Showing papers by "Yale University published in 1983"

How people make their own environments: a theory of genotype greater than environment effects.

Abstract: We propose a theory of development in which experience is directed by genotypes. Genotypic differences are proposed to affect phenotypic differences, both directly and through experience, via 3 kinds of genotype leads to environment effects: a passive kind, through environments provided by biologically related parents; an evocative kind, through responses elicited by individuals from others; and an active kind, through the selection of different environments by different people. The theory adapts the 3 kinds of genotype-environment correlations proposed by Plomin, DeFries, and Loehlin in a developmental model that is used to explain results from studies of deprivation, intervention, twins, and families.

Impossibility of distributed consensus with one faulty process

Abstract: The consensus problem involves an asynchronous system of processes, some of which may be unreliable. The problem is for the reliable processes to agree on a binary value. We show that every protocol for this problem has the possibility of nontermination, even with only one faulty process. By way of contrast, solutions are known for the synchronous case, the "Byzantine Generals" problem.

Effect of fatty acids on glucose production and utilization in man.

Abstract: Since the initial proposal of the glucose fatty acid cycle, considerable controversy has arisen concerning its physiologic significance in vivo. In the present study, we examined the effect of acute, physiologic elevations of FFA concentrations on glucose production and uptake in normal subjects under three controlled experimental conditions. In group A, plasma insulin levels were raised and maintained at approximately 100 microU/ml above base line by an insulin infusion, while holding plasma glucose at the fasting level by a variable glucose infusion. In group B, plasma glucose concentration was raised by 125 mg/100 ml and plasma insulin was clamped at approximately 50 microU/ml by a combined infusion of somatostatin and insulin. In group C, plasma glucose was raised by 200 mg/100 ml above the fasting level, while insulin secretion was inhibited with somatostatin and peripheral glucagon levels were replaced with a glucagon infusion (1 ng/min X kg). Each protocol was repeated in the same subject in combination with a lipid-heparin infusion designed to raise plasma FFA levels by 1.5-2.0 mumol/ml. With euglycemic hyperinsulinemia (study A), lipid infusion caused a significant inhibition of total glucose uptake (6.3 +/- 1.3 vs. 7.4 +/- 0.6 mg/min X kg, P less than 0.02). Endogenous glucose production (estimated by the [3-3H]glucose technique) was completely suppressed both with and without lipid infusion. With hyperglycemic hyperinsulinemia (study B), lipid infusion also induced a marked impairment in glucose utilization (6.2 +/- 1.1 vs. 9.8 +/- 1.9 mg/min X kg, P less than 0.05); endogenous glucose production was again completely inhibited despite the increase in FFA concentrations. Under both conditions (A and B), the percentage inhibition of glucose uptake by FFA was positively correlated with the total rate of glucose uptake (r = 0.69, P less than 0.01). In contrast, when hyperglycemia was associated with relative insulinopenia and hyperglucagonemia (study C), thus simulating a diabetic state, lipid infusion had no effect on glucose uptake (2.9 +/- 0.2 vs. 2.6 +/- 0.2 mg/min X kg) but markedly stimulated endogenous glucose production (1.4 +/- 0.5 vs. 0.5 +/- 0.4 mg/min X kg, P less than 0.005). Under the same conditions as study C, a glycerol infusion producing plasma glycerol levels similar to those achieved with lipid-heparin, enhanced endogenous glucose production (1.5 +/- 0.5 vs. 0.7 +/- 0.6 mg/min X kg, P less than 0.05). We conclude that, in the well-insulinized state raised FFA levels effectively compete with glucose for uptake by peripheral tissues, regardless of the presence of hyperglycemia. When insulin is deficient, on the other hand, elevated rates of lipolysis may contribute to hyperglycemia not by competition for fuel utilization, but through an enhancement of endogenous glucose output.

Inductive Inference: Theory and Methods

Abstract: There has been a great deal of theoretical and experimental work in computer science on inductive inference systems, that is, systems that try to infer general rules from examples. However, a complete and applicable theory of such systems is still a distant goal. This survey highlights and explains the main ideas that have been developed in the study of inductive inference, with special emphasis on the relations between the general theory and the specific algorithms and implementations. 154 references.

