Biomedical subjects

J D Murray

Publications and source records attributed to J D Murray.

At least 109 records · Page 6Linked to original sources

PubMed1994

Travelling waves in a tissue interaction model for skin pattern formation.

Tissue interaction plays a major role in many morphogenetic processes, particularly those associated with skin organ primordia. We examine travelling wave solutions in a tissue interaction model for skin pattern formation which is firmly based on the known biology. From a phase space analysis we conjecture the existence of travelling waves with specific wave speeds. Subsequently, analytical approximations to the wave profiles are derived using perturbation methods. We then show numerically that such travelling wave solutions do exist and that they are in good agreement with out analytical results. Finally, the biological implications of our analysis are discussed.

Animals↗

PubMed1994

Regulation of insulin-like growth factor-I and binding protein-3 expression in oMtla-oGH transgenic mice.

Growth hormone (GH)-transgenic mice provide a model for studying hormonal regulation of gene products responsible for efficient lean growth. Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (BP-3) are two products involved in mediating the growth promoting actions of GH. Mice carrying the ovine metallothionein la-ovine growth hormone (oMtla-oGH) transgene were used to study GH regulation of IGF-I and BP-3 expression because these mice do not exhibit elevated basal oGH levels without transgene stimulation by exogenous zinc. C57B1/6XCBA mice with (transgenic = TG) and without control = C) the oMtla-oGH transgene were activated (+ Zn) or inactivated (-Zn) by the addition or removal of 25 mM zinc sulfate in the drinking water. Plasma IGF-I and BP-3 levels were determined by radioimmunoassay and western ligand blotting, respectively. Hepatic IGF-I and BP-3 mRNA levels were determined by slot-blot analysis. TG+Zn mice had higher plasma IGF-I (p < 0.05) and hepatic IGF-I mRNA (p < 0.05) levels as compared to TG-Zn, C+Zn and C-Zn mice. Plasma IGF-I and hepatic IGF-I mRNA levels in TG-Zn mice were not different from C+Zn and C-Zn mice. Removal of Zn decreased hepatic IGF-I mRNA levels to C levels in TG mice. Plasma BP-3 and hepatic BP-3 mRNA levels in TG+Zn mice were increased (p < 0.05) as compared to TG-Zn, C-Zn and C+Zn. Plasma BP-3 and hepatic BP-3 mRNA levels did not differ between TG-Zn, C-Zn and C+Zn mice. Expression of the transgene also increased the level of plasma BP-3 during pregnancy as compared to that observed for pregnant C mice. We conclude that oGH regulates IGF-I and BP-3 expression in the oMtla-oGH transgenic mouse model system.

Animals↗

PubMed1994

Expression of human lysozyme mRNA in the mammary gland of transgenic mice.

Owing to its inherent antimicrobial effect and positive charge, the expression of human lysozyme in bovine milk could be beneficial by altering the overall microbial level and the functional and physical properties of the milk. We have used transgenic mice as model systems to evaluate the expression of human lysozyme containing fusion gene constructs in the mammary gland. Expression of human lysozyme was targeted to the mammary gland by using the 5' promoter elements of either the bovine beta (line B mice) or alpha s1 (line H mice) casein genes coupled to the cDNA for human lysozyme. Expression of human lysozyme mRNA was not found in mammary tissue from any of line B mice. Tissues were analysed from six lines of H mice and two, H6 and H5, were found to express human lysozyme mRNA in the mammary gland at 42% and 116%, respectively, of the levels of the endogenous mouse whey acidic protein gene. At peak lactation, female mice homozygous for the H5 and H6 transgene have approximately twice the amount of mRNA encoding human lysozyme as hemizygous animals. Expression levels of human lysozyme mRNA in the mammary gland at time points representing late pregnancy, early, peak and late lactation corresponded to the profile of casein gene expression. Human lysozyme mRNA expression was not observed in transgenic males, virgin females or in the kidney, liver, spleen or brain of lactating females. A very low level of expression of human lysozyme mRNA was observed in the salivary gland of line H5.

