Showing papers by "Tufts University published in 1987"

The Intentional Stance

Abstract: How are we able to understand and anticipate each other in everyday life, in our daily interactions? Through the use of such "folk" concepts as belief, desire, intention, and expectation, asserts Daniel Dennett in this first full-scale presentation of a theory of intentionality that he has been developing for almost twenty years. We adopt a stance, he argues, a predictive strategy of interpretation that presupposes the rationality of the people - or other entities - we are hoping to understand and predict.These principles of radical interpretation have far-reaching implications for the metaphysical and scientific status of the processes referred to by the everday terms of folk psychology and their corresponding terms in cognitive science.While Dennett's philosophical stance has been steadfast over the years, his views have undergone successive enrichments, refinements, and extensions. "The Intentional Stance" brings together both previously published and original material: four of the book's ten chapters - its first and the final three - appear here for the first time and push the theory into surprising new territory. The remaining six were published earlier in the 1980s but were not easily accessible; each is followed by a reflection - an essay reconsidering and extending the claims of the earlier work. These reflections and the new chapters represent the vanguard of Dennett's thought. They reveal fresh lines of inquiry into fundamental issues in psychology, artificial intelligence, and evolutionary theory as well as traditional issues in the philosophy of mind.Daniel C. Dennett is Distinguished Arts and Sciences Professor at Tufts University and the author of "Brainstorms" and "Elbow Room." "The Intentional Stance," along with these works, is a Bradford Book.

Cytokine-induced expression of HIV-1 in a chronically infected promonocyte cell line.

Abstract: A model system for cytokine-induced up-regulation of human immunodeficiency virus type 1 (HIV-1) expression in chronically infected promonocyte clones was established. The parent promonocyte cell line U937 was chronically infected with HIV-1 and from this line a clone, U1, was derived. U1 showed minimal constitutive expression of HIV-1, but virus expression was markedly up-regulated by a phytohemagglutinin-induced supernatant containing multiple cytokines and by recombinant granulocyte/macrophage colony-stimulating factor alone. Recombinant interleukin-1 (IL-1), IL-2, interferon-gamma, and tumor necrosis factor-alpha did not up-regulate virus expression. Concomitant with the cytokine-induced up-regulation of HIV-1, expression of membrane-bound IL-1 beta was selectively induced in U1 in the absence of induction of other surface membrane proteins. This cytokine up-regulation of IL-1 beta was not seen in the uninfected parent U937 cell line. These studies have implications for the understanding of the mechanism of progression from a latent or low-level HIV-1 infection to a productive infection with resulting immunosuppression. In addition, this model can be used to delineate the potential mechanisms whereby HIV-1 infection regulates cellular gene expression.

Episodic and Semantic Memory: A Comparison of Amnesic and Demented Patients

Abstract: Episodic (recall of passages) and semantic (letter and category fluency) memory tasks were administered to Alzheimer's Disease (early stages), Huntington's Disease (HD), and alcoholic Korsakoff patients matched for overall severity of dementia. Although all three patient groups were severely (and equally) impaired on memory for passages, only the Alzheimer and Korsakoff patients emitted numerous intrusion errors. On the fluency tasks, the performance of the mild Alzheimer patients was distinguishable from that of the other two patient groups. On both fluency tasks, the HD and Korsakoff patients demonstrated severe and moderate deficits, respectively, whereas the mild Alzheimer patients were impaired only on the category fluency task. As with the episodic memory test, the Alzheimer and Korsakoff patients made more perseverative errors than did the HD patients on letter fluency. These findings suggest that Alzheimer and HD patients' impairments on episodic and semantic memory tasks reflect different underlying processes. The performance of Alzheimer patients is affected by their language dysfunction and an increased sensitivity to proactive interference; the deficits of the HD patients appear due to a general retrieval problem. Similarities in the error patterns (i.e., perseveration errors) of Alzheimer and Korsakoff patients are discussed with regard to recent neuropathological findings.