Risk and Culture: An Essay on the Selection of Technical and Environmental Dangers

Abstract: theory of the relationship between risk and culture; and (2) an application of the theory to explain "the sudden, widespread, across-theboard concern about environmental pollution and personal contamination that has arisen in the Western world in general and with particular force in the United States"2 (a phenomenon that I will call "environmentalism"). Most readers will be struck not by the abstract theory but by its application to the rise of environmentalism. This emphasis is unfortunate. The attempt to "explain" environmentalism makes a few good points, but on the whole this part of the book is crude, shortsighted, and snide. On the other hand, the sections that consider the relationship between risk and culture on a more fundamental level are sensitive and thoughtful. Even at its best, Risk and Culture is not entirely successful at explaining the paradox of risk-the problem of managing the unknown-but parts of the book deserve to be read seriously by people interested in the problem of risk, including environmental lawyers. t Associate Professor of Law, Yale University. 1. M. DOUGLAS & A. WILDAVSKY, RISK AND CULTURE: AN ESSAY ON THE SELECTION OF TECHNICAL AND ENVIRONMENTAL DANGERS (1982) [hereinafter cited by page number only]. 2. P. 10. 3. See Winner, Pollution as Delusion, N.Y. Times, Aug. 8, 1982, § 7 (Book Review), at 8, 18 (accusing Douglas and Wildavsky of "ill-conceived polemic" and "a shabby political critique" of environmentalists). HeinOnline -92 Yale L.J. 888 1982-1983

Mechanism of calcium channel blockade by verapamil, D600, diltiazem and nitrendipine in single dialysed heart cells

Abstract: Organic inhibitors of calcium influx prevent outward as well as inward current through cardiac calcium channels but do not slow current activation. Although block is antagonized by raising external calcium or barium concentrations, the competitive effect of permeant cations does not occur at the same cation binding site at which inorganic blockers act. Organic drugs show varying degrees of use-dependent block, due in part to blockade of open channels. Nitrendipine blockade of calcium currents requires doses >100-fold higher than expected from radioligand binding to isolated membranes.

Membrane fusion proteins of enveloped animal viruses.

Abstract: In a living cell membrane-bound compartments are continuously either separated or united through fusion reactions, and literally thousands of such reactions take place every minute. The formation of membrane vesicles from pre-existing membranes, and their fusion with specific acceptor membranes, constitute a prerequisite for the transport of most impermeant molecules and macromolecules into the cell by endocytosis, out of the cell by exocytosis, and between the cellular organelles (Palade, 1975; Silverstein, 1978; Evered & Collins, 1982). Less frequent, but equally crucial, are fusion events in fertilization, cell division, polykaryon formation, enucleation, etc. (for reviews see Poste & Nicholson, 1978). Although a great deal is known about the properties and consequences of individual forms of membrane fusion in cellular systems, and about fusion in artificial lipid membranes, the molecular basis for the reactions remain largely unclear.

Both a monoclonal antibody and antisera specific for determinants unique to individual cloned helper T cell lines can substitute for antigen and antigen-presenting cells in the activation of T cells.

Abstract: Two antisera and a monoclonal antibody raised in BALB.K mice against cloned, major histocompatibility complex (MHC)-restricted, antigen-specific helper T cell lines are described. These antibodies are specific for individual cloned T cell lines and are potent inducers of T cell proliferation. The induction of T cell proliferation by these antibodies requires the presence of an adherent accessory cell. There is no H-2 restriction between this accessory cell and the cloned T cell, nor is this antibody-induced proliferation blocked by a monoclonal anti-Fc receptor antibody. The requirement for an accessory cell, however, is eliminated in the presence of an IL-1- or IL-2-rich supernatant. Thus this system allows the analysis of helper T cell activation with only a single cell type present. Anti-T cell sera also induce T cell-dependent B cell proliferation and immunoglobulin secretion. The induction of T cell-dependent B cell activation by these sera does not require H-2-matched T cells and B cells. The specificity of these antibodies and their ability to stimulate cloned helper T cells in the absence of antigen and antigen-presenting cells strongly suggest that these antibodies are directed against antigen and/or Ia recognition sites on the T cell.

