Showing papers by "Emory University published in 1997"
TL;DR: In this paper, the authors integrate theory developed in several disciplines to determine five cognitive processes through which industrial buyers can develop trust of a supplier firm and its salesperson and their salesperson.
Abstract: The authors integrate theory developed in several disciplines to determine five cognitive processes through which industrial buyers can develop trust of a supplier firm and its salesperson. These p...
6,637 citations
TL;DR: It is shown that growth factor activation of the PI3'K/Akt signaling pathway culminates in the phosphorylation of the BCL-2 family member BAD, thereby suppressing apoptosis and promoting cell survival.
5,831 citations
TL;DR: One possible role of Bcl-2 in prevention of apoptosis is to block cytochrome c release from mitochondria, which is normally located in the mitochondrial intermembrane space.
Abstract: Bcl-2 is an integral membrane protein located mainly on the outer membrane of mitochondria. Overexpression of Bcl-2 prevents cells from undergoing apoptosis in response to a variety of stimuli. Cytosolic cytochrome c is necessary for the initiation of the apoptotic program, suggesting a possible connection between Bcl-2 and cytochrome c, which is normally located in the mitochondrial intermembrane space. Cells undergoing apoptosis were found to have an elevation of cytochrome c in the cytosol and a corresponding decrease in the mitochondria. Overexpression of Bcl-2 prevented the efflux of cytochrome c from the mitochondria and the initiation of apoptosis. Thus, one possible role of Bcl-2 in prevention of apoptosis is to block cytochrome c release from mitochondria.
4,961 citations
TL;DR: The findings suggest that the mGluRs provide a novel target for development of therepeutic agents that could have a significant impact on neuropharmacology.
Abstract: ▪ Abstract In the mid to late 1980s, studies were published that provided the first evidence for the existence of glutamate receptors that are not ligand-gated cation channels but are coupled to effector systems through GTP-binding proteins. Since those initial reports, tremendous progress has been made in characterizing these metabotropic glutamate receptors (mGluRs), including cloning and characterization of cDNA that encodes a family of eight mGluR subtypes, several of which have multiple splice variants. Also, tremendous progress has been made in developing new highly selective mGluR agonists and antagonists and toward determining the physiologic roles of the mGluRs in mammalian brain. These findings have exciting implications for drug development and suggest that the mGluRs provide a novel target for development of therepeutic agents that could have a significant impact on neuropharmacology.
3,091 citations
TL;DR: It is suggested that maternal behavior serves to "program" hypothalamic-pituitary-adrenal responses to stress in the offspring.
Abstract: Variations in maternal care affect the development of individual differences in neuroendocrine responses to stress in rats. As adults, the offspring of mothers that exhibited more licking and grooming of pups during the first 10 days of life showed reduced plasma adrenocorticotropic hormone and corticosterone responses to acute stress, increased hippocampal glucocorticoid receptor messenger RNA expression, enhanced glucocorticoid feedback sensitivity, and decreased levels of hypothalamic corticotropin-releasing hormone messenger RNA. Each measure was significantly correlated with the frequency of maternal licking and grooming (all r 9s > −0.6). These findings suggest that maternal behavior serves to “program” hypothalamic-pituitary-adrenal responses to stress in the offspring.
3,020 citations
TL;DR: Of the many factors examined that might affect the relation between breast cancer risk and use of HRT, only a woman's weight and body-mass index had a material effect: the increase in the relative risk of breast cancer diagnosed in women using HRT and associated with long durations of use in current and recent users was greater for women of lower than of higher weight or body- mass index.
2,343 citations
TL;DR: In this article, the authors identified and purified from HeLa cytosol a protein that induces DNA fragmentation in coincubated nuclei after it is activated by caspase-3.
1,753 citations
TL;DR: The demands and influences of the environmental movement are evident in the dollar value size of the world's largest companies as mentioned in this paper, as well as the changes in the landscape in which global organizations compete.
Abstract: Environmental concerns have begun to reshape the landscape in which global organizations compete. The demands and influences of the environmental movement are evident in the dollar value size of th...
