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Biomedical subjects

V O'Brien

Publications and source records attributed to V O'Brien.

At least 19 recordsLinked to original sources
PubMed2000

Binding of bovine papillomavirus type 4 E8 to ductin (16K proteolipid), down-regulation of gap junction intercellular communication and full cell transformation are independent events.

The E8 open reading frame of bovine papillomavirus type 4 encodes a small hydrophobic polypeptide that contributes to primary cell transformation by conferring to cells the ability to form foci and to grow in low serum and in suspension. Wild-type E8 binds in vitro to ductin, a component of gap junctions, and this binding is accompanied by a loss of gap junction intercellular communication in transformed bovine fibroblasts. However, through the analysis of a panel of E8 mutants, we show here that binding of E8 to ductin is not sufficient for down-regulation of gap junction communication and that there is no absolute correlation between down-regulation of gap junction communication and the transformed phenotype.

Animals↗
PubMed1999

A mutational analysis of the transforming functions of the E8 protein of bovine papillomavirus type 4.

The E8 protein of BPV-4 contributes to transformation of primary bovine cells (PalFs) by inducing anchorage-independent growth and by down-regulating gap junction intercellular communication, likely due to its binding to 16K ductin. We show here that, in addition, E8 confers on PalF cells the ability to grow in low serum and to escape from contact inhibition (focus formation). E8 also transactivates an exogenous human cyclin A gene promoter, suggesting that overexpression of cyclin A is responsible for the transformed phenotype. Mutant forms of E8 were generated to establish whether the transforming functions of the protein could be segregated. Mutations were introduced both in the hydrophobic domain and in the hydrophilic C-terminal "tail", and chimeras with BPV-1 E5 were constructed. Cells expressing either wild-type E8 or mutant forms were analyzed for their ability to grow in low serum and in suspension and to form foci. Wild-type E8 and its mutants were also analyzed for their ability to transactivate the cyclin A promoter. We show here that the transforming functions of E8 can be segregated and that both the hydrophilic C-terminal tail and the residue at position 17 in the hydrophobic domain are crucial for E8 functions and for the transactivation of the cyclin A promoter. These results support the hypothesis that the different aspects of cellular transformation brought about by E8 might be due to interaction with different cellular targets. They suggest that E8 might function differently from BPV-1 E5 and demonstrate that the separate domains of E5 and E8 are not functionally interchangeable.

Animals↗
PubMed1998

BPV-4 E8 transforms NIH3T3 cells, up-regulates cyclin A and cyclin A-associated kinase activity and de-regulates expression of the cdk inhibitor p27Kip1.

The E8 open reading frame of Bovine papillomavirus type 4 (BPV-4) encodes a small (42 amino acid) hydrophobic polypeptide localized to cellular membranes and capable of conferring an anchorage-independent (AI) growth phenotype on primary bovine cells co-transfected with BPV-4 E7 ORF and an activated ras gene. To further study the function of E8 independently of other viral gene products, we have expressed it in the murine fibroblast cell line, NIH3T3. Cells expressing E8 are capable of AI growth and escape growth arrest after serum withdrawal. E8 deregulates cyclin A expression, induces transactivation of the human cyclin A gene promoter and increases endogenous protein levels in cells maintained in short-term suspension culture and in low-serum (LS). Both these culture conditions promote downregulation of cyclin A in control cells. In LS growth conditions E8 permits sustained cyclin A-associated kinase activity but not cyclin E-cdk2 activity. Cyclin A-cdk2 activity and, in part, cyclin A gene expression are regulated by the cdk inhibitor p27Kip1. Expression of this cdk inhibitor is also de-regulated in E8 cells, with high levels being detected under all culture conditions tested. These data suggest that the ability of BPV-4 E8 to transform NIH3T3 cells is associated with upregulation of cyclin A-associated kinase activity and de-regulated expression of the cdk inhibitor p27Kip1 and does not rely on down-regulation of p27Kip1 expression. Analysis of E8 mutants indicate that the hydrophilic 'tail' of the molecule (residues 31-42) is required for cell transformation, as assessed by anchorage-independent growth, while a form of E8 with expression restricted to the Endoplasmic Reticulum/cis-Golgi membranes by addition of a 'KDEL' retention signal revealed that the sub-cellular localization is an important determinant of E8 biological activity.

3T3 Cells↗
PubMed1996

Expression of the integrin alpha 5 subunit in HT29 colon carcinoma cells suppresses apoptosis triggered by serum deprivation.

It is clear that certain integrins can regulate the growth of tumors, probably by contributing to signal transduction processes. In the present study we have used HT29 human colon carcinoma cells stably transfected with human cDNA for the integrin alpha 5 subunit and studied the effects of alpha 5 expression on the induction of apoptosis. We observe that apoptosis can be triggered in HT29 cells by removal of serum and that this process can be suppressed by the stable expression of full-length integrin alpha 5 subunits. While the mechanism underlying this effect is still unclear, these observations suggest that the alpha 5 beta 1 integrin plays an important role in modulating tumor cell responses to growth factors and nutrients.

