Biomedical subjects
Publications and source records attributed to G Gibson.
Homeotic mutations in Drosophila can result in dramatic phenotypes that suggest the possibility for rapid morphological evolution, but dissection of the genetic pathway downstream of Ultrabithorax is beginning to reveal how wing morphology may have evolved by more gradual transformations.
Sequence analysis of 27 alleles of each of the three Ras-related genes in Drosophila melanogaster indicates that they all have low levels of polymorphism but may experience slightly different evolutionary pressures. No amino acid replacement substitutions were indicated in any of the sequences, or in the sibling species D. simulans and D. mauritiana. The Dras1 gene, which is the major ras homologue in Drosophila, has less within-species variation in D. melanogaster relative to the amount of divergence from the sibling species than does Dras2, although the contrast was not significant by the HKA test. Dras2 appears to be maintaining two classes of haplotype in D. melanogaster, one of which is closer to the alleles observed in the sibling species, suggesting that this is not likely to be a pseudogene despite the absence of a mutant phenotype. Although differences in level of expression may affect the function of the genes, it is concluded that genetic variation in the Ras signal transduction pathways cannot be attributed to catalytic variation in the Ras proteins.
We have previously demonstrated that parathyroid hormone (PTH) infusion decreases glucose disappearance rate (Kg) in vivo. Because in the rodent model used it was not possible to determine whether the PTH itself, the induced hypercalcemia, or both contributed to the glucose intolerance, we examined the effect of vitamin D infusion on insulin-mediated glucose disposal. In this model also hypercalcemia is induced but PTH levels are suppressed. Thirty male Sprague Dawley rats were continuously infused with vit D for 5 days using an Alzet miniosmotic pump, at a rate of 9.7 pmol/hour. Thirty controls were infused with the vehicle alone. On the 5th day, glucose 700 mg/kg and insulin 0.35 U/kg were given as a bolus through the left femoral vein and blood samples were obtained from the right femoral vein just prior to and at 2, 5, 10, and 20 minutes post-glucose/insulin infusion. At the end of 5 days, plasma calcium levels were higher in the vit D-infused rats than in the control rats (12.8 +/- 0.1 versus 10.0 +/- 0.1 mg/dL, P < 0.01) and rat PTH levels were suppressed (2.1 +/- 0.1 versus 62 +/- 12 pg/ml, P < 0. 01). Glucose levels were higher in the vit D animals only at 5 minutes following glucose/insulin bolus (375 +/- 7 versus 350 +/- 6 mg/dL, P < 0.01) but at no other time. There were no differences between serum insulin levels at any time. Unlike previous findings in PTH-infused rats, Kg (measured from 2 to 20 minutes following glucose/insulin bolus) was not different between groups (4.5 +/- 0.3 versus 4.7 +/- 0.2, P = 0.92.) A positive correlation between serum calcium and serum glucose was found only at 5 minutes (r = 0.55, P < 0.01) and only in the vit D animals. The areas under the glucose curves approached statistically significant differences (vit D-infused 5258 +/- 142 mg/dL/18 minutes versus control 4947 +/- 127, P = 0.06.) Analysis of serum glucose data by two-factor analysis of variance (ANOVA) suggests that the two groups differ slightly in glucose values (P = 0.03) but have parallel Kg. In order to define whether different effects of PTH (1-34) and vit D on intracellular calcium [Ca2+]i levels could partly explain the different effects of PTH and vit D infusion on glucose disposal, we investigated the effect of PTH and vit D infusions on basal and concanavalin A (con A)-stimulated changes in mononuclear [Ca+2]i levels. Following 5 days of PTH, vit D, or control infusion, peripheral mononuclear cells were incubated with 50 microgram/ml con A. Changes in [Ca+2]i over 5 minutes were calculated by flow cytometric measurement of the calcium sensitive fluo-3 AM dye. Despite achieving significant and comparable degrees of hypercalcemia in the PTH and vit D infused animals, there were no differences in basal or con A-stimulated [Ca+2]i levels from control. Consequently, we conclude that vit D-induced hypercalcemia associated with suppressed PTH levels has mild affects on glucose homeostasis but does not affect glucose disappearance rate in vivo (Kg) as does hypercalcemia induced by PTH infusion, and that neither chronic PTH infusion nor chronic vit D infusion are associated with long-standing changes in [Ca2+]i levels.