A reinterpretation of mammalian sodium channel gating based on single channel recording

Abstract: Some of the traditionally held views about how sodium channels work are shown to be incorrect and a new approach to physical theories of sodium channel operation is suggested.

The Early Clinical Manifestations of Lyme Disease

Abstract: Lyme disease, caused by a tick-transmitted spirochete, typically begins with a unique skin lesion, erythema chronicum migrans. Of 314 patients with this skin lesion, almost half developed multiple annular secondary lesions; some patients had evanescent red blotches or circles, malar or urticarial rash, conjunctivitis, periorbital edema, or diffuse erythema. Skin manifestations were often accompanied by malaise and fatigue, headache, fever and chills, generalized achiness, and regional lymphadenopathy. In addition, patients sometimes had evidence of meningeal irritation, mild encephalopathy, migratory musculoskeletal pain, hepatitis, generalized lymphadenopathy and splenomegaly, sore throat, nonproductive cough, or testicular swelling. These signs and symptoms were typically intermittent and changing during a period of several weeks. The commonest nonspecific laboratory abnormalities were a high sedimentation rate, an elevated serum IgM level, or an increased aspartate transaminase level. Early Lyme disease can be diagnosed by its dermatologic manifestations, rapidly changing system involvement, and if necessary, by serologic testing.

Intracellular pH regulation in the renal proximal tubule of the salamander. Basolateral HCO3- transport.

Abstract: We have used pH-, Na-, and Cl-sensitive microelectrodes to study basolateral HCO3- transport in isolated, perfused proximal tubules of the tiger salamander Ambystoma tigrinum. In one series of experiments, we lowered basolateral pH (pHb) from 7.5 to 6.8 by reducing [HCO3-]b from 10 to 2 mM at a constant pCO2. This reduction of pHb and [HCO3-]b causes a large (approximately 0.35), rapid fall in pHi as well as a transient depolarization of the basolateral membrane. Returning pHb and [HCO3-]b to normal has the opposite effects. Similar reductions of luminal pH (pHl) and [HCO3-]l have only minor effects. The reduction of [HCO3-]b and pHb also produces a reversible fall in aiNa. In a second series of experiments, we reduced [Na+]b at constant [HCO3-]b and pHb, and also observed a rapid fall in pHi and a transient basolateral depolarization. These changes are reversed by returning [Na+]b to normal. The effects of altering [Na+]l in the presence of HCO3-, or of altering [Na+]b in the nominal absence of HCO3-, are substantially less. Although the effects on pHi and basolateral membrane potential of altering either [HCO3-]b or [Na+]b are largely blocked by 4-acetamido-4-isothiocyanostilbene-2,2'-disulfonate (SITS), they are not affected by removal of Cl-, nor are there accompanying changes in aiCl consistent with a tight linkage between Cl- fluxes and those of Na+ and HCO3-. The aforementioned changes are apparently mediated by a single transport system, not involving Cl-. We conclude that HCO3- transport is restricted to the basolateral membrane, and that HCO3- fluxes are linked to those of Na+. The data are compatible with an electrogenic Na/HCO3 transporter that carries Na+, HCO3-, and net negative charge in the same direction.

Totem and Taboo

Abstract: Freud’s interest in the origins of guilt came relatively late in his work, as he himself acknowledged (1933). It was only after his major clinical accounts had been written that Freud undertook a study of the origins of guilt in Totem and Taboo. In his clinical papers, as well as in his books on dreams and jokes, “disgust, shame, and morality” were simply the counterforces against which sexual longings (libido) contended. Moreover, the origin of these counterforces was at first located in the sexual instincts themselves (see Chapter 4) as sublimations and reaction formations of the sexual instincts. Hostility arose out of frustrated libido; sublimations and reaction formations of hostility (although in the service of the “ego-instincts”) also made use of the energy of the sexual instincts to deflect them into social and moral purposes. In this account, libido theory is the centerpiece of the explanation. Our path might have been easier if Freud had indeed regarded his libido theory as a theory of the emotions (as he said he did in Group Psychology, 1921, p. 90). If one permits libido to stand for the attachment emotions, the origin of hostility and morality in a single source becomes a viable hypothesis. Morality is the affective-cognitive outcome of attachment. Threatened attachment, which first evokes protest aimed at the caretaker—“other,” is then transformed, mainly by identification, into states of shame and guilt that aim at maintaining the attachment.

