Biomedical subjects
Publications and source records attributed to G Gibson.
Comparative studies have revealed a remarkable range of genetic changes in the mechanisms that pattern the nematode vulva. Two new studies identify genetic variation within nematode species that affects cell division and competence in vulval precursors.
Developmental geneticists' contribution to the study of the evolution of morphological divergence has proceeded along two lines: comparative analysis of gene expression and quantitative genetics. Recent studies highlight how complementation tests between species can bridge the gap between these approaches.
The cmc and IC50 values of the beta-amyloid (Abeta) aggregation inhibitors, 3-p-toluoyl-2-[4'-(3-diethylaminopropoxy)-phenyl]-benzofuran 1, and 2-[4'-(3-diethylaminopropoxy)-phenyl]-benzofuran 2 have been determined. After comparison of the cmc data and biological data (IC50 values), we conclude that these active benzofurans do not act as surfactants or micelles at the concentration required to inhibit beta-amyloid-peptide aggregation.
Here we present a statistically rigorous approach to quantifying microarray expression data that allows the relative effects of multiple classes of treatment to be compared and incorporates analytical methods that are common to quantitative genetics. From the magnitude of gene effects and contributions of variance components, we find that gene expression in adult flies is affected most strongly by sex, less so by genotype and only weakly by age (for 1- and 6-wk flies); in addition, sex x genotype interactions may be present for as much as 10% of the Drosophila transcriptome. This interpretation is compromised to some extent by statistical issues relating to power and experimental design. Nevertheless, we show that changes in expression as small as 1.2-fold can be highly significant. Genotypic contributions to transcriptional variance may be of a similar magnitude to those relating to some quantitative phenotypes and should be considered when assessing the significance of experimental treatments.
Afrotropical malaria vectors of the Anopheles gambiae complex (Diptera: Culicidae), particularly An. gambiae sensu stricto, are attracted mainly to human hosts. A major source of human volatile emissions is sweat, from which key human-specific components are the carboxylic acids (E)- and (Z)-3-methyl-2-hexenoic acid and 7-octenoic acid. Electrophysiological studies on the antennae of An. gambiae s.s. showed selective sensitivity to these compounds, with a threshold at 10(-6) g comparable to that of known olfactory stimulants 1-octen-3-ol, p-cresol, isovaleric acid, and lower than threshold sensitivity to L-lactic acid and the synthetic mosquito repellent N,N-diethyltoluamide (DEET). A combination of the acids released at concentrations > 10(-5) g in wind tunnel bioassays significantly reduced the response to CO2, the major attractant released by human hosts, for strains of An. gambiae s.s. originating from East and West Africa. Field trials with odour-baited entry traps (OBETs) in Burkina Faso showed that 7-octenoic acid significantly increased (by 1.7-fold) the catch of females of An. gambiae sensu lato (comprising two sibling species: An. arabiensis Patton and An. gambiae s.s.) in OBETs baited with CO2, whereas combinations of the acids significantly reduced the catch in CO2-baited traps (by 2.1-fold) and in whole human odour-baited traps (by 1.5-fold). The pure (E) and (Z) geometric isomers of 3-methyl-2-hexenoic acid gave comparable results to the (EIZ) isomer mixture. These results provide the first experimental evidence that human-specific compounds affect the behaviour of highly anthropophilic An. gambiae s.l. mosquitoes. The compounds appear to inhibit the upwind flight' response to known long-range attractants, and may serve either to mask' the attractants present or, more probably, to 'arrest' upwind flight when mosquitoes arrive at a host under natural conditions. In the final approach to hosts, vectors are known to reduce their flight speed and increase their turning rate, to avoid overshooting the source. In our experimental apparatus, these changes in flight behaviour would reduce the number of mosquitoes entering the ports of the collection devices.