1,032 citations
TL;DR: Because features of a transcription-primed mechanism appear to be conserved in vertebrates, a general model for initiation of vertebrate heavy-strand DNA synthesis is proposed.
Abstract: The discovery that mutations in mitochondrial DNA (mtDNA) can be pathogenic in humans has increased interest in understanding mtDNA maintenance. The functional state of mtDNA requires a great number of factors for gene expression, DNA replication, and DNA repair. These processes are ultimately controlled by the cell nucleus, because the requisite proteins are all encoded by nuclear genes and imported into the mitochondrion. DNA replication and transcription are linked in vertebrate mitochondria because RNA transcripts initiated at the light-strand promoter are the primers for mtDNA replication at the heavy-strand origin. Study of this transcription-primed DNA replication mechanism has led to isolation of key factors involved in mtDNA replication and transcription and to elucidation of unique nucleic acid structures formed at this origin. Because features of a transcription-primed mechanism appear to be conserved in vertebrates, a general model for initiation of vertebrate heavy-strand DNA synthesis is proposed. In many organisms, mtDNA maintenance requires not only faithful mtDNA replication, but also mtDNA repair and recombination. The extent to which these latter two processes are involved in mtDNA maintenance in vertebrates is also appraised.
992 citations
TL;DR: In this article, the authors analyze the growth of international non-governmental organizations between 1875 and 1973 using a data set on almost 6,000 organizations, identifying universalism, individualism, voluntaristic authority, rational progress, and world citizenship as central elements of world culture.
Abstract: The authors analyze the growth of international non-governmental organizations between 1875 and 1973 using a data set on almost 6,000 organizations. Although these organizations are highly interconnected with the expanding state system and world economy, as reflections of and contributors to world culture they have helped construct a world polity that cannot be reduced to networks of economic and political interaction. Their analysis of the structure and aims of these organizations identifies the principles of universalism, individualism, voluntaristic authority, rational progress, and world citizenship as central elements of world culture. They also describe the structure of world culture by studying the distribution of these organizations across major social sectors, highlighting the centrality of rationalizing scientific, technical, economic, and infrastructural organizations that go largely unnoticed. Finally, they review sectoral historical studies showing how these organizations shape world culture and influence states and intergovernmental organizations
902 citations
TL;DR: This neural diathesis-stress model is consistent with findings on prenatal factors and brain abnormalities in schizophrenia, and it provides a framework for explaining some key features of the developmental course and clinical presentation.
Abstract: There is a substantive literature on the behavioral effects of psychosocial stressors on schizophrenia. More recently, research has been conducted on neurohormonal indicators of stress responsivity, particularly cortisol release resulting from activation of the hypothalamic-pituitary-adrenal (HPA) axis. This article integrates the psychosocial and biological literatures on stress in schizophrenia, and it offers specific hypotheses about the neural mechanisms involved in the effects of stressors on the diathesis. Both the behavioral and biological data indicate that stress worsens symptoms and that the diathesis is associated with a heightened response to stressors. A neural mechanism for these phenomena is suggested by the augmenting effect of the HPA axis on dopamine (DA) synthesis and receptors. Assuming the diathesis for schizophrenia involves an abnormality in DA receptors, it is proposed that the HPA axis acts as a potentiating system by means of its effects on DA. At the same time, DA receptor abnormality and hippocampal damage render the patient hypersensitive to stress. This neural diathesis-stress model is consistent with findings on prenatal factors and brain abnormalities in schizophrenia, and it provides a framework for explaining some key features of the developmental course and clinical presentation.
TL;DR: Hypertension caused by chronically elevated angiotensin II is mediated in part by .O2-, likely via degradation of endothelium-derived NO, and may contribute to vascular disease in high renin/angiotens in II states.