Antigens, CD↗
PubMed1995

Signal transduction by cell adhesion receptors.

Over the last few years, it has become clear that cell adhesion receptors function in signal transduction processes leading to the regulation of cell growth and differentiation. Signal transduction by both integrins and CAMs has been shown to involve activation of tyrosine kinases, while CAM signaling in neural cells involves G proteins as well. In the case of integrins, some of the downstream signaling events intersect with the Ras pathway, particularly the activation of MAP kinases. In fibroblasts, integrin mediated anchorage to the substratum regulates cell cycle traverse, while in epithelial cells, loss of anchorage can trigger programmed cell death. In many cell types, but particularly monocytic cells, integrin ligation has a profound impact on gene expression. Preliminary evidence also implicates CAMs and selectins in gene regulation. A consistent theme in signal transduction mediated by adhesion receptors concerns the role of the cytoskeleton. Integrin mediated signaling processes are interrupted by cytoskeletal disassembly. Identification of the APC and neurofibromatosis type 2 tumor suppressors suggest that cytoskeletal complexes also play a key role in signaling by cadherins and CD44, respectively. Thus, signaling by cell adhesion receptors may involve aspects that impinge on previously known signaling pathways including the RTK/Ras pathway and serpentine receptor/G protein pathways. However, novel aspects of signal transduction involving cytoskeletal assemblies may also be critical.

Animals↗
PubMed1991

The development of competence in resting B cells. The induction of cyclic AMP and ornithine decarboxylase activity after direct contact between B and T helper cells.

In the present communication, an experimental approach is utilized that facilitates the study of biochemical processes induced in B cells after their interaction with Th cells. In this approach, Th cell clones are stimulated for 18 h upon anti-CD3-coated plates, fixed with paraformaldehyde, and added at a 2 to 3:1 ratio to small, resting B cells (isolated from Percoll gradients). Th cells not stimulated on anti-CD3-coated plates, but fixed with paraformaldehyde, serve as controls for these experiments. The activated, fixed Th cells induce a transient, sixfold increase in B cell levels of cAMP, as well as an increase in B cell expression of ornithine decarboxylase (ODC) activity. This enzyme initiates the synthesis of polyamines and has been shown to be increased as cells enter the growth phase. In addition, previous studies have shown that the cellular levels of ODC activity are controlled by a multi-tiered regulatory cascade. To examine this aspect, polyclonally stimulated B cells were studied. Such cells demonstrated a gradual increase in ODC mRNA levels that peaked between 6 and 15 h and can be partially explained by a three- to fourfold increase in mRNA stability but not by changes in the enzyme affinity for substrate. The increase in ODC mRNA occurs in the absence of protein synthesis, suggesting that the ODC gene is a member of the immediate/early gene family. Finally, the early increase in ODC mRNA was enhanced in cells in which cAMP levels were artificially elevated, suggesting the possibility that the cAMP-dependent signaling pathway participates during the regulation of this gene expression. The significance of these experimental results concerning the process of B cell activation is discussed.

Animals↗
PubMed1990

The relationship between form and space perception, constructional abilities, and clumsiness in children.

The Sensory Integration and Praxis Tests (SIPT) (Ayres, 1989) were administered to 21 children with learning disabilities and 18 children without learning disabilities, aged 5 to 8 years. The children with learning disabilities were divided into two groups, clumsy and nonclumsy, on the basis of their scores on the Test of Motor Impairment (Stott, Moyes, & Henderson, 1984). It was hypothesized that the learning-disabled children in the clumsy group would score significantly lower than the learning-disabled children in the nonclumsy group on the six SIPT subtests that measure form and space perception and visual construction and that the nonclumsy learning-disabled children, in turn, would score significantly lower than the non-learning-disabled children. It was further hypothesized that there would be a significant correlation between the degree of clumsiness and the degree of visual-perceptual and constructional deficits. An analysis of the data indicated that both groups of learning-disabled children scored lower than the non-learning-disabled children on four of the six SIPT subtests. The clumsy and nonclumsy children with learning disabilities, however, differed from each other on only two subtests. The degree of clumsiness correlated significantly with three of the six subtests. The results are discussed in terms of variations in perceptual and motor skills related to subtypes of learning disabilities.

Child↗
PubMed1989

Estimation of pulsatile ocular blood flow from intraocular pressure.