The determination of a list of differentially expressed genes is a basic objective in many cDNA microarray experiments. We present a statistical approach that allows direct control over the percentage of false positives in such a list and, under certain reasonable assumptions, improves on existing methods with respect to the percentage of false negatives. The method accommodates a wide variety of experimental designs and can simultaneously assess significant differences between multiple types of biological samples. Two interconnected mixed linear models are central to the method and provide a flexible means to properly account for variability both across and within genes. The mixed model also provides a convenient framework for evaluating the statistical power of any particular experimental design and thus enables a researcher to a priori select an appropriate number of replicates. We also suggest some basic graphics for visualizing lists of significant genes. Analyses of published experiments studying human cancer and yeast cells illustrate the results.
Drosophila melanogaster appears to be well suited as a model organism for quantitative pharmacogenetic analysis. A genome-wide deficiency screen for haploinsufficient effects on prepupal heart rate identified nine regions of the genome that significantly reduce (five deficiencies) or increase (four deficiencies) heart rate across a range of genetic backgrounds. Candidate genes include several neurotransmitter receptor loci, particularly monoamine receptors, consistent with results of prior pharmacological manipulations of heart rate, as well as genes associated with paralytic phenotypes. Significant genetic variation is also shown to exist for a suite of four autonomic behaviors that are exhibited spontaneously upon decapitation, namely, grooming, grasping, righting, and quivering. Overall activity levels are increased by application of particular concentrations of the drugs octopamine and nicotine, but due to high environmental variance both within and among replicate vials, the significance of genetic variation among wild-type lines for response to the drugs is difficult to establish. An interval mapping design was also used to map two or three QTL for each behavioral trait in a set of recombinant inbred lines derived from the laboratory stocks Oregon-R and 2b.
A sample of 115 urban, working-class, predominantly minority men and women was interviewed by telephone to assess knowledge, beliefs, and barriers relevant to colorectal cancer (CRC) and CRC screening. More than half (53.9%) were unable to name a CRC screening test. Misconceptions were common. Dispelling inaccurate beliefs, establishing an individual's preference for fecal occult blood tests or flexible sigmoidoscopy, and helping individuals take a proactive role in the receipt of CRC screening are important goals for health education efforts aimed at increasing rates of CRC screening. Participants' willingness to engage in detailed telephone conversations about CRC and CRC screening was encouraging.
The apoptosis of hypertrophic chondrocytes at the interface between growth cartilage and invading vessels is at the center of a series of critical events in endochondral formation. We have shown that the hypertrophy and apoptosis of chick chondrocytes in culture is associated with the release and activation of transforming growth factor beta2 (TGF-beta2). Supplementation of the culture medium with agents that influenced the maintenance of hypertrophic differentiation also influenced the release of TGF-beta2. A large proportion of the TGF-beta2 released from the cells was shown to be in an active form-particularly TGF-beta2 associated with the support matrix. Inhibition of apoptosis with a broad-spectrum caspase inhibitor inhibited activation of the matrix-associated TGF-beta2. However, inhibition of apoptosis did not diminish the release of TGF-beta2. Release of TGF-beta2 by chondrocytes at a late stage of their terminal differentiation and its activation in association with apoptosis may provide a mechanism controlling the processes of vascular invasion of growth cartilage and the deposition of bone matrix on nearby cartilage remnants.
Labor unions that represent health care workers encounter unique circumstances. This study focuses on 1199--the largest health care workers' union in the United States, based in New York City--and describes how the union and its National Benefit Fund have structured a managed indemnity health insurance program that provides extensive benefits for its members. The authors detail the workings of the National Benefit Fund and the ways in which it can improve the health care of its members through its union structure. The Fund represents a model for improving the provision of health care to Americans.
Two Drosophila Hox genes involved in segmentation, fushi tarazu and bicoid, appear to have acquired these roles by functional divergence from classical homeotic genes. Recent results indicate how genes with critical functions in development can evolve completely different functions among species.