Animals↗

PubMed1994

Expression of an ovine growth hormone transgene in mice increases arachidonic acid in cellular membranes.

The degree of unsaturation of membrane lipids has been implicated in a number of physiological disorders, yet its regulation remains poorly understood, especially the regulation of the synthesis and distribution of arachidonic acid levels, the most abundant long chain polyunsaturated fatty acid in membranes. Transgenic mice expressing the ovine metallothionein 1a-ovine growth hormone (oMt1a-oGH) fusion gene exhibited significantly elevated levels of a number of long chain polyunsaturated fatty acids in serum, including arachidonic acid. In oMt1a-oGH transgenic mice the products of all three desaturation pathways are affected by the expression of the ovine growth hormone transgene. The essential precursors of membrane long chain polyunsaturated fatty acids, 18:2n-6 and 18:3n-3, were reduced in transgenics relative to controls, and their desaturation and elongation products, arachidonic acid (20:4n-6) and docosahexaenoic acid (22:6n-3), were elevated. As rare intermediate long chain polyunsaturated fatty acids such as eicosatrienoic acid (20:3n-9) were also significantly elevated, we conclude that these observations reflect increased activity of the delta-5 and delta-6 desaturase enzymes. In contrast, the products of the stearoyl CoA or delta-9 desaturase, were significantly reduced in oMt1a-oGH expressing transgenics relative to their levels in control mice.

Animals↗

PubMed1994

Dependence of increased linear bone growth on age at oMT1a-oGH transgene expression in mice.

We have previously shown that growth hormone (GH) accelerates the rate and extends the duration of linear bone growth in a GH-transgenic mouse model. To determine if this GH effect was temporally regulated, bone lengths and growth plate widths were determined in transgenic mice carrying an ovine metallothionein 1a-ovine growth hormone (oMT1a-oGH) transgene. Transgene expression was initiated in oMT1a-oGH hemizygous transgenic mice by addition of 25 mM ZnSO4 to the water at 21 d of age; littermate control mice were also ZnSO4 supplemented. These mice were maintained on ZnSO4 until 70 d of age at which time the mice were killed and the ulna, humerus, and tibia were collected. Additional transgenic and control mice were stimulated at 21 d and the ZnSO4 stimulus withdrawn after 21 d of treatment and killed at 70 d or stimulated at 28 d with the stimulus withdrawn after 28 d and killed at 70 d. Continuously stimulated transgenic mice had longer bones than those of comparable control mice. The increased bone length in the transgenics was correlated with wider growth plates. Transgene expression initiated at 21 d of age increased bone length to the same or greater extent than that observed for mice with transgene expression initiated at 28 d but maintained for a longer interval thereby indicating that the age of GH initiation is more critical in bone elongation than the duration of GH exposure. The elevated GH effects were independent of circulating thyroid hormones and attainment of puberty. Elevated GH also increased the widths of all growth plate zones to the same extent by increasing cell numbers, rather than enhancing matrix production or individual cellular area.

Aging↗

PubMed1993

Is morphogenesis an intrinsically robust process?

Because morphogenesis is dynamically complex, involving many processes operating over different spatial and temporal scales, it is generally assumed that the stability and repeatability of development depends primarily upon accurate control over parameter values i.e. a precise genetic program. However, it is possible that the dynamic coupling between the different mechanisms involved in development reduces the choices available to the system because of bias in successive symmetry-breaking events. Evidence for such stable cascades in morphogenetic processes is described, and a general argument is presented for morphogenesis as an intrinsically robust process. The evolutionary implications of the hypothesis are considerable.

Acetabularia↗

PubMed1993

Chemical control of eukaryotic cell movement: a new model.

