Showing papers in "Nature in 1988"
TL;DR: Back-propagation repeatedly adjusts the weights of the connections in the network so as to minimize a measure of the difference between the actual output vector of the net and the desired output vector, which helps to represent important features of the task domain.
Abstract: We describe a new learning procedure, back-propagation, for networks of neurone-like units. The procedure repeatedly adjusts the weights of the connections in the network so as to minimize a measure of the difference between the actual output vector of the net and the desired output vector. As a result of the weight adjustments, internal ‘hidden’ units which are not part of the input or output come to represent important features of the task domain, and the regularities in the task are captured by the interactions of these units. The ability to create useful new features distinguishes back-propagation from earlier, simpler methods such as the perceptron-convergence procedure1.
23,814 citations
TL;DR: Cloning and sequencing of preproendothelin complementary DNA shows that mature endothelin is generated through an unusual proteolytic processing, and regional homologies to a group of neurotoxins suggest that endothelins is an endogenous modulator of voltage-dependent ion channels.
Abstract: An endothelium-derived 21-residue vasoconstrictor peptide, endothelin, has been isolated, and shown to be one of the most potent vasoconstrictors known. Cloning and sequencing of preproendothelin complementary DNA shows that mature endothelin is generated through an unusual proteolytic processing, and regional homologies to a group of neurotoxins suggest that endothelin is an endogenous modulator of voltage-dependent ion channels. Expression of the endothelin gene is regulated by several vasoactive agents, indicating the existence of a novel cardiovascular control system.
10,651 citations
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TL;DR: In this paper, a sedimentological core and petrographic characterisation of samples from eleven boreholes from the Lower Carboniferous of Bowland Basin (Northwest England) is presented.
Abstract: Deposits of clastic carbonate-dominated (calciclastic) sedimentary slope systems in the rock record have been identified mostly as linearly-consistent carbonate apron deposits, even though most ancient clastic carbonate slope deposits fit the submarine fan systems better. Calciclastic submarine fans are consequently rarely described and are poorly understood. Subsequently, very little is known especially in mud-dominated calciclastic submarine fan systems. Presented in this study are a sedimentological core and petrographic characterisation of samples from eleven boreholes from the Lower Carboniferous of Bowland Basin (Northwest England) that reveals a >250 m thick calciturbidite complex deposited in a calciclastic submarine fan setting. Seven facies are recognised from core and thin section characterisation and are grouped into three carbonate turbidite sequences. They include: 1) Calciturbidites, comprising mostly of highto low-density, wavy-laminated bioclast-rich facies; 2) low-density densite mudstones which are characterised by planar laminated and unlaminated muddominated facies; and 3) Calcidebrites which are muddy or hyper-concentrated debrisflow deposits occurring as poorly-sorted, chaotic, mud-supported floatstones. These
9,929 citations
TL;DR: It is demonstrated that NO can be synthesized from L-arginine by porcine aortic endothelial cells in culture and the strict substrate specificity of this reaction suggests that L- arginine is the precursor for NO synthesis in vascular endothelium cells.
Abstract: Nitric oxide (NO) released by vascular endothelial cells accounts for the relaxation of strips of vascular tissue1 and for the inhibition of platelet aggregation2 and platelet adhesion3 attributed to endothelium-derived relaxing factor4. We now demonstrate that NO can be synthesized from L-arginine by porcine aortic endothelial cells in culture. Nitric oxide was detected by bioassay5, chemiluminescence1 or by mass spectrometry. Release of NO from the endothelial cells induced by bradykinin and the calcium ionophore A23187 was reversibly enhanced by infusions of L-arginine and L-citrulline, but not D-arginine or other close structural analogues. Mass spectrometry studies using 15N-labelled L-arginine indicated that this enhancement was due to the formation of NO from the terminal guanidino nitrogen atom(s) of L-arginine. The strict substrate specificity of this reaction suggests that L-arginine is the precursor for NO synthesis in vascular endothelial cells.
4,803 citations
TL;DR: Protein kinase C is now known to be a large family of proteins, with multiple subspecies that have subtle individual enzymological characteristics, and probably have distinct functions in the processing and modulation of a variety of physiological and pathological responses to external signals.