Abstract: Background The major source of superoxide (·O2−) in vascular tissues is an NADH/NADPH-dependent, membrane-bound oxidase. We have previously shown that this oxidase is activated in angiotensin II– but not norepinephrine-induced hypertension. We hypothesized that hypertension associated with chronically elevated angiotensin II might be caused in part by vascular ·O2− production. Methods and Results We produced hypertension in rats by a 5-day infusion of angiotensin II or norepinephrine. Rats were also treated with liposome-encapsulated superoxide dismutase (SOD) or empty liposomes. Arterial pressure was measured in conscious rats under baseline conditions and during bolus injections of either acetylcholine or nitroprusside. Vascular ·O2− production was assessed by lucigenin chemiluminescence. In vitro vascular relaxations were examined in organ chambers. Norepinephrine infusion increased blood pressure to a similar extent as angiotensin II infusion (179±5 and 189±4 mm Hg, respectively). In contrast, angiote...
TL;DR: The Aneurysm Detection and Management (ADAM) study is an ongoing randomized clinical trial comparing two strategies for the management of AAA in patients 50 to 79 years of age with asymptomatic AAAs.
Abstract: Background: Independent risk factors for abdominal aortic aneurysm (AAA) have not been clearly defined in multivariable analyses of large patient populations. Objective: To identify factors that ar...
TL;DR: This work presents a meta-anatomy of the adrenal gland and its role in the development and management of disease and urges further investigation into the role of “cell reprograming” and “reconcretization” in the course of disease progression.
TL;DR: It is demonstrated that CD8+ T cells when compared with CD4+ T Cells are preferentially responsive to both early activation events and proliferative signals provided via the TCR and 4-1BB.
Abstract: The 4-1BB receptor is an inducible type I membrane protein and member of the tumor necrosis factor receptor (TNFR) superfamily that is rapidly expressed on the surface of CD4+ and CD8+ T cells after antigen- or mitogen-induced activation. Cross-linking of 4-1BB and the T cell receptor (TCR) on activated T cells has been shown to deliver a costimulatory signal to T cells. Here, we expand upon previously published studies by demonstrating that CD8+ T cells when compared with CD4+ T cells are preferentially responsive to both early activation events and proliferative signals provided via the TCR and 4-1BB. In comparison, CD28-mediated costimulatory signals appear to function in a reciprocal manner to those induced through 4-1BB costimulation. In vivo examination of the effects of anti-4-1BB monoclonal antibodies (mAbs) on antigen-induced T cell activation have shown that the administration of epitope-specific anti-4-1BB mAbs amplified the generation of H-2d–specific cytotoxic T cells in a murine model of acute graft versus host disease (GVHD) and enhanced the rapidity of cardiac allograft or skin transplant rejection in mice. Cytokine analysis of in vitro activated CD4+ and CD8+ T cells revealed that anti-4-1BB costimulation markedly enhanced interferon-γ production by CD8+ T cells and that anti-4-1BB mediated proliferation of CD8+ T cells appears to be IL-2 independent. The results of these studies suggest that regulatory signals delivered by the 4-1BB receptor play an important role in the regulation of cytotoxic T cells in cellular immune responses to antigen.
TL;DR: The observation of the prolonged serum concentrations in the vaginal group suggests that vaginal administration could be dosed at longer intervals than oral, and there are significant differences in the pharmacokinetics of misoprostol administered by vaginal and oral routes that may explain the difference observed in clinical efficacy.
Journal Article•
TL;DR: Novel findings, not widely described previously, suggest that many of the individual drugs studied in these experiments possess some structural characteristic that determines affinity for several G protein-coupled, but not muscarinic, receptors.