Interleukin 1 induces interleukin 1. I: Induction of circulating interleukin 1 in rabbits in vivo and in human mononuclear cells in vitro

Abstract: Interleukin 1 (IL-1) plays an important role in host defense mechanisms by increasing body temperature, inducing the synthesis of a variety of lymphokines and hepatic acute phase proteins and acting as a chemoattractant for lymphocytes However, in some microenvironments such as injured tissue or joint spaces, elevated IL-1 levels may contribute to pathologic processes, for example, proliferation and fibrosis of tissue involved in pannus formation as well as degradation of matrix and abnormal tissue architecture To investigate potential mechanisms that may lead to excessive production of IL-1, we have examined the ability of IL-1 to participate in an amplification event by inducing its own gene expression leading to synthesis of biologically active IL-1 When injected into rabbits, recombinant human IL-1-alpha induced biphasic fevers, and during the second temperature elevation 3 hr later, a circulating pyrogenic material was detected by passive transfer of plasma to other rabbits Induction of the biphasic fever was not caused by endotoxin contamination of the recombinant IL-1 The 3-hr circulating pyrogen was heat-labile and was not residual injected IL-1-alpha Chromatographic separation of this plasma and biologic assay suggested that it was new IL-1 of rabbit origin We next incubated human blood mononuclear cells with recombinant IL-1-alpha and measured the intracellular and extracellular levels of IL-1 by bioassay using the D10G41 murine T cell line In order to control for the carryover of recombinant IL-1-alpha used to stimulate the mononuclear cells (MNC), we used neutralizing antibodies that were specific for IL-1-alpha or IL-1-beta The results of these neutralizations showed that recombinant human IL-1-alpha induces the synthesis of IL-1-beta in human MNC in vitro These results were verified with a radioimmunoassay specific for IL-1-beta At concentrations of 100 ng/ml, IL-1-alpha induced prostaglandin E2 production in the MNC culture, and this was associated with decreased production of immunoreactive IL-1-beta Adding indomethacin to the cultures prevented the decreased production of IL-1-beta induced by high concentrations of IL-1-alpha Using nonadherent MNC, we observed an increase in IL-1-beta as well as IL-1-alpha mRNA after 4 hr of exposure to recombinant IL-1-alpha These results demonstrate that IL-1-alpha induces biologically active and immunoreactive IL-1-beta from MNC in vitro and that the same concentrations of IL-1-alpha induce gene expression for both forms of IL-1(ABSTRACT TRUNCATED AT 400 WORDS)

Gravitational particle creation and inflation

Abstract: Particle creation due to the changing spacetime metric at the end of an inflationary era in the early Universe is discussed. The Universe is assumed to make a transition from de Sitter space to either a radiation-dominated or matter-dominated universe. A perturbation approach is used to calculate the number density and energy density of massless, nonconformally coupled particles created by this transition. It is found that their energy density is typically of the order of ${\ensuremath{\rho}}_{v}$${\mathrm{}}^{2}$/${\ensuremath{\rho}}_{\mathrm{Pl}}$, where ${\ensuremath{\rho}}_{v}$ is the value of the cosmological constant in the de Sitter phase and ${\ensuremath{\rho}}_{\mathrm{Pl}}$ is the Planck energy density. This is approximately the energy density of a thermal bath at the Gibbons-Hawking temperature of de Sitter space. The possible applications of this effect to inflationary models is discussed. It is shown that gravitational particle creation is capable of reheating the Universe after inflation and of being the source of the matter in the Universe. This effect makes it possible to avoid the difficulty with reheating which inflationary models with weakly coupled scalar fields otherwise encounter.

Effect of gender, age, and lipid status on low density lipoprotein subfraction distribution. results from the framingham offspring study