Abstract: Protein kinase C is now known to be a large family of proteins, with multiple subspecies that have subtle individual enzymological characteristics. Some members of the family exhibit distinct patterns of tissue expression and intracellular localization; different kinases probably have distinct functions in the processing and modulation of a variety of physiological and pathological responses to external signals.
4,107 citations
TL;DR: Calculated loading rates of trace metals into the three environmental compartments demonstrate that human activities now have major impacts on the global and regional cycles of most of the trace elements.
Abstract: Calculated loading rates of trace metals into the three environmental compartments demonstrate that human activities now have major impacts on the global and regional cycles of most of the trace elements. There is significant contamination of freshwater resources and an accelerating accumulation of toxic metals in the human food chain.
4,097 citations
TL;DR: Results argue that bcl-2 provided a distinct survival signal to the cell and may contribute to neoplasia by allowing a clone to persist until other oncogenes, such as c-myc, become activated.
Abstract: A common feature of follicular lymphoma, the most prevalent haematological malignancy in humans, is a chromosome translocation (t(14;18] that has coupled the immunoglobulin heavy chain locus to a chromosome 18 gene denoted bcl-2. By analogy with the translocated c-myc oncogene in other B-lymphoid tumours bcl-2 is a candidate oncogene, but no biological effects of bcl-2 have yet been reported. To test whether bcl-2 influences the growth of haematopoietic cells, either alone or together with a deregulated c-myc gene, we have introduced a human bcl-2 complementary DNA using a retroviral vector into bone marrow cells from either normal or E mu-myc transgenic mice, in which B-lineage cells constitutively express the c-myc gene. Bcl-2 cooperated with c-myc to promote proliferation of B-cell precursors, some of which became tumorigenic. To determine how bcl-2 expression impinges on growth factor requirements, the gene was introduced into a lymphoid and a myeloid cell line that require interleukin 3 (IL-3). In the absence of IL-3, bcl-2 promoted the survival of the infected cells but they persisted in a G0 state, rather than proliferating. These results argue that bcl-2 provided a distinct survival signal to the cell and may contribute to neoplasia by allowing a clone to persist until other oncogenes, such as c-myc, become activated.
3,238 citations
TL;DR: A human IgGI antibody has been reshaped for serotherapy in humans by introducing the six hypervariable regions from the heavy- and light-chain variable domains of a rat antibody directed against human lymphocytes.
Abstract: A human IgGI antibody has been reshaped for serotherapy in humans by introducing the six hypervariable regions from the heavy- and light-chain variable domains of a rat antibody directed against human lymphocytes. The reshaped human antibody is as effective as the rat antibody in complement and is more effective in cell-mediated lysis of human lymphocytes.
3,167 citations
TL;DR: This view of T-cell recognition has implications for how the receptors might be selected in the thymus and how they (and immunoglobulins) may have arisen during evolution.
Abstract: The four distinct T-cell antigen receptor polypeptides (alpha, beta, gamma, delta) form two different heterodimers (alpha:beta and gamma:delta) that are very similar to immunoglobulins in primary sequence, gene organization and modes of rearrangement. Whereas antibodies have both soluble and membrane forms that can bind to antigens alone, T-cell receptors exist only on cell surfaces and recognize antigen fragments only when they are embedded in major histocompatibility complex (MHC) molecules. Patterns of diversity in T-cell receptor genes together with structural features of immunoglobulin and MHC molecules suggest a model for how this recognition might occur. This view of T-cell recognition has implications for how the receptors might be selected in the thymus and how they (and immunoglobulins) may have arisen during evolution.
2,858 citations
TL;DR: It is reported here that by acting on NMDA (N-methyl-D-aspartate) receptors on cerebellar cells, glutamate induces the release of a diffusible messenger with strikingly similar properties to EDRF that accounts for the cGMP responses that take place following NMDA receptor activation.