Abstract: Several new antidepressants that inhibit the serotonin (SERT) and norepinephrine transporters (NET) have been introduced into clinical practice the past several years. This report focuses on the further pharmacologic characterization of nefazodone and its metabolites within the serotonergic and noradrenergic systems, in comparison with other antidepressants. By use of radioligand binding assays, we measured the affinity (Ki) of 13 antidepressants and 6 metabolites for the rat and human SERT and NET. The Ki values for eight of the antidepressants and three metabolites were also determined for the rat 5-HT1A, 5-HT2A and muscarinic cholinergic receptors, the guinea pig histamine1 receptor and the human alpha-1 and alpha-2 receptors. These data are useful for predicting side effect profiles and the potential for pharmacodynamic drug-drug interactions of antidepressants. Of particular interest were the findings that paroxetine, generally thought of as a selective SERT antagonist, possesses moderately high affinity for the NET and that venlafaxine, which has been described as a "dual uptake inhibitor", possesses weak affinity for the NET. We observed significant correlations in SERT (r = 0.965) or NET (r = 0.983) affinity between rat and human transporters. Significant correlations were also observed between muscarinic cholinergic and NET affinity. There are several significant correlations between affinities for the 5-HT1A, 5-HT2A, histamine1, alpha-1 and alpha-2 receptors. These novel findings, not widely described previously, suggest that many of the individual drugs studied in these experiments possess some structural characteristic that determines affinity for several G protein-coupled, but not muscarinic, receptors.
TL;DR: Findings illustrate how an understanding of the function of sphingolipids can help solve questions in toxicology and this is undoubtedly only the beginning of this story.
Posted Content•
TL;DR: In this article, the authors developed and tested an option-style valuation model, whose main prediction is that equity value is a convex function of both earnings and book value, where the function depends on the relative values of earnings and Book value.
Abstract: This paper develops and tests an option-style valuation model, whose main prediction is that equity value is a convex function of both earnings and book value, where the function depends on the relative values of earnings and book value. Earnings provides a measure of how the firm's resources are currently used. Book value provides a measure of the value of the firm's resources, independent of how the resources are currently used. When the ratio earnings/book value is high, the firm is likely to continue its current way of using resources, and earnings is the more important determinant of equity value. When earnings/book value is low, the firm is more likely to exercise the option to adapt its resources to a superior alternative use, and book value becomes the more important determinant of equity value. Evidence from a variety of empirical specifications is consistent with the convexity prediction.
TL;DR: Data indicate that, even in the absence of any subsequent movement, the left premotor cortex processes objects that, like tools, have a motor valence, and suggests a role for these two areas in understanding object semantics.
TL;DR: A review of deubiquitination enzymes concentrates on recent findings and new insights into this fascinating class of enzymes.
Abstract: An astounding number of important regulatory and structural proteins are subject to modification by the attachment of ubiquitin or ubiquitin-like proteins. This modification acts as a targeting signal, delivering the modified protein to different locations in the cell and modifying its activity, macromolecular interactions, or half-life. Deubiquitination, or the removal of this modification, is being recognized as an important regulatory strategy. This reaction is catalyzed by processing proteases known as deubiquitinating enzymes (DUBs). More than 60 DUBs are already known, although little is known about their biological roles. This review concentrates on recent findings and new insights into this fascinating class of enzymes.
TL;DR: In this paper, a taxonomy of environmentally-friendly best practices within the operations management value chain is developed, which is then extended to develop a group of propositions concerning the role of management in promoting environmentallyfriendly practices.
TL;DR: This classification system will categorize ocular injuries at the time of initial examination and is designed to promote the use of standard terminology and assessment, with applications to clinical management and research studies regarding eye injuries.
TL;DR: In this article, the authors use store-level data to document the exact process of changing prices and to directly measure menu costs at five multistore supermarket chains and show that changing prices in these establishments is a complex process, requiring dozens of steps and a nontrivial amount of resources.
Abstract: We use store-level data to document the exact process of changing prices and to directly measure menu costs at five multistore supermarket chains We show that changing prices in these establishments is a complex process, requiring dozens of steps and a nontrivial amount of resources The menu costs average $105,887/year per store, comprising 070 percent of revenues, 352 percent of net margins, and $052/price change These menu costs may be forming a barrier to price changes Specifically, (1) a supermarket chain facing higher menu costs (due to item pricing laws that require a separate price tag on each item) changes prices two and one-half times less frequently than the other four chains; (2) within this chain the prices of products exempt from the law are changed over three times more frequently than the products subject to the law "In principle, fixed costs of changing prices can be observed and measured In practice, such costs take disparate forms in different firms, and we have no data on their magnitude So the theory can be tested at best indirectly, at worst not at all" [Alan Blinder 1991, p 90]
TL;DR: The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD.
