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S Jacobs

Publications and source records attributed to S Jacobs.

At least 235 records · Page 13Linked to original sources
PubMed1976

The mobile receptor hypothesis and "cooperativity" of hormone binding. Application to insulin.

The mobile receptor hypothesis has been proposed to describe the process by which hormone receptor binding initiates a biological response; it states that receptors, which can diffuse independently in the plane of the membrane, reversibly associate with effectors to regulate their activity. The affinity for effector is greater when the receptor is occupied by hormone. A mathematical expression of the mobile receptor hypothesis is used to show that: (1) The predicted kinetics of hormone receptor binding may be indistinguishable from "negative cooperativity." (2) Receptor occupancy and biological response may be coupled in a non-linear fashion. By choosing specific parameters, most of the existing data on insulin binding and biological responses can be explained in terms of the mobile receptor hypothesis. Thus, the following are easily explained: (1) A single homogeneous receptor may appear kinetically to be composed of two classes (of high and low affinity) of receptors. (2) Occupancy of the apparent class of high affinity receptors is related linearly to the biological response. (3) The same receptor in different tissues may appear to have different affinity. (4) The binding of different biologically active insulin analogues may exhibit different degrees of "cooperativity." These considerations may also be pertinent to interpretations of other hormone-receptor systems and of various ligand-macromolecule interactions.

Binding Sites↗
PubMed1976

Relationship of infectious murine leukemia virus and virus-related antigens in genetic crosses between AKR and the Fv-1 compatible strain C57L.

In a further genetic study of murine leukemia virus (MuLV) and its components we examined the backcross C57L X (C57L X AKR). This population was selected because strains AKR and C57L are both Fv-1n, and the restriction which the Fu-1b allele imposes on the output of virus was thereby obviated. The segregants were scored for three characters: (a) infectious Gross-AKR-type MuLV (V), in the tail; (b) group-specific antigen indicative of p30 internal viral protein, in spleen; and (c) GIX antigen, now thought to be indicative of gp69/71 viral envelope glycoprotein, on thymocytes. Our conclusions are: (a) It is confirmed that the AKR mouse has two unlinked chromosomal genes, Akv-1 and Akv-2, each of which can independently give rise to the life-long high output of MuLV that is characteristic of AKR mice. (b) Of the eight phenotypes that could possibly be derived from segregation of the three pairs of independent alternative traits, seven were observed, but on progeny testing only three were shown to reflect stably heritable genotypes; these were V+p30+GIX+ and V-p30-GIX- (the parental types) and V-p30+GIX+. A third, newly identified AKR gene, designated Akvp, segregating independently of Akv-1 and Akv-2, also determines expression of p30 and GIX but in this case independently of XC-detectable MuLV. (c) The four remaining observed phenotypes, which did not breed true on progeny testing, involved mostly antigen-negative parents yielding antigen-positive progeny; it is likely that these discrepancies represented suppression of phenotype by a maternal resistance factor.

Animals↗
PubMed1976

Recent life events and acute schizophrenic psychosis: a controlled study.

In this case control study, first admission schizophrenic patients were found to report more recent life events overall and more events categorized as undesirable, familial, relocation, and legal than controls. Interpretation of the observations should be ventured cautiously given the small difference between schizophrenics and controls, the small number of subjects, the retrospective strategy, and the failure of events "independent of one's control" or events characterized as "threatening" to confirm the positive relationship of recent life events to the occurrence of illness. The present work is part of considerable recent research documenting a relationship between the amount and/or significance of recent life events and the occurrence of psychological symptomatology and major psychiatric syndromes. The overall difference between schizophrenics and normals in reporting events appears to be smaller in magnitude than the difference found between depressives and normals. Further, the significance of events for schizophrenics and for depressives is different. The number, type, severity, and pattern of recent life events reported by schizophrenics suggest a precipitating role of events rather than a formative one. These results are consistent with one other controlled study on schizophrenia and recent life experience.

Acute Disease↗
PubMed1975

Quantitative aspects of hormone-receptor interactions of high affinity. Effect of receptor concentration and measurement of dissociation constants of labeled and unlabeled hormones.

It is demonstrated that because of limitations in the magnitude of the specific activity of radiolabeled hormone derivatives, direct binding studies of hormone-receptor interactions of high affinity (10(-9) -10(-11) M, depending on whether 3H- or 123I-labeled hormones are used) will be subject to artifactual distortions due to the need to utilize high concentrations of the receptor. If the concentration of the receptor is not ten times lower than the true affinity constant, the apparent dissociation constant obtained from direct concentration binding curves will vary as a linear function of the receptor concentration. In addition, at high receptor concentrations saturability becomes difficult to demonstrate experimentally and the binding data yield apparently non-hyperbolic, sigmoidal curves which can be mistakenly interpreted to depict cooperative interactions. Similar artifacts related to receptor concentration are predicted for measurements of the hormone concentration dependence of biological proce-ses (e.g. activation of adenylate cyclase, transport processes, etc.). Methods for detecting these effects, and correctly measuring affinities for labeled and unlabeled hormones under these conditions, are described. The implications for measuring the binding properties of hormone-receptor interactions are discussed, especially in reference to studies of the comparative analysis of receptor function in altered metabolic states and to studies relating the biological and binding properties of hormones.