Abstract: In the vascular system, endothelium-derived relaxing factor (EDRF) is the name of the local hormone released from endothelial cells in response to vasodilators such as acetylcholine, bradykinin and histamine. It diffuses into underlying smooth muscle where it causes relaxation by activating guanylate cyclase, so producing a rise in cyclic GMP levels. It has been known for many years that in the central nervous system (CNS) the excitatory neurotransmitter glutamate can elicit large increases in cGMP levels, particularly in the cerebellum where the turnover rate of cGMP is low. Recent evidence indicates that cell-cell interactions are involved in this response. We report here that by acting on NMDA (N-methyl-D-aspartate) receptors on cerebellar cells, glutamate induces the release of a diffusible messenger with strikingly similar properties to EDRF. This messenger is released in a Ca2+-dependent manner and its activity accounts for the cGMP responses that take place following NMDA receptor activation. In the CNS, EDRF may link activation of postsynaptic NMDA receptors to functional modifications in neighbouring presynaptic terminals and glial cells.
2,581 citations
TL;DR: The use of positron emission tomography to measure regional changes in average blood flow during processing of individual auditory and visual words provides support for multiple, parallel routes between localized sensory-specific, phonological, articulatory and semantic-coding areas.
Abstract: The use of positron emission tomography to measure regional changes in average blood flow during processing of individual auditory and visual words provides support for multiple, parallel routes between localized sensory-specific, phonological, articulatory and semantic-coding areas.
TL;DR: In this paper, a recombinant myeloid leukaemia inhibitory factor (LIF) was used to replace DIA in the maintenance of totipotent ES cell lines that retain the potential to form chimaeric mice.
Abstract: Embryonic stem (ES) cells, the totipotent outgrowths of blastocysts, can be cultured and manipulated in vitro and then returned to the embryonic environment where they develop normally and can contribute to all cell lineages. Maintenance of the stem-cell phenotype in vitro requires the presence of a feeder layer of fibroblasts or of a soluble factor, differentiation inhibitory activity (DIA) produced by a number of sources; in the absence of DIA the ES cells differentiate into a wide variety of cell types. We recently noted several similarities between partially purified DIA and a haemopoietic regulator, myeloid leukaemia inhibitory factor (LIF), a molecule which induces differentiation in M1 myeloid leukaemic cells and which we have recently purified, cloned and characterized. We demonstrate here that purified, recombinant LIF can substitute for DIA in the maintenance of totipotent ES cell lines that retain the potential to form chimaeric mice.
TL;DR: DIA and human interleukin DA/leukaemia inhibitory factor have been identified as related multifunctional regulatory factors with distinct biological activities in both early embryonic and haemopoetic stem cell systems.
Abstract: Murine embryonic stem (ES) cells are pluripotent cell lines established directly from the early embryo which can contribute differentiated progeny to all adult tissues, including the germ-cell lineage, after re-incorporation into the normal embryo. They provide both a cellular vector for the generation of transgenic animals and a useful system for the identification of polypeptide factors controlling differentiation processes in early development. In particular, medium conditioned by Buffalo rat liver cells contains a polypeptide factor, ES cell differentiation inhibitory activity (DIA), which specifically suppresses the spontaneous differentiation of ES cells in vitro, thereby permitting their growth as homogeneous stem cell populations in the absence of heterologous feeder cells. ES cell pluripotentiality, including the ability to give rise to functional gametes, is preserved after prolonged culture in Buffalo rat liver media as a source of DIA. Here, we report that purified DIA is related in structure and function to the recently identified hematopoietic regulatory factors human interleukin for DA cells and leukaemia inhibitory factor. DIA and human interleukin DA/leukaemia inhibitory factor have thus been identified as related multifunctional regulatory factors with distinct biological activities in both early embryonic and hematopoietic stem cell systems.
TL;DR: In this article, the authors reported that the addition of nmol amounts of dissolved iron resulted in the nearly complete utilization of excess NO3, whereas in the controls, without added Fe, only 25% of the available NO3 was used.
Abstract: An interesting oceanographic problem concerns the excess major plant nutrients (PO4, NO3, SiO3) occurring in offshore surface waters of the Antarctic1–3 and north-east Pacific subarctic Oceans4 In a previous study5, we presented indirect evidence suggesting that inadequate Fe input was responsible for this limitation of growth; recently we had the opportunity to seek direct evidence for this hypothesis in the north-east Pacific subarctic We report here that the addition of nmol amounts of dissolved iron resulted in the nearly complete utilization of excess NO3, whereas in the controls—without added Fe—only 25% of the available NO3 was used We also observed that the amounts of chlorophyll in the phytoplankton increased in proportion to the Fe added We conclude that Fe deficiency is limiting phytoplankton growth in these major-nutrient-rich waters
TL;DR: A novel mechanism of initiation on poliovirus RNA occurs by binding of ribosomes to an internal sequence within the 5′ noncoding region, which may explain the disparate translation of several other eukaryotic messenger RNAs.