A moderate resolution single nucleotide polymorphism (SNP) map of the genome of Drosophila melanogaster that is designed for use in quantitative genetic mapping is described. Seventeen approximately 500 nucleotide gene sequences spaced at 10 to 20 centimorgan intervals were combined with 49 shorter sequence tag sites (STSs) at 5 to 10 centimorgan intervals to generate a map that should not leave any gaps greater than one half of a chromosome arm when any two wild type lines are compared. Of 20 markers with sufficient polymorphism to construct haplotype cladograms, 13 showed evidence for two divergent classes of haplotype. The possible mechanisms for and implications of the unexpected finding that two thirds of all short gene sequences in D. melanogaster may be dimorphic are discussed, including the suggestion that admixture between two separate lineages may have been a major event in the history of the species.
Canalization is an elusive concept. The notion that biological systems ought to evolve to a state of higher stability against mutational and environmental perturbations seems simple enough, but has been exceedingly difficult to prove. Part of the problem has been the lack of a definition of canalization that incorporates an evolutionary genetic perspective and provides a framework for both mathematical and empirical study. After briefly reviewing the importance of canalization in studies of evolution and development, we aim, with this essay, to outline a research program that builds upon the definition of canalization as the reduction in variability of a trait, and uses molecular genetic approaches to shed light on the problems of canalization.
We examine stochastic effects, in particular environmental variability, in population models of biological systems. Some simple models of environmental stochasticity are suggested, and we demonstrate a number of analytic approximations and simulation-based approaches that can usefully be applied to them. Initially, these techniques, including moment-closure approximations and local linearization, are explored in the context of a simple and relatively tractable process. Our presentation seeks to introduce these techniques to a broad-based audience of applied modellers. Therefore, as a test case, we study a natural stochastic formulation of a non-linear deterministic model for nematode infections in ruminants, proposed by Roberts and Grenfell (1991). This system is particularly suitable for our purposes, since it captures the essence of more complicated formulations of parasite demography and herd immunity found in the literature. We explore two modes of behaviour. In the endemic regime the stochastic dynamic fluctuates widely around the non-zero fixed points of the deterministic model. Enhancement of these fluctuations in the presence of environmental stochasticity can lead to extinction events. Using a simple model of environmental fluctuations we show that the magnitude of this system response reflects not only the variance of environmental noise, but also its autocorrelation structure. In the managed regime host-replacement is modelled via periodic perturbation of the population variables. In the absence of environmental variation stochastic effects are negligible, and we examine the system response to a realistic environmental perturbation based on the effect of micro-climatic fluctuations on the contact rate. The resultant stochastic effects and the relevance of analytic approximations based on simple models of environmental stochasticity are discussed.
Quantitative complementation tests provide a quick test of the hypothesis that a particular gene contributes to segregating phenotypic variation. A set of wild-type alleles is assayed for variation in their ability to complement the degree of dominance of the quantitative effect of a loss of function allele. Analysis of 15 loci known to be involved in wing patterning in Drosophila melanogaster suggests that the genes decapentaplegic, thickveins, EGFR, argos and hedgehog, each of which are involved in secreted growth factor signaling, may contribute to wing shape variation. The phenotype of one deficiency, Df(2R)Px2, which removes blistered/Plexate, is also highly sensitive to the wild-type genetic background and at intermediate expressivity reveals six ectopic veins. These form in the same locations as a projection of the ancestral pattern of dipteran wing veins on- to the D. melanogaster wing. This atavistic phenotype indicates that the wing vein prepatterning mechanism can be conserved in highly derived species, and implies that homoplasic venation patterns may be produced by derepression of vein primordia.
