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E A Murphy

Publications and source records attributed to E A Murphy.

At least 73 records · Page 4Linked to original sources
PubMed1990

A truncation mutation in the avian beta-adrenergic receptor causes agonist-induced internalization and GTP-sensitive agonist binding characteristic of mammalian receptors.

Recombinant turkey erythrocyte beta-adrenergic receptors expressed in murine L cells exhibited characteristic avian subtype selectivity for agonists and antagonists. In 10 of the 11 clones studied, no agonist-induced internalization of receptor was observed, although agonist-induced uncoupling of receptor and adenylyl cyclase occurred rapidly. GTP caused little or no decrease in affinity for beta-adrenergic agonists. Such behavior is commonly observed in avian erythrocytes. In contrast, one clone was susceptible to agonist-induced receptor internalization and down-regulation even though it exhibited characteristic avian beta-adrenergic ligand-binding properties. The affinity of this variant receptor for agonists was also notably reduced by GTP. Electrophoresis of affinity-labeled receptor from this clone indicated an apparent size of about 33 kDa, about 12 kDa less than that of the native or recombinant turkey beta-adrenergic receptor. Genomic DNA from this cell line that encodes the receptor was cloned and partially sequenced. The coding region of the original receptor cDNA was interrupted after codon 412 (out of 483) and was followed by 36 base pairs of novel sequence prior to the first in-frame stop codon. These results suggest that the lack of both hormone-induced internalization and GTP-sensitive, high affinity binding of agonists that is characteristic of the beta-adrenergic receptor in avian erythrocytes is due to intrinsic properties of the receptor. The restoration of these phenomena in a C-terminally truncated mutant receptor suggests the importance of the C-terminal domain in determining these processes.

Adenylyl Cyclases↗
PubMed1990

Dynamics of quantitative homeostasis: VIII. Processes that oscillate finitely many times.

There is no well-established method of dealing with medical processes that oscillate only a finite number of times. A lagged homeostatic model of higher power in certain circumstances follows such a pattern and critical values are here explored by numerical integration. Abrupt ending of the oscillation occurs with processes of higher powers. The model is illustrated by clonus, chosen because reflexes are naturally lagged responses and because clonus may be unsustained. In applying the model to clonus, there are some incongruities (notably inertia) that call for caution; however, published data suggest that they may not be important. These imperfections notwithstanding, the correspondence is remarkably good. The model dealt with here, being simple and economical, is a useful first step to genetics; and some empirically testable deductions from the model are listed.

Homeostasis↗
PubMed1990

Angular homeostasis: VI. Threshold processes with bivariate liabilities.

The general structure of the threshold model of multifactorial determination is discussed. It is supposed that in place of a single liability (in Falconer's sense) there are two separate liabilities; and whether or not the pathological trait is present depends on a non-additive interaction between the liabilities, so that the region has curved boundaries. The genetics of ontogeny of a process involving spatial orientation (e.g., cardiac ontogeny) is used as a substantive illustration. Genetic analysis of the trait (as contrasted with the liabilities) yields results that on the one hand may seem quite counterintuitive, yet on the other hand they correspond to the kind of bizarre patterns encountered in quasi-empirical genetic counseling for cleft palate or neural tube defect. The impact of refinement of phenotype made possible by non-invasive methods is sketched. This model can be generalized to any number of liabilities, independent or not.

Embryonic and Fetal Development↗
PubMed1989

Angular homeostasis: III. The formalism of discrete orbits in ontogeny.

The formal properties of orbits in a plane are explored by elementary topology. The notions developed from first principles include: convex and polygonal orbits; convexity; orientation, winding number and interior; convex and star-shaped regions. It is shown that an orbit that is convex with respect to each of its interior points bounds a convex region. Also, an orbit that is convex with respect to a fixed point bounds a star-shaped region. Biological considerations that directed interest to these patterns are indicated, and the implications of the prospect of higher orders of star-shapedness mentioned.

Cell Communication↗
PubMed1989

Angular homeostasis: IV. Polygonal orbits.