Abstract: Poliovirus RNA is naturally uncapped, therefore its translation must proceed via a cap-independent mechanism. Translation initiation on poliovirus RNA occurs by binding of ribosomes to an internal sequence within the 5' noncoding region. This novel mechanism of initiation may explain the disparate translation of several other eukaryotic messenger RNAs.
TL;DR: Examination of the pattern of nucleotide substitution between polymorphic alleles in the region of the antigen recognition site (ARS) indicates that in ARS the rate of nonsynonymous substitution is significantly higher than that of synonymous substitution in both humans and mice, whereas in other regions the reverse is true.
Abstract: The major histocompatibility complex (MHC) loci are known to be highly polymorphic in humans, mice and certain other mammals, with heterozygosity as high as 80-90% (ref. 1). Four different hypotheses have been proposed to explain this high degree of polymorphism: (1) a high mutation rate, (2) gene conversion or interlocus genetic exchange, (3) over dominant selection and (4) frequency-dependent selection. In an attempt to establish which of these hypotheses is correct, we examined the pattern of nucleotide substitution between polymorphic alleles in the region of the antigen recognition site (ARS) and other regions of human and mouse class I MHC genes. The results indicate that in ARS the rate of nonsynonymous (amino acid altering) substitution is significantly higher than that of synonymous substitution in both humans and mice, whereas in other regions the reverse is true. This observation, together with a theoretical study and other considerations, supports the hypothesis of overdominant selection (heterozygote advantage).
TL;DR: The brain natriuretic peptide (BNP) as mentioned in this paper was identified in porcine brain of a novel peptide of 26 amino acid residues, eliciting a pharmacological spectrum very similar to that of ANP.
Abstract: Atrial natriuretic peptide (ANP), a hormone secreted from mammalian atria, regulates the homoeostatic balance of body fluid and blood pressure. ANP-like immunoreactivity is also present in the brain, suggesting that the peptide functions as a neuropeptide. We report here identification in porcine brain of a novel peptide of 26 amino-acid residues, eliciting a pharmacological spectrum very similar to that of ANP, such as natriuretic-diuretic, hypotensive and chick rectum relaxant activities. The complete amino-acid sequence determined for the peptide is remarkably similar to but definitely distinct from the known sequence of ANP, indicating that the genes for the two are distinct. Thus, we have designated the peptide 'brain natriuretic peptide' (BNP). The occurrence of BNP with ANP in mammalian brain suggests the possibility that the physiological functions so far thought to be mediated by ANP may be regulated through a dual mechanism involving both ANP and BNP.
TL;DR: A positive and negative selection procedure is described that enriches 2,000-fold for those cells that contain a targeted mutation in mouse embryo-derived stem cells.
Abstract: Gene targeting—homologous recombination of DNA sequences residing in the chromosome with newly introduced DNA sequences—in mouse embryo-derived stem cells promises to provide a means to generate mice of any desired genotype. We describe a positive and negative selection procedure that enriches 2,000-fold for those cells that contain a targeted mutation. The procedure was applied to the isolation of hprt− and int-2− mutants, but it should be applicable to any gene
TL;DR: Observations demonstrate that mtDNA heteroplasmy can occur in man and that human disease may be associated with defects of the mitochondrial genome.