Abstract: Objective: To evaluate the therapeutic effects of selective cholinergic replacement with xanomeline tartrate, an ml and m4 selective muscarinic receptor (mAChR) agonist in patients with probable Alzheimer disease (AD). Design: A 6-month, randomized, double-blind, placebocontrolled, parallel-group trial followed by a 1-month, single-blind, placebo washout. Setting: Outpatients at 17 centers in the United States and Canada. Participants: A total of 343 men and women at least 60 years of age with mild to moderate AD. Interventions: Patients received 75, 150, or 225 mg (low, medium, and high doses) of xanomeline per day or placebo for 6 months. Outcome Measures: Scores on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), the Clinician's Interview-Based Impression of Change (CIBIC+), the Alzheimer's Disease Symptomatology Scale (ADSS), and the Nurses' Observational Scale for Geriatric Patients (NOSGER). Results: A significant treatment effect existed for ADAS-Cog (high dose vs placebo;P≤.05), and CIBIC+ (high dose vs placebo;P≤.02). Treatment Emergent Signs and Symptoms analysis of the ADSS, which assesses behavioral symptoms in patients with AD, disclosed significant (P≤.002) dose-dependent reductions in vocal Out-bursts, bursts, suspiciousness, delusions, agitation, and hallucinations. On end-point analysis, NOSGER, which assesses memory, instrumental activities of daily living, self-care, mood, social behavior, and disturbing behavior in the elderly, also showed a significant dose-response relationship (P≤.02). In the high-dose arm, 52% of patients discontinued treatment because of adverse events; dose-dependent adverse events were predominantly gastrointestinal in nature. Syncope, defined as loss of consciousness and muscle tone, occurred in 12.6% of patients in the high-dose group. Conclusions: The observed improvements in ADAS-Cog and CIBIC+ following treatment with xanomeline provide the first evidence, from a large-scale, placebo-controlled clinical trial, that a direct-acting muscarinic receptor agonist can improve cognitive function in patients with AD. Furthermore, the dramatic and favorable effects on disturbing behaviors in AD suggest a novel approach for treatment of noncognitive symptoms.
TL;DR: The findings suggest that Ang II-induced hypertension activates the NADPH/NADH oxidase system by upregulating mRNA levels of one or several components of this oxid enzyme system, including the p22phox, and that the NAD PH/NadH oxidases system is associated with the pathology of hypertension in vivo.
Abstract: Recent studies suggest that superoxide production by the NADPH/NADH oxidase may be involved in smooth muscle cell growth and the pathogenesis of hypertension. We previously showed that angiotensin II (Ang II) activates a p22phoxbased NADPH/NADH oxidase in cultured rat vascular smooth muscle cells and in animals made hypertensive by infusion of Ang II. To investigate the mechanism responsible for this increased oxidase activity, we examined p22phox mRNA expression in rats made hypertensive by implanting an osmotic minipump that delivered Ang II (0.7 mg/kg per day). Blood pressure began to increase 3 days after the start of Ang II infusion and remained elevated for up to 14 days. Expression of p22phox mRNA in aorta was also increased after 3 days and reached a maximum increase of 338 +/- 41% by 5 days after pump implantation compared with the value after sham operation. This increase in mRNA expression was accompanied by an increase in the content of the corresponding cytochrome (twofold) and NADPH oxidase activity (179 +/- 11% of that in sham-operated rats 5 days after pump implantation). Treatment with the antihypertensive agents losartan (25 mg/kg per day) or hydralazine (15 mg/kg per day) inhibited this upregulation of mRNA levels and activity. Furthermore, infusion of recombinant heparin-binding superoxide dismutase decreased both blood pressure and p22phox mRNA expression. In situ hybridization of aortic tissue showed that p22phox mRNA was expressed in medial smooth muscle as well as in the adventitia. These findings suggest that Ang II-induced hypertension activates the NADPH/NADH oxidase system by upregulating mRNA levels of one or several components of this oxidase system, including the p22phox, and that the NADPH/NADH oxidase system is associated with the pathology of hypertension in vivo.