Cellular chemotaxis and chemokinesis play important roles in many biological processes. Most continuum mathematical models for these regulatory mechanisms are based on the model of Keller & Segel (1971 a, b), in which cells respond directly to the local concentration of extracellular chemical. We have developed a new model which reflects the receptor-based mechanisms underlying chemical control of cell motion. Our model consists of three coupled partial differential equations, and we use the Boyden chamber (millipore) assay to compare it with a simpler model based on the Keller-Segel approach. The predictions of our model capture the key qualitative features of the experimental data, whereas the simpler model only does so when appropriate functional forms are chosen for the dependence of the transport coefficients on chemical concentration. Using experimental data on the variation of receptor kinetic parameters with temperature, we use our model to predict the effect of decreasing the temperature on both the "leading front" and "migrated cell" measurements taken from Boyden chamber assays. Our results show that changes in the kinetic parameters play a key role in controlling the temperature dependence of cell chemotaxis and chemokinesis.

Chemoreceptor Cells↗

PubMed1993

Mechanistic model of wound contraction.

The interplay between cellular, biochemical, and biomechanical phenomena which result in wound contraction is examined with the aid of a mathematical model. The model accounts for fibroblasts repopulating the wound extracellular matrix (ECM) by a combination of migration and proliferation and, in the course of exerting traction forces associated with their motility, their deformation of the local ECM, which has a viscoelastic character. A base model, which assumes that cell and tissue properties are the same irrespective of position with respect to the wound center, is found to be inconsistent with wound contraction. Extensions of the base model which account for the possible influence of a concentration gradient of an inflammation-derived mediator on the traction, growth, or chemotactic properties of the fibroblasts do predict the qualitative features of a contracting wound. In particular, the case where traction is prescribed to increase as fibroblasts approach the wound center is shown to obey the commonly observed exponential rate contraction law and to be largely consistent with the findings of McGrath and Simon (Plast. Reconstr. Surg. 72, 66, 1983) concerning the independence of the contraction rate constant and final extent of contraction from initial wound size and geometry.

Animals↗

PubMed1993

Sexing and detection of gene construct in microinjected bovine blastocysts using the polymerase chain reaction.

We present a polymerase chain reaction (PCR)-based procedure for rapid bovine embryo sexing and classifying embryos for the presence of exogenous DNA. Fourteen bovine blastocysts microinjected with gene construct DNA at the pronuclear stage were divided into quarters and subjected to amplification with construct-specific and sex gene-specific (ZFY/ZFX) primers in the same initial PCR reaction. Blastocysts carrying microinjected construct DNA could be identified by the presence of construct-specific PCR product in approximately 4 h. Approximately half of the microinjected and two of 16 non-microinjected blastocysts typed PCR-positive for the construct DNA. Owing to erroneous amplifications in the two non-microinjected control blastocysts, and the inability of the system to distinguish integrated from non-integrated copies of the microinjected construct, the number of construct-positive blastocysts determined in our assay most likely overestimates the number of true transgenic embryos. Nevertheless, using this assay, we were able to determine that approximately half of the microinjected embryos were negative for the transgene construct and thus could be eliminated from transfer to a recipient cow. Embryo sexing was achieved in less than 6 h by restriction fragment length polymorphism analysis of nested ZFY/ZFX PCR products reamplified from initial PCR reactions. In 11/14 microinjected blastocysts all sections assayed unambiguously as the same sex. In one embryo, only one section was analysed, while two other blastocysts showed some discrepancies of sexing results between the sections analysed.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Suicide substrate reaction--diffusion equations: varying the source.

The suicide substrate reaction is a model for certain enzyme-inhibiting drugs. This reaction system is examined assuming that the substrate diffuses freely while the enzyme remains fixed. Two sets of initial and boundary conditions are examined: one modelling an instantaneous point source, akin to an injection of substrate, the other, a continuous point source, akin to a continuing influx, or intravenous drip, of substrate. The quasi-steady-state assumption is applied to obtain analytical solutions for a limited parameter space. Finally, further applications of numerical and analytical experimentation on pharmaceutical mechanisms are described.