Abstract: In vitro studies of muscle mitochondrial metabolism in patients with mitochondrial myopathy have identified a variety of functional defects of the mitochondrial respiratory chain, predominantly affecting complex I (NADH-CoQ reductase) or complex III (ubiquinol-cytochrome c reductase) in adult cases. These two enzymes consist of approximately 36 subunits, eight of which are encoded by mitochondrial DNA (mtDNA). The increased incidence of maternal, as opposed to paternal, transmission in familial mitochondrial myopathy suggests that these disorders may be caused by mutations of mtDNA. Multiple restriction endonuclease analysis of leukocyte mtDNA from patients with the disease, and their relatives, showed no differences in cleavage patterns between affected and unaffected individuals in any single maternal line. When muscle mtDNA was studied, nine of 25 patients were found to have two populations of muscle mtDNA, one of which had deletions of up to 7 kilobases in length. These observations demonstrate that mtDNA heteroplasmy can occur in man and that human disease may be associated with defects of the mitochondrial genome.
TL;DR: A specific protein, bound to DNA, can activate transcription of a wide array of genes in many eukaryotes and is controlled by the immune system.
Abstract: A specific protein, bound to DNA, can activate transcription of a wide array of genes in many eukaryotes. Further analysis suggests a general outline for how eukaryotic transcriptional activators function and are controlled.
TL;DR: It is reported that myeloma cells freshly isolated from patients produce BSF-2 and express its receptors, direct evidence that an autocrine loop is operating in oncogenesis of human myelomas.
Abstract: Human B cell stimulatory factor 2 (BSF-2) was originally characterized and isolated as a T cell-derived factor that caused the terminal maturation of activated B cells to immunoglobulin-producing cells. Molecular cloning of the complementary DNA predicts that BSF-2 is a protein of relative molecular mass (Mr) 26,000 similar or identical to interferon beta 2, hybridoma plasmacytoma growth factor and hepatocyte stimulating factor. IL-6 has been proposed as a name for this molecule. It is now known that BSF-2 has a wide variety of biological functions and that its target cells are not restricted to normal B cells. Responses are also seen in T cells, plasmacytomas, hepatocytes, haematopoietic stem cells, fibroblasts and rat phoeochromocytoma, PC12 (Satoh, T. et al., manuscript in preparation). Of particular interest to this report is that human BSF-2 is a potent growth factor for murine plasmacytomas and hybridomas. This observation suggested to us that constitutive expression of BSF-2 or its receptor could be responsible for the generation of human myelomas. In this study we report that myeloma cells freshly isolated from patients produce BSF-2 and express its receptors. Moreover, anti-BSF-2 antibody inhibits the in vitro growth of myeloma cells. This is direct evidence that an autocrine loop is operating in oncogenesis of human myelomas.
TL;DR: The mechanism of self-tolerance is studied in T-cell-receptor transgenic mice expressing a receptor in many of their T cells for the male (H–Y) antigen in the context of class I H–2Db MHC antigens.
Abstract: The mechanism of self-tolerance is studied in T-cell-receptor transgenic mice expressing a receptor in many of their T cells for the male (H-Y) antigen in the context of class I H-2Db MHC antigens. Autospecific T cells are deleted in male mice. The deletion affects only transgene-expressing cells with a relatively high surface-density of CD8 molecules, including nonmature CD4+ CD8+ thymocytes, and is not caused by anti-idiotype cells.
TL;DR: It is speculated that this self-recognition of guanine-rich motifs of DNA serves to bring together, and to zipper up in register, the four homologous chromatids during meiosis.
Abstract: We have discovered that single-stranded DNA containing short guanine-rich motifs will self-associate at physiological salt concentrations to make four-stranded structures in which the strands run in parallel fashion. We believe these complexes are held together by guanines bonded to each other by Hoogsteen pairing. Such guanine-rich sequences occur in immunoglobulin switch regions, in gene promoters, and in chromosomal telomeres. We speculate that this self-recognition of guanine-rich motifs of DNA serves to bring together, and to zipper up in register, the four homologous chromatids during meiosis.
TL;DR: The first use of a complete RFLP linkage map to resolve quantitative traits into discrete Mendelian factors, in an interspecific back-cross of tomato is reported, broadly applicable to the genetic dissection of quantitative inheritance of physiological, morphological and behavioural traits in any higher plant or animal.