Synapsin I (protein I), a nerve terminal-specific phosphoprotein. I. Its general distribution in synapses of the central and peripheral nervous system demonstrated by immunofluorescence in frozen and plastic sections.

Abstract: Synapsin I (formerly referred to as protein I) is the collective name for two almost identical phosphoproteins, synapsin Ia and synapsin Ib (protein Ia and protein Ib), present in the nervous system Synapsin I has previously been shown by immunoperoxidase studies (De Camilli, P, T Ueda, F E Bloom, E Battenberg, and P Greengard, 1979, Proc Natl Acad Sci USA, 76:5977-5981; Bloom, F E, T Ueda, E Battenberg, and P Greengard, 1979, Proc Natl Acad Sci USA 76:5982-5986) to be a neuron-specific protein, present in both the central and peripheral nervous systems and concentrated in the synaptic region of nerve cells In those preliminary studies, the occurrence of synapsin I could be demonstrated in only a portion of synapses We have now carried out a detailed examination of the distribution of synapsin I immunoreactivity in the central and peripheral nervous systems In this study we have attempted to maximize the level of resolution of immunohistochemical light microscopy images in order to estimate the proportion of immunoreactive synapses and to establish their precise distribution Optimal results were obtained by the use of immunofluorescence in semithin sections (approximately 1 micron) prepared from Epon-embedded nonosmicated tissues after the Epon had been removed Our results confirm the previous observations on the specific localization of synapsin I in nerve cells and synapses In addition, the results strongly suggest that, with a few possible exceptions involving highly specialized neurons, all synapses contain synapsin I Finally, immunocytochemical experiments indicate that synapsin I appearance in the various regions of the developing nervous system correlates topographically and temporally with the appearance of synapses In two accompanying papers (De Camilli, P, S M Harris, Jr, W B Huttner, and P Greengard, and Huttner, W B, W Schiebler, P Greengard, and P De Camilli, 1983, J Cell Biol 96:1355-1373 and 1374-1388, respectively), evidence is presented that synapsin I is specifically associated with synaptic vesicles in nerve endings

Regulation of Splanchnic and Peripheral Glucose Uptake by Insulin and Hyperglycemia in Man