Enzyme Inhibitors↗

PubMed1993

Reproductive wastage in the androstenedione-immune ewe.

An experiment was carried out using 320 adult Merino ewes to examine the effects of immunization against an androstenedione human serum albumin conjugate (Fecundin) on ovulation rate, fertilization rate and embryo viability at days 2, 9 and 13-14 after fertilization. The ovulation rate of immunized ewes (2.19 +/- 0.06) was greater (P < 0.001) than that of control ewes (1.43 +/- 0.04). The recovery rate of embryos or of unfertilized oocytes on day 2 was reduced in immunized ewes, but fertilization rate of recovered oocytes was unaffected by immunization. The mean number of normal embryos per ewe pregnant (prolificacy) was higher and the proportion of ewes pregnant (fertility) was lower in immunized than in the control ewes. The distribution of the number of cells per embryo showed no differences in developmental age over the period of sampling, the majority of embryos at this time being at the two- to four-cell stage of development. At day 9 of pregnancy, blastocyst recovery rates were lower in immunized than in control ewes. About 90% of blastocysts recovered were developing normally in control ewes compared with 64% in immunized ewes. The majority of blastocysts recovered on day 9 had hatched from the zona pellucida prior to recovery (mean values were 94.2% and 87.8% for control and immunized groups, respectively). In control ewes single blastocysts were larger than twin blastocysts, but for the immunized ewes this difference was not significant. Both single blastocysts (P < 0.01) and twin blastocysts (P < 0.05) from immunized ewes were smaller than those from control ewes.(ABSTRACT TRUNCATED AT 250 WORDS)

Androstenedione↗

PubMed1993

Microinjection of bovine embryos with a foreign gene and its detection at the blastocyst stage.

This study was designed to measure the survival and development of pronuclear stage bovine zygotes after microinjection with DNA and either culture in vitro or incubation in the sheep oviduct and to determine the percentage of embryos that retain exogenous DNA at the blastocyst stage. In vitro matured and fertilized oocytes were examined for pronuclear development 18 to 20 h after coincubation with sperm. An ovine somatotropin gene construct was microinjected into ova with visible pronuclei. Microinjected ova and unmanipulated ova from the same in vitro derived pool were cocultured with oviductal epithelial cells or incubated in the sheep oviduct and cocultured, respectively, for 7 d. Blastocysts were subjected to polymerase chain reaction analysis for detection of exogenous DNA. The percentage of cleaved embryos that formed blastocysts was similar for microinjected and unmanipulated cultured ova. The percentage of blastocysts recovered from the sheep oviduct that hatched was higher than for blastocysts that developed in coculture. Fourteen of 26 (54%) blastocysts that developed from microinjected ova were positive for the exogenous DNA by polymerase chain reaction. The implications are discussed for polymerase chain reaction detection of the exogenous gene construct in a relatively high proportion of microinjected blastocysts.

Animals↗

PubMed1993

The epigenetic influence of growth hormone on skeletal development.

We studied the epigenetic effect of growth hormone using mice that were transgenic for a sheep metallothionein 1a-sheep growth hormone, which was expressed beginning at 21 days postnatal age. The impact of exogenous growth hormone (GH) on various skeletal traits with special emphasis on the mandible was examined by conventional statistical analysis and finite element scaling analysis. In long bones, growth hormone enhances the proliferation rate of cartilage cells in the growth plate and should thus lead to increased lengths. Further, growth hormone is known to increase muscle mass. Our results are consistent with these developmental considerations. We found that the lengths of long bones increased in the transgenic mice compared to the control mice, while the differences in long bone width were less pronounced. In the mandible and skull, the impact of GH is most pronounced in areas of major muscle attachment, i.e., the proximal part of the mandible and the occipital and malar bones in the skull.

Animals↗

PubMed1993

Mathematical modelling of ethanol metabolism in normal subjects and chronic alcohol misusers.