Despite mounting evidence that key developmental regulator genes are involved in significant macroevolutionary changes, there have been few studies demonstrating the functional significance of variation in such genes for the generation of population-level variation. In this study we examined and compared the expression domains of three Hox gene homeobox sequences in embryos derived from two morphologically distinct populations of the threespine stickleback, Gasterosteus aculeatus. We found within-population variation in the location of anterior limits, particularly in more 5' Hox genes whose anterior expression domains showed graded distributions of transcripts over several somites. However, despite considerable and statistically significant differences in the anteroposterior pattern of the axial and median skeletons between the two stickleback populations, this phenotypic variation was not found to be correlated with any of the variation in Hox gene expression. The possible functional significance of the combinatorial Hox code in fish species is discussed with respect to the buffering of development in fluctuating environments, and it is argued that population and quantitative genetic perspectives should also be taken into account in considering the function and evolution of Hox genes.
Understanding the patterning mechanisms that operate to promote differentiation of individual segments along the main body axis is an important goal of both developmental and evolutionary biology. In order to gain a better insight into the role of Hox genes in generating diversity of axial plans seen in vertebrates, we have cloned 11 homeobox sequences from an acanthopterygian teleost, the threespine stickleback, and analyzed the expression of 7 of these during embryogenesis. Transcripts are observed in a variety of tissues, including the neural tube, paraxial mesoderm, lateral plate mesoderm, pectoral fins, pronephric ducts, as well as some neural crest-derived structures. Anterior limits of expression in the central nervous system and paraxial mesoderm exhibited both similarities and differences to those of mouse and zebrafish homologs. In both stickleback and zebrafish embryos expression limits within the paraxial mesoderm were detected only within the trunk region in which ribs are attached to all vertebrae. The finding of this pattern in two divergent teleosts as well as in various tetrapod species supports the hypothesis that a Hox precode was present prior to the divergence of ray-finned and lobe-finned fishes and was subsequently used to generate different types of vertebrae in tetrapods. We also describe a dynamic pattern of expression of several stickleback Hox genes associated with the development of the caudal paraxial mesoderm, which suggests uncoupling of the process of segmentation from segmental identity determination. We propose that in fishes the patterning of the tail region is under the control of a separate mechanism from the trunk, which utilizes Hox genes in a different manner.
Heart rate in pre-pupae of Drosophila melanogaster is shown to vary over a wide range from 2.5 to 3.7 beats per second. Quantitative genetic analysis of a sample of 11 highly inbred lines indicates that approaching one-quarter of the total variance in natural populations can be attributed to genetic differences between flies. A hypomorphic allele of the potassium channel gene ether-a-gogo, which is homologous to a human long-QT syndrome susceptibility gene (HERG), has a heart rate at the low end of the wild-type range, but this effect can be suppressed in certain wild-type genetic backgrounds. This study provides a baseline for investigation of pharmacological and other physiological influences on heart rate in the model organism, and implies that quantitative genetic dissection will provide insight into the molecular basis for variation in normal and arrhythmic heart function.
Key biotic and environmental constraints on the host-orientated behaviour of haematophagous Diptera are summarized. For each major group of biting Diptera, responses to host stimuli are reviewed, including activation and ranging behaviour, long-range and short-range olfactory responses and visual responses. Limitations to the comparison of results between groups of species, and the practical problems of experimental method and equipment are discussed.
Introgression of homeotic mutations into wild-type genetic backgrounds results in a wide variety of phenotypes and implies that major effect modifiers of extreme phenotypes are not uncommon in natural populations of Drosophila. A composite interval mapping procedure was used to demonstrate that one major effect locus accounts for three-quarters of the variance for haltere to wing margin transformation in Ultrabithorax flies, yet has no obvious effect on wild-type development. Several other genetic backgrounds result in enlargement of the haltere significantly beyond the normal range of haploinsufficient phenotypes, suggesting genetic variation in cofactors that mediate homeotic protein function. Introgression of Antennapedia produces lines with heritable phenotypes ranging from almost complete suppression to perfect antennal leg formation, as well as transformations that are restricted to either the distal or proximal portion of the appendage. It is argued that the existence of "potential" variance, which is genetic variation whose effects are not observable in wild-type individuals, is a prerequisite for the uncoupling of genetic from phenotypic divergence.