TL;DR: The assumptions regarding function and structure that underlie contingency theory are exposed and a functional equivalence view of design is developed, which implies a different agenda and emphasis for research on structure and design and has normative implications for how managers should design to achieve performance.
Abstract: Theorists have often acknowledged the importance of equifinality in organization design and, in recent years, several studies have demonstrated the concept empirically. This article exposes the assumptions regarding function and structure that underlie contingency theory and develops a functional equivalence view of design. By examining the degree of conflict in functional demands together with the latitude of structural options available, we reveal and describe three different types of equifinality: suboptimal. tradeoff, and configurational. The functional equivalence approach implies a different agenda and emphasis for research on structure and design and has normative implications for how managers should design to achieve performance.
TL;DR: Dendritic localization, which was confirmed by co-fractionation of F MRP with synaptosomal ribosomes, suggests a possible role of FMRP in the translation of proteins involved in dendritic structure or function and relevant for the mental retardation occurring in fragile X syndrome.
Abstract: Fragile X syndrome, a leading cause of inherited mental retardation, is attributable to the unstable expansion of a CGG-repeat within the FMR1 gene that results in the absence of the encoded protein. The fragile X mental retardation protein (FMRP) is a ribosome-associated RNA-binding protein of uncertain function that contains nuclear localization and export signals. We show here detailed cellular localization studies using both biochemical and immunocytochemical approaches. FMRP was highly expressed in neurons but not glia throughout the rat brain, as detected by light microscopy. Although certain structures, such as hippocampus, revealed a strong signal, the regional variation in staining intensity appeared to be related to neuron size and density. In human cell lines and mouse brain, FMRP co-fractionated primarily with polysomes and rough endoplasmic reticulum. Ultrastructural studies in rat brain revealed high levels of FMRP immunoreactivity in neuronal perikarya, where it is concentrated in regions rich in ribosomes, particularly near or between rough endoplasmic reticulum cisternae. Immunogold studies also provided evidence of nucleocytoplasmic shuttling of FMRP, which was localized in neuronal nucleoplasm and within nuclear pores. Moreover, labeling was observed in large- and small-caliber dendrites, in dendritic branch points, at the origins of spine necks, and in spine heads, all known locations of neuronal polysomes. Dendritic localization, which was confirmed by co-fractionation of FMRP with synaptosomal ribosomes, suggests a possible role of FMRP in the translation of proteins involved in dendritic structure or function and relevant for the mental retardation occurring in fragile X syndrome.
TL;DR: ‘knockout’ mice deficient in the heart/muscle isoform of the adenine nucleotide translocator (Ant1) have the biochemical, histological, metabolic and physiological characteristics of mitochondrial myopathy and cardiomyopathy.
Abstract: In an attempt to create an animal model of tissue-specif ic mitochondrial disease, we generated ‘knockout’ mice deficient in the heart/muscle isoform of the adenine nucleotide translocator (Ant1). Histological and ultrastructural examination of skeletal muscle from Ant1 null mutants revealed ragged-red muscle fibers and a dramatic proliferation of mitochondria, while examination of the heart revealed cardiac hypertrophy with mitochondrial proliferation. Mitochondria isolated from mutant skeletal muscle exhibited a severe defect in coupled respiration. Ant1 mutant adults also had a resting serum lactate level fourfold higher than that of controls, indicative of metabolic acidosis. Significantly, mutant adults manifested severe exercise intolerance. Therefore, Ant1 mutant mice have the biochemical, histological, metabolic and physiological characteristics of mitochondrial myopathy and cardiomyopathy.
TL;DR: It is shown here that normal FMRP associates with elongating polyribosomes via large mRNP particles, implying that the mechanism of the severe phenotype in the I304N patient lies in the sequestration of bound mRNAs in nontranslatable mR NP particles.