Abstract: We investigated the effects of hyperinsulinemia and hyperglycemia on peripheral glucose uptake, hepatic glucose production, and splanchnic glucose uptake in man. Euglycemic and hyperglycemic clamp studies were carried out in 37 healthy subjects in combination with hepatic vein catheterization and [3H-3]glgcose infusion. In the basal state, hepatic glucose production ([3H-3]glucose) exceeded net splanchnic glucose output (catheter) in every subject (2.3 ± 0.04 versus 1.7 ± 0.07 mg/min · kg, P < 0.001), indicating uptake of glucose by the splanchnic region at a rate of 0.6 ± 0.05 mg/ min · kg. In agreement with this estimate, [3H-3]glucose concentration was consistently lower in hepatic venous than in arterial blood, by 3.0 ± 0.2% (P < 0.001). When plasma insulin levels were raised to 37 ± 2, 53 ± 2, 101 ± 2, 428 ± 37, and 1189 ± 14 μU/ml, with maintenance of euglycemia, total glucose uptake rose to 2.9 ± 0.4, 3.9 ± 1.0, 5.1 ± 0.4, 9.9 ±1.1, and 11.8 ± 1.3 mg/min · kg, respectively. The whole body glucose clearance rose significantly above baseline at each hyperinsulinemic plateau (P < 0.05 or less). Hepatic glucose production fell by 68% (P < 0.01) at the lowest hyperinsulinemic level, by 87% at insulin levels of 53 ± 2 μU/ml, and by over 95% with each higher insulin dose. Splanchnic glucose uptake was not significantly increased over basal values at any insulin concentration. When plasma glucose levels were raised to 137 ± 3 and 224 ± 2 mg/dl peripheral plasma insulin levels rose to 20 ± 4 and 55 ± 5 μU/ml, respectively. Total glucose uptake was enhanced (2.5 ± 0.4 and 5.3 ± 1.0 mg/min · kg, P < 0.05 and P < 0.01, respectively). Suppression of hepatic glucose production was <90% at the lower hyperglycemic level, and virtually complete at the higher one. Splanchnic glucose uptake was not changed by mild hyperglycemia (0.5 ± 0.05 mg/min · kg), but rose significantly (1.3 ± 0.3 mg/ min · kg, P < 0.01) with further hyperglycemia. The latter effect resulted primarily from increased glucose delivery to the splanchnic area, since the splanchnic glucose extraction ratio (4.0 ± 0.3%) was not different from baseline (3.0 ± 0.3%). When hyperglycemia (224 ± 1 mg/dl) was combined with a somatostatin infusion, thereby reducing plasma insulin from 15 ± 3 to 10 ± 1 μU/ml (P < 0.01), both total glucose uptake (2.8 ± 0.03 mg/min · kg) and clearance (1.3 ± 0.01 mg/min · kg) were significantly (P < 0.01) lower than in the hyperglycemic studies in which insulin secretion was not blocked. Hepatic glucose production, however, was effectively suppressed (by 74%, P < 0.001), whereas splanchnic glucose uptake was only slightly increased above baseline. Replacement of insulin (via an exogenous infusion at a rate of 0.3 mU/min · kg) restored total glucose uptake, splanchnic glucose uptake, and suppression of hepatic glucose production to the levels seen with hyperglycemia without somatostatin. When hyperglycemia (216 ± 2 mg/dl) was combined with somatostatin and glucagon replacement (no insulin), hepatic glucose production was still suppressed by 47 ± 1% to 1.18 ± 0.01 mg/kg · min (P < 0.001 versus hyperglycemia + SRIF without glucagon replacement). The results indicate that both hyperglycemia and hypoglucagonemia contribute to the decline in hepatic glucose production following somatostatin infusion. In conclusion, hyperinsulinemia alone stimulates glucose uptake by peripheral but not splanchnic tissues. The dose-response characteristics of stimulation of peripheral glucose uptake and inhibition of hepatic glucose production by insulin are very different, the half-maxima being ∼120 and ∼50 μU/ml, respectively. Hyperglycemia enhances glucose uptake by both peripheral and splanchnic tissues, but this action requires an intact endogenous insulin response. In contrast, hyperglycemia can suppress endogenous glucose production even in the presence of low insulin levels.

Pharmacology of mesocortical dopamine neurons.

Abstract: The current information on the pharmacology and function of the DA innervation to the prefrontal cortex is a synthesis of data from several initially distinct areas of research. Some possible functions of the mesocortical DA system are suggested from the extensive studies conducted on the role of the prefrontal cortex in behavior, and also from the data on prefrontal cortical modulation of the output of subcortical DA systems. Meanwhile, anatomical, behavioral, biochemical, and electrophysiological studies on mesocortical DA neurons have largely resulted from interest in determining the site(s) and mechanism(s) of action of various psychotropic drugs, and particularly the antipsychotic drugs (DA antagonists). An interrelated field of study has investigated the functional role of DA autoreceptors. The mesocortical DA system possesses many unique characteristics compared to the nigrostriatal/mesolimbic DA systems, including 1) a higher DA turnover rate, 2) a higher rate and different pattern of neuronal discharge, 3) a greatly diminished responsiveness to DA agonists and antagonists, 4) a lack of tolerance to the effect of chronically administered DA antagonists, and 5) a selective activation by footshock stress. These characteristics may be due to the fact that the DA cells projecting to the prefrontal cortex lack DA autoreceptors, an important site for the physiological and pharmacological modulation of subcortical DA systems. This contention is further supported by recent studies on two distinct DA systems innervating, respectively, the anterior cingulate and piriform cortices: the former system, which lacks DA autoreceptors, responds much like the prefrontal cortical DA sy stem; the latter system, which possesses functional DA autoreceptors, manifests a pharmacological responsiveness similar to the nigrostriatal/mesolimbic DA systems (11, 14, 118, 119, 38). Autoreceptors may be an important target for future rational drug design. For example, DA agonists more selective for DA autoreceptors (65, 72) may be useful agents in the treatment of schizophrenia. If, however, these drugs prove ineffective in schizophrenic patients, it might help to explain the equivocal results obtained to date in the treatment of schizophrenia with low (autoreceptor-specific) doses of less selective DA agonists (for a review, see Ref. 97). A lack of clinical efficacy of DA autoreceptor agonists might also suggest that if a DA system is indirectly involved in schizophrenia the site of therapeutic action of antipsychotic drugs is a DA system (such as that innervating the prefrontal cortex) that lacks autoreceptors.