A relationship has been derived between intraocular pressure and pulsatile blood flow in the eye. Measurements of intraocular pressure show a time variation that is associated with the pulsatile component of arterial pressure. Experimental results provide a means of transforming intraocular pressure changes into ocular volume changes. The eye is represented by a chamber with elastic walls, a pulsatile incoming flow of incompressible fluid (blood), and a steady outgoing flow of blood. Under these conditions, the rate of pulsatile blood flow through the eye can be approximated from the instantaneous intraocular pressure measurements. Data from a healthy human eye are used to illustrate the analysis.

Blood Flow Velocity↗
PubMed1989

Malnutrition in aboriginal children at Yalata, South Australia.

Comparative studies of body weight, height, intracellular water representing cell mass, and age, and plasma concentrations of albumin, vitamins, trace elements and iron stores in Aboriginal children aged 6 to 13.5 years, from two rural Aboriginal settlements and one rural Caucasian school (Hawker) provided evidence of significant deficits in one of the Aboriginal settlements (Yalata). Yalata Aboriginal children had lower body weights and heights for age and lower intracellular water values. Plasma albumin, zinc, iron, alpha-tocopherol, beta-carotene and retinol concentrations were lower relative to the normally grown Aboriginal children at Nepabunna. The latter children did not differ from rural Caucasian children for the parameters studied. The reasons for this poorer growth at Yalata may reside in poor nutrition, or repeated bowel infection in postnatal life leading to malabsorption, or both. Limited observational evidence suggests that Giardiasis has a high prevalence at Yalata, and it has been shown elsewhere that Giardiasis is capable of inducing malabsorption with resulting nutritional deficiencies.

Adolescent↗
PubMed1988

The relationship between visual-perceptual motor abilities and clumsiness in children with and without learning disabilities.

One visual-perceptual test, four visual-motor tests, and a test of motor impairment were administered to 22 children with learning disabilities and 22 children without learning disabilities, aged 5 to 8 years. The children with learning disabilities were divided into two groups--"clumsy" and "nonclumsy"--based on their scores on the motor impairment test. It was hypothesized that the clumsy children with learning disabilities would score significantly lower on visual-perceptual and visual-motor tests than the nonclumsy children with learning disabilities who, in turn, would score significantly lower than the children without learning disabilities. It was further hypothesized that there would be a significant correlation between the degree of clumsiness and the degree of visual-perceptual and visual-motor deficit. Analysis of the data indicated that, as expected, the clumsy children with learning disabilities scored significantly lower than the children without learning disabilities (the control group). There was no significant difference between the clumsy and nonclumsy children with learning disabilities or between the nonclumsy children with learning disabilities and the control group. Degree of clumsiness significantly correlated with scores on four of five tests. Results are discussed in terms of subtypes of learning disabilities and sample size.

Analysis of Variance↗
PubMed1985

Simple pulsatile flow in an artery with a constriction.

A smooth isolated, axisymmetric occlusion in a straight vascular tube is a tractable problem for pulsatile flow calculations via finite-difference approximations to the Navier-Stokes equation. Steady flow depends on the Reynolds number and two geometric parameters which describe the stenosis. The mere addition of a simple harmonic to the mean flow adds two more parameters. One is the reduced frequency, or Strokes number, and the other epsilon, the ratio of unsteady to steady flux. After describing steady stenosis flow examples, the dynamic patterns of pulsatile flow are illustrated indicating the inadequacy of basing hypotheses of atherosclerosis on mean (steady) flow.

Arterial Occlusive Diseases↗
PubMed1985

A system approach to new service development for hospitals.

A systematic approach to evaluating, planning and implementing new consumer services is necessary to ensure a successful program. Presented here are the three phases of the new service development process for hospitals--assessment, development, and execution--and the evolution and interaction among the health care delivery system, service, and market dimensions. Before, during, and after development, the need for hospital communications and effective marketing is also stressed.

Health Services Needs and Demand↗
PubMed1975

Calculations of pulsatile flow through a branch: implications for the hemodynamics of atherogenesis.

Numerical simulations of pulsatile blood flow through a symmetrical branch modeling the aortic bifurcation were carried out to assess several hemodynamic theories of atherogenesis by comparing the distribution of hemodynamic variables with that of early lesions in arterial branches. Considerable spatial and temporal variations in wall shear were found when the flow was pulsatile; the highest values occurred at the convex corner on the outer wall of the branch and in the neighborhood of the flow divider tip, and the lowest shears were experienced by the outer wall of the daughter vessel a short distance distal to the corner. Transient flow reversal occurred almost everywhere in the branch, and a transient separated region was found corresponding to the low-shear region in the daughter vessel. The shear profiles and the calculated separated region were influenced to some degree by the extent of flow development at the branch inlet and markedly by the branch area ratio. All of the proposed hemodynamic promoters of atherosclerosis that were examined--high shear, low shear, and separation--were found at sites in the branch where lesions commonly develop. Comparisons with a steady-flow calculation at the same mean flow rate showed that the severity of all of these proposed hemodynamic determinants was increased by pulsatility.

Arteries↗