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We consider the problem of fitting mathematical models for bacterial growth and decline to experimental data. Using models which represent the phases of the growth and decline cycle in a piecewise manner, we describe how least-squares fitting can lead to potentially misleading parameter estimates. We show how these difficulties can be overcome by extending a data set to include hypothetical observations (dummy data points) which reflect biological beliefs, and the resulting stabilization of parameter estimates is analysed mathematically. The techniques are illustrated using real and simulated data sets.
Endochondral ossification involves an ordered progression from cell division through hypertrophic differentiation to cell death. The apoptotic nature of chondrocyte death was first suggested by characteristic changes in morphology; and more recently by the pattern of DNA fragmentation and other characteristic features of apoptosis. In situ detection, although controversial, suggests that DNA fragmentation probably does not occur until late in hypertrophic differentiation. From observations of key features of apoptosis, including activation of the caspase cascade, changes in mitochondrial function, and expression of apoptosis inhibitors, the commitment of chondrocytes to apoptosis, appears to occur very early in hypertrophic differentiation. It is proposed that these changes produce effects that go far beyond the process of cell death and exert a focal influence on the endochondral ossification processes occurring in the microenvironment of the growth cartilage vascular interface. Endochondral ossification processes mediated by chondrocyte apoptosis may include intracellular calcium accumulation and release; matrix calcification; matrix resorption; maintenance of growth plate homeostasis; attraction of blood vessels and osteoblast precursors; and stimulation of bone formation.
The signal transduction pathway controlling determination of the identity of the R7 photoreceptor in the Drosophila eye is shown to harbor high levels of naturally occurring genetic variation. The number of ectopic R7 cells induced by the dosage-sensitive SevS11.1 transgene that encodes a mildly activated form of the Sevenless tyrosine kinase receptor is highly sensitive to the wild-type genetic background. Phenotypes range from complete suppression to massive overproduction of photoreceptors that exceeds reported effects of known single gene modifiers, and are to some extent sex-dependent. Signaling from the dominant gain-of-function Drosophila Epidermal Growth Factor Receptor (DER-Ellipse) mutations is also sensitive to the genetic backgrounds, but there is no correlation with the effects on SevS11.1. This implies that different genes and/or alleles modify the two activated receptor genotypes. The evolutionary significance of the existence of high levels of genetic variation in the absence of normal phenotypic variation is discussed.
Alterations in amyloid precursor protein (APP) metabolism, calcium regulation, oxidative metabolism, and transduction systems have been implicated in Alzheimer's disease (AD). Limitations to the use of postmortem brain for examining molecular mechanisms underscore the need to develop a human tissue model representative of the pathophysiological processes that characterize AD. The use of peripheral tissues, particularly of cultured skin fibroblasts derived from AD patients, could complement studies of autopsy samples and provide a useful tool with which to investigate such dynamic processes as signal transduction systems, ionic homeostasis, oxidative metabolism, and APP processing. Peripheral cells as well as body fluids (i.e., plasma and CSF) could also provide peripheral biological markers for the diagnosis of AD. The criteria required for a definite diagnosis of AD presently include clinical criteria in association with histopathologic evidence obtained from biopsy or autopsy. Thus, the use of peripheral markers as a diagnostic tool, either to predict or at least to confirm a diagnosis, may be of great importance.
Inadequate saliva can have devastating consequences for a patient, including oral discomfort, rampant caries, increased candida infections, and desiccation of restorative and esthetic dental treatment. Diagnosis of the cause of xerostomia is imperative to treating the condition, and multiple causes should be considered. Treatment options for xerostomia consists of treatment for hyposalivation, palliative and preventive care to combat the results of long-term dry mouth. Treatment of xerostomia should be based on the etiologic factors of the disease, with prevention of further oral destruction and comfort being the primary goals of treatment.