PURPOSE: Several studies have found that depression and the use of antidepressant medications are associated with an increased risk of cardiovascular disease. We assessed the association between the use of antidepressant drugs and myocardial infarction, and whether that association differs between the tricyclic and selective serotonin reuptake inhibitor (SSRI) classes of medication. PARTICIPANTS AND METHODS: We compared the experience of a cohort of 2,247 working, union health plan members who received at least one prescription for an antidepressant in an accrual period of 1991-1992 with that of 52,750 members who did not. Patients were followed for up to 4.5 years (minimum 6 months). Three antidepressant medication classes were defined: tricyclics, SSRIs, and others. The primary outcome was hospitalization or death due to myocardial infarction. RESULTS: Adjusted for age and sex, antidepressant users had a relative risk of myocardial infarction of 2.2 (95% confidence interval [CI] 1.3 to 3.7) compared with nonusers of antidepressants. There were 16 myocardial infarctions among 1,650 users of tricyclic antidepressants, 2 among 655 SSRI users, and none among 279 users of other antidepressants. Adjusting for age, gender, baseline heart disease, diabetes, hypertension, hyperlipidemia, anxiety, and cancer, the relative risk of myocardial infarction was 2.2 (95% CI 1.2 to 3.8) in users of tricyclic agents and 0.8 (95% CI 0.2 to 3.5) in users of SSRIs, as compared with subjects who did not use antidepressants. CONCLUSION: The association between use of tricyclic antidepressants, but not SSRIs, with an increased risk of myocardial infarction in our patients suggests that an earlier report that there is no difference in risk between the antidepressant classes, based on short-term studies, may not apply to long-term adverse cardiovascular outcomes.
Two composite multiple regression-interval mapping analyses were performed to identify candidate quantitative trait loci (QTL) affecting components of wing shape in Drosophila melanogaster defined by eight relative warp-based measures. A recombinant inbred line design was used to map QTL for the shape of two intervein regions in the anterior compartment of the wing, using a high resolution map of retrotransposon insertion sites between Oregon-R and Russian 2b. A total of 35 QTL representing up to 23 different loci were identified, many of which are located near components of the epidermal growth factor-Ras signal transduction pathway that regulates vein vs. intervein decision making and vein placement. Over one-half of the loci were detected in both sexes, and just under one-half were detected at two different growth temperatures. Different loci were found to affect aspects of shape in each intervein region, confirming that the shape of the whole wing should be regarded as a compound trait composed of several developmental units. In addition, a reciprocal backcross design was used to map QTL affecting shape in the posterior compartment of the wings of 831 flies, using a molecular map of 16 allele-specific oligohybridization single nucleotide polymorphism (SNP) markers between two divergent inbred lines. A total of 13 QTL were detected and shown to have generally additive effects on separable components of shape, in both sexes. By contrast, 8 QTL that affected wing size in these backcrosses were nearly dominant in their effects. The results confirm at the genetic level that wing shape is regulated independent of wing size and set up the hypothesis that wing shape is regulated in part through the regulation of the length and positioning of wing veins, involving quantitative regulation of the activity of secreted growth factors.
Culex quinquefasciatus Say is a vector of St. Louis encephalitis (SLE) in Texas. This disease is endemic and prevalent in the Houston area. Disease prevention through mosquito control is mainly targeted against adults by application of a resmethrin-piperonyl butoxide formulation (Scourge). Immature mosquitoes were collected from eight areas in Harris County during 1998. The susceptibility status of these populations to Scourge, malathion, and resmethrin, the latter alone or with an esterase inhibitor as a synergist, was determined using a bottle assay with females. The population structure was investigated by electrophoretic analysis of esterases and their activity. Individual females were also analyzed for esterase activity by plate assay and for isoenzyme pattern by native PAGE. Bioassays indicated high levels of resistance to malathion in all areas. In addition, the effectiveness of Scourge in mosquitoes from area 51 deteriorated throughout the season. A localized, distinctive esterase pattern and activity level was observed in mosquitoes from different areas. Overall, the frequency of esterases Est alpha 2 (A2)/Est beta 2 (B2) was higher than that of Est beta 1 (B1). Altogether, these results indicate the onset of a fragile situation for mosquito control that should be further analyzed to effectively maintain the SLE prevention program for Harris County.