Very Long Instruction Word architectures and the ELI-512

Abstract: By compiling ordinary scientific applications programs with a radical technique called trace scheduling, we are generating code for a parallel machine that will run these programs faster than an equivalent sequential machine—we expect 10 to 30 times faster. Trace scheduling generates code for machines called Very Long Instruction Word architectures. In Very Long Instruction Word machines, many statically scheduled, tightly coupled, fine-grained operations execute in parallel within a single instruction stream. VLIWs are more parallel extensions of several current architectures. These current architectures have never cracked a fundamental barrier. The speedup they get from parallelism is never more than a factor of 2 to 3. Not that we couldn't build more parallel machines of this type; but until trace scheduling we didn't know how to generate code for them. Trace scheduling finds sufficient parallelism in ordinary code to justify thinking about a highly parallel VLIW. At Yale we are actually building one. Our machine, the ELI-512, has a horizontal instruction word of over 500 bits and will do 10 to 30 RISC-level operations per cycle [Patterson 82]. ELI stands for Enormously Longword Instructions; 512 is the size of the instruction word we hope to achieve. (The current design has a 1200-bit instruction word.) Once it became clear that we could actually compile code for a VLIW machine, some new questions appeared, and answers are presented in this paper. How do we put enough tests in each cycle without making the machine too big? How do we put enough memory references in each cycle without making the machine too slow?

Stress, personal coping resources, and psychiatric symptoms: An investigation of interactive models.

Abstract: In the last ten years, there has been considerable interest in the moderating influence of coping resources on the effects of stress; research has focused mainly on environmental coping resources, such as social support. This paper explores possible interactions between stressors, both acute and chronic, and personal coping resources; interactions are estimated separately for schizophrenic, depression and anxiety symptom clusters. Personal coping resources are conceived of in terms of individual dispositions that may have consequences for either the amount of typical coping effort expended or coping ability. Two related dispositional characteristics are considered: fatalism and inflexibility. Both low fatalism and low inflexibility are found to have a strong moderating influence on the impact of stress, but, perhaps more important, these effects depend both on the type of stress and the symptom outcome considered. These findings are interpreted in terms of a general contingency theory for the role of socialfactors in explaining psychiatric disorder, emphasizing the differences between the types of symptoms involved.

Protein phosphorylation in the brain

Abstract: Protein phosphorylation represents an approach, sometimes the only approach available, to study the molecular basis for a wide variety of neurophysiological phenomena. The injection of protein kinases or protein kinase inhibitors into neurones has provided direct evidence that activation of protein kinases has an obligatory role in the mechanisms by which numerous extracellular signals produce specific physiological responses in neurones. A diversity of substrate proteins for the kinases have already been found. In several instances, the identity and functional role of these substrate proteins have been established.

Comprehending verbal comprehension.

Abstract: Il est debattu des fondements cognitifs de la comprehension verbale et on met surtout l'accent sur le role du contexte dans la comprehension verbale. Apres un tour d'horizon sur les autres approches theoriques de la comprehension verbale, sont exposees les conceptions qui inspirent l'auteur ainsi qu'un certain nombre de donnees empiriques. Sont enfin ebauchees quelques-unes des implications de la nouvelle theorie pour la comprehension de l'intelligence en general

Truncated-newtono algorithms for large-scale unconstrained optimization

Abstract: We present an algorithm for large-scale unconstrained optimization based onNewton's method. In large-scale optimization, solving the Newton equations at each iteration can be expensive and may not be justified when far from a solution. Instead, an inaccurate solution to the Newton equations is computed using a conjugate gradient method. The resulting algorithm is shown to have strong convergence properties and has the unusual feature that the asymptotic convergence rate is a user specified parameter which can be set to anything between linear and quadratic convergence. Some numerical results on a 916 vriable test problem are given. Finally, we contrast the computational behavior of our algorithm with Newton's method and that of a nonlinear conjugate gradient algorithm.