Binding Sites↗
PubMed1975

Calf blood flow in intermittent claudication.

Calf blood flow was correlated with severity of symptoms in 24 patients with intermittent claudication. Calf blood flow was measured (Whitney strain gauge) at three levels of demand--at rest, after exercise ("open"), and after exercise with total vascular occlusion by a tourniquet about the thigh ("closed"). The results showed significant correlation between the patients' reported capacity to walk and measured exercise tolerance on an ergometer (P less than or equal to .01). The coefficients of correlation between exercise tolerance and calf blood flow (resting, postopen or postclosed exercise) or the vascular reserve (difference between postopen and postclosed exercise hyperemia) were not significant. It is concluded that capacity for walking in cases of intermittent claudication is not a reliable index of the calf blood flow. The relationship between these factors would be clearer if the patients pain threshold and calf tissue metabolic activity were known also.

Adult↗
PubMed1975

Irreversible stimulation of adenylate cyclase activity of fat cell membranes of phosphoramidate and phosphonate analogs of GTP.

The ability of 5'-guanylylimidodiphosphate (Gpp(NH)p) to stimulate irreversibly the adenylate cyclease activity of fat cell membranes has been studied by preincubating the membranes with this or related analogs followed by assaying after thoroughly washing the membranes. Activation can occur in a simple Tris-HCl buffer, in the absence of added divalent cations and in the presence of EDTA. Dithiothreitol enhances the apparent degree of activation, perhaps by stabilization. The importance of utilizing optimal conditions for stabilizing enzyme activity, and of measuring the simultaneous changes in the control enzyme, is illustrated. The organomercurial, p-aminophenylmercuric acetate, inhibits profoundly the activity of the native as well as the Gpp(NH)p-stimulated adenylate cyclase, but in both cases subsequent exposure to dithiothreitol restores fully the original enzyme activity. However, the mercurial-inactivated enzyme does not react with Gpp(NP)p, as evidenced by the subsequent restoration of only the control enzyme activity upon exposure to dithiothreitol. Thus, reaction with Gpp(NH)p requires intact sulfhydryl groups, but the activated state is not irreversibly destroyed by the inactivation caused by sulfhydryl blockade. GTP and, less effectively, GDP and ATP inhibit activation by Gpp(NH)p, but interpretations are complicated by the facts that this inhibition is overcome with time and that GTP and ATP can protect potently from spontaneous inactivation. These two nucleotides can be used in the Gpp(NH)p preincubation to stabilize the enzyme. The Gpp(NH)p-activated enzyme cannot be reversed spontaneously during prolonged incubation at 30 degrees C in the absence or presence of GTP, ATP, MgCl2, glycine, dithiothreitol, NaF or EDTA. The strong nucleophile, neutral hydroxylamine, decreases the Gpp(NH)p-activated enzyme activity and no subsequent activation is detected upon re-exposure to the nucleotide.

Adenosine Triphosphate↗
PubMed1975

Activation of adenylate cyclase by phosphoramidate and phosphonate analogs of GTP: possible role of covalent enzyme-substrate intermediates in the mechanism of hormonal activation.

Incubation of rat fat pad membranes with 5-guanylyliminodiphosphonate [Gpp-(NH)p] and 5-guanylylmethylenediphosphonate [Gpp(CH2)p], but not GTP (with or without hormones), at 24 degrees or 30 degrees (but not at 4 degrees) greatly stimulates adenylate cyclase activity [ATP pyrophosphate-lyase (cyclizing), EC 4.6.1.1] measured after thoroughly washing the membranes. The rate of activation is relatively slow, even with very high (and saturating) concentrations of the analogs. Binding alone appears to be insufficient for activation. Hormones (catecholamines, glucagon) increase the rate but not the extent of activation, even when saturating analog concentrations are used. The dependence on analog concentration (apparent Km) varies with the time of incubation. GTP and very high concentrations of ATP inhibit the activation by Gpp(NH)p, but this effect is dependent on the length of incubation and can be overcome with time. The activated state is not reversed upon incubation of the washed membranes at 30 degrees, even in the presence of GTP, or by solubilization with nonionic detergents. Also, Gpp(NH)p can directly stimulate the control, solubilized enzyme. The activated state of the solubilized enzyme persists upon specific adsorption to and subsequent elution from an organomercurial-agarose column. It is suggested that after forming reversible Michaelis complexes of relatively low affinity, these analogs may react irreversibly with the GTP regulatory site of the enzyme, perhaps forming p(NH)p- and p(CH2)p-covalent enzyme intermediates which capture the activated state of the enzyme. GTP, after binding, may normally activate the enzyme by forming a "labile" pyrophosphoryl enzyme intermediate, and hormone receptors may function to increase the rate of formation (and thus concentration) of this active state of the enzyme.

Adenylyl Cyclases↗