The structure of personality disorder traits was examined in a sample of 400 undergraduates who completed the personality disorder questionnaire from the Structured Clinical Interview for DSM-III-R (SCID-II). The relations between personality disorder and normal personality traits indexed by the Eysenck Personality Questionnaire-Revised (EPQ-R) were examined. The three-cluster model of personality traits--as described in the DSM scheme--found equivocal support. Exploratory principal components analysis and confirmatory factor analysis found four broad factors of personality disorder that overlapped with normal personality traits: an asthenic factor related to neuroticism; an antisocial factor associated with psychoticism; an asocial factor linked to introversion-extraversion; and an anankastic (obsessive-compulsive) factor. There is growing agreement about the number and type of broad personality disorder dimensions; similar dimensions may be found in clinical and non-clinical samples, suggesting that those people with personality disorders differ quantitatively rather than qualitatively from others; and there is substantial overlap between normal and abnormal personality dimensions.
The authors designed a pilot study to examine issues that affect women's oral health. They found a substantial lack of awareness regarding important oral health issues, and that 44 percent of the participants reportedly did not have regular dental care. High perceived dental need was reported concurrently with low dental care attendance. Additionally, reported lack of dental insurance and self-perception of low income and of poor dental health were important explanatory factors for the women who reportedly did not have regular dental care.
The role of odors in mosquito host preferences was studied in a village near Ouagadougou, Burkina Faso. Two odor-baited entry-traps were put beside one another and a choice of host odor-laden air was blown out of them. Odors of a human and a calf (of similar mass) were drawn from two tents in which each was separately concealed. Allowances were made for trap position, differences in human-subject attractiveness, CO2 levels, and trap contamination with alternative host odors. Choices for the human-baited trap greater than the 0.5 random expectation were made by Anopheles gambiae s.l. (0.96) and An. pharoensis (0.68). The choices for the human-baited trap of Culex antennatus were significantly lower than 0.5 (0.25), whereas for the Cx. decens species group (0.56), the difference was not significant. Interpretation of the latter result was complicated by the significant effect of CO2 levels on the index. Species caught in low numbers but whose trap distribution showed a bias towards the human-baited trap were An. funestus (total numbers in the human-baited trap to the calf-baited trap = 9:0), Mansonia africana (17: 1), Aedes dalzieli (22:4), and Ae. hirsutus (13:1); species showing bias towards the calf-baited trap were An. rufipes (0:11), Cx. duttoni (0:17), and Cx. nebulosus (2:35). Mansonia uniformis was the only species distributed randomly between the two traps. Molecular identification of the An. gambiae s.l. samples revealed a marked difference in trap distribution: for the human-baited trap the ratio was 52% An. arabiensis to 48% An. gambiae s.s.; for the calf-baited trap, it was 92% An. arabiensis to 8% An. gambiae s.s.
We illustrate the importance of stochastic effects in population models of biological systems and demonstrate a number of analytic and simulation-based approaches that can usefully be applied to such models. In so doing, we compare the stochastic approach to the more usual deterministic one. The model studied represents the gastrointestinal infection of ruminants by nematodes when the hosts maintain a fixed density. The incorporation of a feedback mechanism, which accounts for the immune response of the infected animals, results in a highly nonlinear model; similar forms of nonlinearity are a feature of many plausible models in population biology. In the absence of an analytic solution to the full stochastic model we explore a number of approximations and compare them to simulations of the full stochastic process. We explore three modes of behaviour of the system. In the endemic regime the stochastic system fluctuates widely around the non-zero fixed points of the deterministic model. In the managed regime, where the system is subject to external periodic perturbation, stochastic effects are negligible. Finally, we find that in a regime in which the deterministic model predicts the long-term persistence of oscillations the stochastic model shows that extinction can occur. Of the approximation procedures we consider, the Normal approximation to the full stochastic process is the most generally applicable, and it is also the most accurate in the light of simulation results. Local linearization provides reasonably accurate prediction of the variance-covariance structure, and a transfer function approach allows calculation of the time-lagged auto- and cross-correlations in the endemic regime. Linearization of the stochastic updates themselves results in poor prediction of the population variances.