Some properties are discussed of regular polygons that may result from angular homeostatic processes in stable orbit. To characterize these "homeostatic polygons" we need to discuss the winding number, the sidedness (integer, fractional and irrational), multiplicity, envelopes, and density. A regular (i.e., equilateral, equiangular) polygon may be closed in one revolution about its unique center, in multiple revolutions, or not at all. A homeostatic polygon can be generated only if all vertices are included in a single polygon, which occurs if and only if the number of vertices and the number of revolutions required to complete the polygon are relatively prime. For the homeostatic polygon to have a finite number of sides (without repeating itself) the angle subtended by any two successive vertices at the center must be a rational multiple of 2 pi. Biological implications of these properties are illustrated.

Cell Communication↗
PubMed1989

Genetics and congenital heart disease: perspectives and prospects.

Elucidating the role of genes in the ontogenesis of the cardiovascular system is a task that involves many fields of inquiry. Recent dramatic advances in the molecular biology of transcription and its variations and the prospects for sequencing the entire human genome must not induce complacency; the major task of determining how a one-dimensional code specifies a three-dimensional structure demands an understanding of biologic systems considerably beyond the current level. The study of pathologic cardiovascular ontogeny is equally in need of new insight and fresh approaches. Although all clinicians might agree that genes are important contributors to both the etiology and the pathogenesis of congenital heart defects, with the exception of a few Mendelian conditions, this knowledge cannot be put to practice beyond crude statements of empirically determined probabilities. In this review, we selectively examine studies that are addressing what we perceive as provocative issues and suggest some areas, such as chaos theory, in which new ideas might be found.

Genetic Linkage↗
PubMed1989

Public and private hypotheses.

The uses of hypothesis in scientific medicine and in clinical medicine are broadly similar; but they differ in subtle but important logical details. The key distinction is that scientific medicine deals with broad ("public") hypotheses about entire populations; and the predominant problem of inference is statistics in the face of epistemological uncertainty. In contrast, clinical medicine deals with individual, tailor-made ("private") hypotheses; the uncertainty (e.g. the diagnosis or recurrence risk in relatives) is ontological, and the main feature of the analysis is probability. The same logical rules are at times mistakenly applied to both. Disregard of these subtleties may lead to paradoxes, contradictions, and at times diastrously false conclusion. The basic principles and distinctions are laid out with illustrations that are most readily provided from medical genetics, but apply to all branches of medicine.

Epidemiologic Methods↗
PubMed1988

Angular homeostasis II: Pursuit of a moving target in a plane and some implications for cardiac teratology.

A model of cardiac ontogenesis is analyzed. It is cast in terms of the geometry of the pursuit of a linearly moving target by the growth of a chain of cells in the same plane, the pursuer, which at each step adjusts its direction of growth towards the current position of the target. The endpoint is the fusion between them, which can occur in 2 modes: either by the leading cell of the pursuer catching up with the target (pursuer-mediated fusion, or PMF) or by the target running into the preformed side of the pursuer (target-mediated fusion, or TMF). The causal specifications are the step size, the speed of the pursuer, the speed of the target, the restoration constant, and the initial direction of the pursuer; the outcome variables are the number of steps to fusion and the mode of fusion. The pattern of behavior is complicated, being more-or-less regular over large tracts of values, interspersed with abrupt, threshold-like changes that may generate a dichotomous pattern of inheritance despite a continuous gradation of genetic or other causes. The temporary abolition of the correction process (a change introduced to simulate the pattern of the effect of a teratogen) may delay fusion and suggest how a septum may fail to fuse, the ductus arteriosus to close, or an endocardial cushion to form. But the model also predicts that under certain plausible conditions, the "teratogen" would speed up fusion and hence perhaps offset a genetic predisposition to a congenital defect.

Heart Defects, Congenital↗
PubMed1988

Angular homeostasis. V: Some issues in genetics, ontogeny, and evolution.

We discuss a provisional model that deals with aspects of normal control of the direction in which cells grow; hence, the organization of structure. The interacting issues of genetics, ontogeny, and phylogeny in relationship to normal development and its defects are addressed. Our main goal is to define a model with a small and sufficient set of conditions that would make it possible to undertake statistically efficient genetic studies of certain congenital defects. But to do so in plausible and heuristic terms, one must address two classical questions: 1) How is the genome translated (or sometimes mistranslated) into a phenotype that is clinically conspicuous and that can be the object of genetic selection, and hence of evolution? 2) Granted that evolution of species occurs in small, rare steps, what is the path that calls for the smallest number of mutations through which ontogenesis could have developed, the intermediate stages being conserved because of actual phenotypic advantage?