Abstract: The presence of low molecular weight low density lipoprotein (LDL) particles in plasma has been associated with premature coronary artery disease. In this study we have examined factors affecting LDL subfraction distribution as determined by 2% to 16% polyacrylamide-agarose gradient gel electrophoresis of whole plasma in a normal, primarily middle-aged, population of adult male and female participants (n = 280, ages 25 to 75 years) in the Framingham Offspring Study. Seven major LDL bands (LDL-1 to LDL-7) were observed in different individuals, with most subjects having either one or two major bands. The presence of low molecular weight LDL (LDL-4 to LDL-7) in plasma as the predominant LDL type was significantly more common in men than in women (43.5% versus 14.8%, p less than 0.001). The presence of low molecular weight LDL was correlated (p less than 0.01) with increased age, plasma triglyceride, total cholesterol, very low density lipoprotein (VLDL) cholesterol, LDL cholesterol (in women only), and apolipoprotein (apo) B concentrations, as well as with decreased high density lipoprotein (HDL) cholesterol and apo A-I levels. Approximately 69% of the variability in LDL subfractions could be accounted for by alterations in plasma triglyceride and HDL cholesterol levels. These data are consistent with the concept that LDL subfraction distribution is influenced by gender and plasma lipoprotein levels and can be determined readily by the use of whole plasma.

Transcriptional regulation of the tyrosine hydroxylase gene by glucocorticoid and cyclic AMP.

Abstract: Glucocorticoid and cyclic AMP increase tyrosine hydroxylase (TH) activity and mRNA levels in pheochromocytoma cultures. The transcriptional activity of the TH gene, as measured by nuclear run-on assay, is also increased when cultures are treated with the synthetic glucocorticoid dexamethasone or agents that increase intracellular cyclic AMP, such as forskolin and 8-BrcAMP. Both inducers effect transcriptional changes within 10 min after treatment and are maximal after 30 min for forskolin and after 60 min for dexamethasone. The 5' flanking sequences of the TH gene were fused to the bacterial gene chloramphenicol acetyltransferase (CAT), and the hybrid gene was transfected into pheochromocytoma cultures and GH4 pituitary cells. In both cell lines, a region of the TH gene containing bases -272 to +27 conferred induction of CAT by cyclic AMP, but not by glucocorticoid. The same results were found when a region of the TH gene containing -773 to +27 was used. Thus, the sequences required for induction of TH by cyclic AMP are contained within 272 bases of 5' flanking sequence, but sequences sufficient for glucocorticoid regulation are not contained within 773 bases.

Ultraviolet radiation directly induces pigment production by cultured human melanocytes.

Abstract: In humans the major stimulus for cutaneous pigmentation is ultraviolet radiation (UVR) Little is known about the mechanism underlying this response, in part because of the complexity of interactions in whole epidermis Using a recently developed culture system, human melanocytes were exposed daily to a physiologic range of UVR doses from a solar simulator Responses were determined 24 hours after the last exposure There was a dose-related increase in melanin content per cell and uptake of 14C-DOPA, accompanied by growth inhibition Cells from donors of different racial origin gave proportionately similar increases in melanin, although there were approximately tenfold differences in basal values Light and electron microscopy revealed UVR-stimulated increases in dendricity as well as melanosome number and degree of melanization, analogous to the well-recognized melanocyte changes following sun exposure of intact skin Similar responses were seen with Cloudman S91 melanoma cells, although this murine cell line required lower UVR dosages and fewer exposures for maximal stimulation These data establish that UVR is capable of directly stimulating melanogenesis Because cyclic AMP elevation has been associated in some settings with increased pigment production by cultured melanocytes, preliminary experiments were conducted to see if the effects of UVR were mediated by cAMP Both alpha-MSH and isobutylmethylxanthine (IBMX), as positive controls, caused a fourfold increase in cAMP level in human melanocytes and/or S91 cells, but following a dose of UVR sufficient to stimulate pigment production there was no change in cAMP level up to 4 hours after exposure Thus it appears that the UVR-induced melanogenesis is mediated by cAMP-independent mechanisms

Cosmological-constant damping by unstable scalar fields.

Abstract: The damping of the effective value of the cosmological constant by an unstable scalar field is investigated. It is shown that an instability induced by coupling to spacetime curvature can cause cosmological-constant-damping behavior which reduces the present-day value of the cosmological constant to a value which is consistent with observation. It is also shown that localized distributions of matter such as stars need not be unstable in the presence of such unstable fields.

Evidence for two distinct phosphatidylinositol kinases in fibroblasts. Implications for cellular regulation.