The time course of ethanol disappearance from the blood has been examined in normal males and females and in alcohol misusers. Blood alcohol estimations were made over a period of 3 hr, following an oral dose of ethanol (0.8 g/kg body weight) administered in the form of whisky. Attempts were made to fit the data to zero order, first order and mixed zero + first order kinetics. In the majority (75%) of normal females the blood ethanol concentrations was still increasing at 30 min. This was only seen in 50% of normal males and in 50% of non-dependent alcohol misusers, but not in dependent alcohol misusers. In all of the normal females the disappearance of ethanol could be adequately described by zero order kinetics. However, in the normal male group only 20% could be described by zero order kinetics, 10% fitted first order kinetics and the remainder required a mixed model of zero + first order. The rate constant for the zero order component of the control male group was identical to zero order rate constant obtained for the female control group. In the female alcohol misuser group, 40% of the curves could not be described by zero order kinetics and fitted best to a mixed model. The zero order component of the entire group was significantly increased (by 35%) compared to that obtained for the female control group. In the male dependent and non-dependent alcohol misuser groups, all blood alcohol concentration curves fitted best to mixed zero and first order kinetics.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1992

Continuum model of fibroblast-driven wound contraction: inflammation-mediation.

We propose a mathematical model to aid the understanding of how events in wound healing are orchestrated to result in wound contraction. Ultimately, a validated model could provide a predictive means for enhancing or mitigating contraction as is appropriate for managing a particular wound. The complex nature of wound healing and the lack of a modeling framework which can account for both the relevant cell biology and biomechanics are major reasons for the absence of models to date. Here we adapt a model originally proposed by Murray and co-workers to show how cell traction forces can result in spatial patterns of cell aggregates since it offers a framework for understanding how traction exerted by wound fibroblasts drives wound contraction. Since it is a continuum model based on conservation laws which reflect assumed cell and tissue properties, it is readily extended to account for emerging understanding of the cell biology of wound healing and its relationship to inflammation. We consider various sets of assumed properties, based on current knowledge, within a base model of dermal wound healing and compare predictions of the rate and extent of wound contraction to published experimental results.

Extracellular Matrix↗

PubMed1992

Modelling coccidial infection in chickens: emphasis on vaccination by in-feed delivery of oocysts.

Trickle immunization of poultry by incorporating wildtype strains of coccidia in the feed has been shown to be an effective and practical means of controlling coccidiosis. Here we develop a mathematical model of the life cycle of Eimeria tenella and estimate the model parameters from extant experimental studies. Numerical solutions of the model compare well with experiment. The model provides quantitative estimates of the required trickle immunization hitherto only available after extensive time-consuming trials.

Animal Feed↗

PubMed1992

Analysis of dynamic and stationary pattern formation in the cell cortex.

We study a sol-gel mechanochemical model for cellular cytoplasm. Using conservation equations and a force balance equation, we derive equations for the sol-gel dynamics. Regular perturbation analysis suggests the growth of patterns which may be either dynamic or stationary, depending on parameter values. Nonlinear analysis, which indicates that these patterns remain bounded, is confirmed by numerically solving the mechanochemical equations. We use these analytical and numerical results to model two different biological problems: the dynamic formation of filopodia in nerve growth cones, and the growth of microvilli in epithelial cells.

Actins↗

PubMed1992

Mathematical models of wound healing in embryonic and adult epidermis.

Epidermal wound healing occurs by quite different mechanisms in embryos and adults. In the latter case, it has long been known that cells crawl inwards via lamellipodia to close the defect. In the embryonic system, recent evidence suggests that healing may be caused by a quite different mechanism, namely the contraction of a cable of filamentous actin at the wound edge. The authors use mathematical modelling to investigate both systems. A mechanical model for the initial formation of the actin cable in embryonic epidermal wounds is presented, which incorporates the important phenomenon of stress-induced microfilament alignment. Also discussed is a reaction-diffusion model for the healing of adult wounds subject to autoregulation of cell division. In both cases, the results suggest possible biological mechanisms for key aspects of the healing process.

Actins↗