214 gene encodes multiple transcripts. Furthermore, no transcripts of the same size and having the same developmental profile as those generated by the wild-type E10 fragment were identified by probes covering the remainder of the cloned region. This suggests that at least the larger transcripts hybridizing to E10 are partly transcribed from sequences located outside the cloned region, which indicates that the lethal(1)B214 gene extends for more than 20 kb and contains other transcriptionally active sequences within it.

Animals↗