Abstract: Phosphatidylinositol (PtdIns) kinase activities from non-transformed and polyoma-middle-T-transformed murine fibroblasts were examined. Both normal and transformed 3T3 fibroblasts have two PtdIns kinases, which can be separated by anion-exchange chromatography. One of these activities (Type I) has a Km for ATP of 10 microM, is resistant to inhibition by adenosine, AMP or ADP, and is inhibited by non-ionic detergents. The other activity (Type II) has a somewhat higher Km for ATP (35 microM) and is inhibited competitively by ADP, AMP and adenosine at concentrations suggesting regulation of this activity by the energy charge of the cell. The Type II PtdIns kinase is activated by non-ionic detergents. We have previously reported the specific association of a PtdIns kinase activity with polyoma-middle-T immunoprecipitates [Whitman, Kaplan, Schaffhausen, Cantley & Roberts (1985) Nature (London) 315, 239-242; Kaplan, Whitman, Schaffhausen, Raptis, Garcea, Pallas, Roberts & Cantley (1986) Proc. Natl. Acad. Sci. U.S.A. 83, 3624-3628]. Comparison of the immunoprecipitated PtdIns kinase with the activities identified by ion-exchange chromatography indicates that it is the Type I enzyme which specifically associates with the middle-T/pp60c-src complex. This PtdIns kinase activity is separable from both middle T and pp60c-src. Type I PtdIns kinase also associates with pp60v-src immunoprecipitates from Rous-sarcoma-virus-transformed cells. Furthermore, this PtdIns kinase appears to co-precipitate with partially purified platelet derived growth factor (PDGF) receptor. The amount of this activity found in anti-phosphotyrosine immunoprecipitates or in wheat-germ-lectin-agarose precipitates is increased 50-fold by stimulation of quiescent Balb/C 3T3 fibroblasts with PDGF. These results suggest that the Type I PtdIns kinase is regulated by agents which affect cell growth and transformation, whereas the Type II PtdIns kinase may be regulated by the local [ATP]/[ADP] ratio.

Molecular determinants of protein half-lives in eukaryotic cells.

Abstract: Multiple pathways of intracellular protein breakdown operate within cells, and the activities of different pathways can be regulated under different physiological conditions. Recent studies suggest that molecular determinants within proteins target them for different pathways of proteolysis. Proteins that are partially unfolded and have an unblocked amino-terminal amino acid with a bulky side chain appear to be good substrates for cytosolic, ubiquitin-mediated pathways of proteolysis. Certain modifications of internal residues such as oxidation of methionines also increase the susceptibility of certain proteins to ubiquitin-mediated proteolysis. Rapidly degraded normal proteins contain peptide regions rich in proline, glutamate, serine, and threonine (PEST regions). The pathway of degradation for these proteins has not been established, but they may be good substrates for calcium-activated proteases. In addition, a lysosomal pathway of protein degradation is activated when serum is withdrawn from cultured cells and is selective for cytosolic proteins containing peptide regions similar to Lys-Phe-Glu-Arg-Gln (KFERQ). This short review summarizes our current understanding of mechanisms of protein breakdown in eukaryotes and evaluates potential molecular determinants of protein half-lives.

Murine monoclonal anti-DNA antibodies bind directly to glomerular antigens and form immune deposits.

Abstract: The capacity of monoclonal anti-DNA antibodies, derived spontaneously from MRL-lpr/lpr mice, to bind directly to intrinsic glomerular antigens and form immune deposits was evaluated. Two antibodies, H130 (IgM-kappa) and H241 (IgG2a-kappa), bound to normal glomeruli in vitro. This binding was not inhibited by DNAase, but it was, in the case of H130, inhibited by the anti-idiotype anti-H130. Both antibodies also bound to glomerular digests on nitrocellulose. After i.v. injection, however, H241 bound to glomeruli and formed glomerular immune deposits, whereas H130 did not. Similarly, after i.p. injection of H241 hybridomas to normal mice, all mice developed glomerular immune deposits. In contrast, administration of H130 hybridomas, other anti-DNA-producing hybridomas, and other unrelated hybridomas did not lead to glomerular immune deposit formation. We conclude that certain lupus auto-antibodies can form glomerular immune deposits by binding directly to non-DNA antigenic structures that are normally present in extracellular locations within normal glomeruli.