Cell Division↗
PubMed1988

Age-dependent expression of familial risk in Alzheimer's disease.

There is growing evidence for genetic causes of Alzheimer's disease; therefore, consideration of its age at onset among genetically predisposed individuals is timely. The authors studied the onset of Alzheimer-like dementia in families of 79 probands ascertained clinically for the Bronx Veterans Administration/Mt. Sinai School of Medicine longitudinal studies of Alzheimer's disease. Analyses among their 379 first-degree relatives, living and decreased, suggested that 1) early onsets form a distribution that is distinct from that of later onsets, and thus, different causes or mechanisms may operate in early- and late-appearing disease; 2) age at onset varies as a familial characteristic; 3) with present population survival, only one third of the theoretical predisposition to Alzheimer's disease will become manifest during the lifetime of relatives at risk; and 4) a stable annual incidence of 1.5 per cent in the early ninth decade, reported by others, can be explained by the operation of a dominant gene with a population allele frequency of 0.13. The authors conclude that different (possibly genetic) causes of Alzheimer's disease may operate in different families or individuals, although much of its predisposition remains latent during the lifetime of those at risk.

Age Factors↗
PubMed1988

Spirometry and chest wall dimensions in achondroplasia.

Standard values for pulmonary function in short-limbed dwarfism are not available. Therefore, chest diameters and expiratory spirograms were measured in 58 female and 44 male subjects between 7 and 60 years of age with achondroplasia, the most common form of dwarfism. Standing height in adults was 49.6 +/- 3.2 (SD) inches with a sitting/standing height ratio of 0.66 (normal 0.52-0.53). Despite extremely short stature, only AP chest diameters in males were smaller than control subjects of similar age. The following equations were derived for forced vital capacity (FVC): males (under 25 years), FVC(L) = -3.56 + 0.162 X sitting height (in) + 0.067 X age (yrs); males (over 25 years), FVC(L) = -0.73 + 0.162 X sitting height (in) -0.047 X age (yrs); females (under 20 years), FVC(L) = -3.56 + 0.150 X sitting height (in) + 0.067 X age (yrs); females (over 20 years), FVC(L) = -1.92 + 0.150 X sitting height (in) -0.016 X age (years). Similar prediction equations were derived for FEV1 and FEF25-75%: FEV1/FVC % was 84.2 (+/- 6.5) for females and 88.0 (+/- 6.5) for males. We also compared the observed FVC measurements to values calculated using standing heights derived from the subject's sitting height, assuming a normal body proportion. The observed vital capacity in achondroplasia was only 67.6 (+/- 19.2) percent of that predicted for normally proportioned females and 72.4 (+/- 13.6) percent for males, suggesting reduced vital capacity in achondroplasia, due to reduced chest wall compliance or abnormal lung growth.

Achondroplasia↗
PubMed1987

The dynamics of angular homeostasis: I. General principles.

A general model is proposed casting aspects of ontogeny in quantitative terms amenable to genetic analysis. Its primordial construct is a chain of cells (termed a "pursuer") growing under the influence of a signal towards a fixed structure termed a "target." There is provision for graduated correction of the direction of growth of the pursuer. The determinants of scale include the size of the cells and the distance from the target. The minimum number of parameters is two: the initial angle of growth; and the force of the correction of errors of direction. Both are potentially of genetic interest. The impact of variation in these factors on the path of growth is studied. These findings are readily translated into biological terms, notably in congenital defects of the heart. Besides the primordial purposes, there are other objectives to the process. Some membranes require free edges, or large curvatures, or circular arrays. These secondary qualities require that the cells never reach the target. The target then becomes simply a construction point: that is, while remaining a center of attraction, it is no longer a true goal. If, because of undercorrection, the cell line misses the target at the first pass, it assumes a permanent orbit about it. The orbit rapidly comes to lie on a circle, with a radius independent of the initial angle of growth but related to the cell size and the restoration constant. From this property, several kinds of structures other than a simple bridge may result, especially when a series of lines of growth together form a tissue: a cusp, a free-floating membrane, or a circular membrane to fill a gap.

Growth↗