Relationship of human variable region heavy chain germ-line genes to genes encoding anti-DNA autoantibodies.

Abstract: In order to identify the V region genes encoding systemic lupus erythematosus (SLE)-derived anti-DNA autoantibodies, we have determined the nucleotide sequence of heavy chain mRNA from several DNA-binding immunoglobulins secreted by human hybridomas. We used the technique of cDNA primer extension for determining sequences of the VH, D, and JH gene segments of anti-DNA autoantibodies from three different primary hybridoma growths from an SLE patient and one hybridoma from a leprosy patient. Immunoglobulins from two of the SLE hybridomas expressed the same idiotype, Id-16/6, which is also expressed on immunoglobulins in sera of patients with active SLE. Their mRNA sequences showed complete homology to each other in the V, D, and J genes and more than 99% homology to the VH26 germ-line gene sequence, a member of the human VHIII gene family. The VH mRNA sequence of the third SLE hybridoma, 21/28, which was idiotypically unrelated to the other two, was 93% homologous to a different VH germ-line gene sequence, HA2, a member of the human VHI gene family. The fourth anti-DNA-producing hybridoma, 8E10, was derived from a leprosy patient of different ethnic origin than the SLE patient. It was idiotypically related to 21/28 and expressed a VH segment gene identical to that of 21/28. Hybridomas 21/28 and 8E10 shared sequence homology with the VH26 anti-DNA antibodies in the first complementarity-determining region. In addition, 21/28 shared sequence homology with the Id-16/6+ group in the region encoded by the D and J gene segments. Our findings indicate that some SLE autoantibodies are encoded by unmodified or scarcely modified VH germ-line genes that are conserved in the human population and identify two distinct VH germ-line genes that can encode segments of anti-DNA immunoglobulins.

Genomic organization and deduced amino acid sequence of a putative sodium channel gene in Drosophila.

Abstract: The deduced amino acid sequence of a Drosophila gene isolated with a vertebrate sodium channel complementary DNA probe revealed an organization virtually identical to the vertebrate sodium channel protein; four homologous domains containing all putative membrane-spanning regions are repeated in tandem with connecting linkers of various sizes. All areas of the protein presumed to be critical for channel function show high evolutionary conservation. These include those proposed to function in voltage-sensitive gating, inactivation, and ion selectivity. All 24 putative gating charges of the vertebrate protein are in identical positions in the Drosophila gene. Ten introns interrupt the coding regions of the four homology units; introns with positions conserved among homology units bracket a region hypothesized to be the selectivity filter for the channel. The Drosophila gene maps to the right arm of the second chromosome in region 60D-E. This position does not coincide with any known mutations that confer behavioral phenotypes, but is close to the seizure locus (60A-B), which has been hypothesized to code for a voltage-sensitive sodium channel.

Induction of a cationic shift in IgG anti-DNA autoantibodies. Role of T helper cells with classical and novel phenotypes in three murine models of lupus nephritis.

Abstract: We investigated the underlying mechanisms of systemic autoimmune disease in MRL-+/+, (NZB X NZW)F1, and (NZB X SWR)F1 mice, since these strains develop glomerulonephritis without the superimposition of any secondary lupus-accelerating genes. All three strains manifested a common immunoregulatory defect specific for the production of pathogenic anti-DNA autoantibodies that are of IgG class and cationic in charge. At or just before the age they began to develop lupus nephritis, spleen cells of the mice contained a subpopulation of Th cells that selectively induced their B cells in vitro to produce highly cationic IgG autoantibodies to both single-stranded DNA (ssDNA) and double-stranded DNA (dsDNA). By contrast, T cells from younger preautoimmune mice were incapable of providing this help. Moreover, only B cells of the older lupus mice could be induced to secrete cationic anti-DNA antibodies of IgG class. B cells of young lupus mice could not produce the cationic autoantibodies even with the help of T cells from the older mice, nor upon stimulation with mitogens. In the older lupus mice we found two sets of Th cells that spontaneously induced the cationic shift in autoantibodies; one set belonged to the classical Th category with L3T4+,Lyt-2- phenotype, whereas the other surprisingly belonged to a double-negative (L3T4-,Lyt-2-), Lyt-1+ subpopulation. The latter set of unusual Th cells were unexpected in these lupus mice since they lacked the lpr (lympho-proliferation) gene. Thus three apparently different murine models of systemic lupus erythematosus possess a common underlying mechanism specific for the spontaneous production of pathogenic anti-DNA autoantibodies.

Lectin histochemistry of mammalian endothelium.

Abstract: Lectin-histochemical studies were performed on formalin-fixed, paraffin-embedded tissues from ten mammalian species to demonstrate the pattern of carbohydrate residues in vascular endothelium. Ten different biotinylated lectins were used as probes and avidin-biotin-peroxidase complex (ABC) was used as visualant. Ricinus communis agglutinin-I (RCA-I) and wheat germ agglutinin (WGA) stained vascular endothelium in all species. Peanut agglutinin (PNA) stained vascular endothelium in all species only after preincubation with neuraminidase. Bandeirea simplicifolia agglutinin-I (BS-I) stained vascular endothelium in all species but human, while Ulex europeus agglutinin-I (UEA-I) stained only human endothelium. Individual differences in staining of human vascular endothelium were noted with BS-I and succinylated-WGA (SWGA). Similarly, individual differences in staining of animal vascular endothelium were noted with soybean agglutinin (SBA) after preincubation with neuraminidase. Finally, Concanavalia ensiformis agglutinin (Con A), Dolichos biflorus agglutinin (DBA) and Lens culinaris agglutinin (LCA) did not stain vascular endothelium in any of the species studied.

C5a induction of human interleukin 1. Synergistic effect with endotoxin or interferon-gamma.

Abstract: Interleukin-1 (IL-1) is a potent cytokine which possesses the ability to mediate systemic acute phase responses as well as local tissue inflammation. In these studies, we have examined the ability of C5a and C5a des Arg to induce IL-1 production in vitro. Human C5a and C5a des Arg were purified to homogeneity and were found to stimulate IL-1 release from freshly obtained human mononuclear cells into the extracellular medium. Only 2 hr of exposure to the purified complement components were necessary in order to stimulate IL-1 production. The minimal concentration of C5a required was 25 ng/ml, whereas 125 ng/ml of C5a des Arg induced comparable amounts of IL-1. This dose relationship was maintained at higher concentrations (150 ng/ml vs 750 ng/ml, respectively). That the effect was due to the anaphylatoxins themselves, and not endotoxin contamination, was shown by negative Limulus amebocyte lysate tests and employing preincubation of C5a/C5a des Arg with polymyxin B. The latter blocked a wide dose range of endotoxin-stimulated IL-1 production. However, when endotoxin was added to C5a or C5a des Arg, significant synergism in the stimulation of IL-1 production was observed, occurring at various concentrations of either agent. A similar synergism with C5a/C5a des Arg was seen with interferon-gamma. In these studies, IL-1 production was measured by bioassay employing cloned D . 10 . G4 . 1 murine T cells and by radioimmunoassay for human IL-1 beta; using C5a/C5a des Arg as stimulants, there was a high degree of correlation (r = 0.82) between the two assays. Since traumatic, infectious, and inflammatory diseases may result in the simultaneous appearance of these stimuli, the synergism described herein is likely to be clinically relevant.

Hyaluronate inhibition of cell proliferation.

Abstract: The proliferation of rabbit synovial cells, 3T3 cells, or simian virus-transformed 3T3 cells in cell culture was inhibited by the addition of hyaluronate to the culture medium. This effect was markedly dependent on the molecular weight and concentration of the hyaluronate. At the molecular weight and concentration of hyaluronate present in normal synovial fluid, proliferation was inhibited. At lower molecular weights or concentrations, as found in rheumatoid synovial fluid, hyaluronate was significantly less inhibitory. Thus, the changes in synovial fluid hyaluronate that are associated with arthropathies may contribute to a favorable environment for rheumatoid pannus expansion.