Abstract: The conflict between the Mendelian theory of particulate inheritance and the observation of continuous variation for most traits in nature was resolved in the early 1900s by the concept that quantitative traits can result from segregation of multiple genes, modified by environmental effects. Although pioneering experiments showed that linkage could occasionally be detected to such quantitative trait loci (QTLs), accurate and systematic mapping of QTLs has not been possible because the inheritance of an entire genome could not be studied with genetic markers. The use of restriction fragment length polymorphisms (RFLPs) has made such investigations possible, at least in principle. Here, we report the first use of a complete RFLP linkage map to resolve quantitative traits into discrete Mendelian factors, in an interspecific back-cross of tomato. Applying new analytical methods, we mapped at least six QTLs controlling fruit mass, four QTLs for the concentration of soluble solids and five QTLs for fruit pH. This approach is broadly applicable to the genetic dissection of quantitative inheritance of physiological, morphological and behavioural traits in any higher plant or animal.
TL;DR: In this paper, it was shown that stars in galactic nuclei can be captured or tidally disrupted by a central black hole, and the remainder would be swallowed by the hole, causing a bright flare lasting at most a few years.
Abstract: Stars in galactic nuclei can be captured or tidally disrupted by a central black hole. Some debris would be ejected at high speed', the remainder would be swallowed by the hole, causing a bright flare lasting at most a few years. Such phenomena are compatible with the presence of 106–108 M⊙ holes in the nuclei of many nearby galaxies. Stellar disruption may have interesting consequences in our own Galactic Centre if a ∼106 M⊙ hole lurks there.
TL;DR: The interaction between E1A and the retinoblastoma gene product is the first demonstration of a physical link between an oncogene and an anti-oncogene.
Abstract: One of the cellular targets implicated in the process of transformation by the adenovirus E1A proteins is a 105K cellular protein. Previously, this protein had been shown to form stable protein/protein complexes with the E1A polypeptides but its identity was unknown. Here, we demonstrate that it is the product of the retinoblastoma gene. The interaction between E1A and the retinoblastoma gene product is the first demonstration of a physical link between an oncogene and an anti-oncogene.
TL;DR: Findings indicate that self tolerance may result from mechanisms other than clonal deletion, and are consistent with the hypothesis that IgD may have a unique role in B-cell tolerance.
Abstract: Immunological tolerance has been demonstrated in double-transgenic mice expressing the genes for a neo-self antigen, hen egg lysozyme, and a high affinity anti-lysozyme antibody. The majority of anti-lysozyme B-cells did not undergo clonal deletion, but were no longer able to secrete anti-lysozyme antibody and displayed markedly reduced levels of surface IgM while continuing to express high levels of surface IgD. These findings indicate that self tolerance may result from mechanisms other than clonal deletion, and are consistent with the hypothesis that IgD may have a unique role in B-cell tolerance.
TL;DR: Depletion of a subset of 7OK stress proteins in yeast mutants shows that they are involved in the post-translational import of precursor polypeptides into both mitochondria and the lumen of the endoplasmic reticulum.
Abstract: Depletion of a subset of 7OK stress proteins in yeast mutants shows that they are involved in the post-translational import of precursor polypeptides into both mitochondria and the lumen of the endoplasmic reticulum. The identification of such a basic function may explain the remarkable evolutionary conservation of the gene family encoding these proteins.
TL;DR: In vitro mutagenesis of sequences required for the self-catalysed cleavage of a plant virus satellite RNA has allowed definition of an RNA segment with endoribonuclease activity.
Abstract: In vitro mutagenesis of sequences required for the self-catalysed cleavage of a plant virus satellite RNA has allowed definition of an RNA segment with endoribonuclease activity. General rules have been deduced for the design of new RNA enzymes capable of highly specific RNA cleavage, and have been successfully tested against a new target sequence.
TL;DR: Changes in the pattern of polypeptides synthesized during the pre-implantation stages of human development are described, and it is demonstrated that some of the major qualitative changes which occur between the four- and eight-cell stages are dependent on transcription.
Abstract: The earliest stages of development in most animals, including the few mammalian species that have been investigated, are regulated by maternally inherited information. Dependence on expression of the embryonic genome cannot be detected until the mid two-cell stage in the mouse, the four-cell stage in the pig (J. Osborn & C. Polge, personal communication), and the eight-cell stage in the sheep. Information about the timing of activation of the embryonic genome in the human is of relevance not only to the therapeutic practice of in vitro fertilization and embryo transfer (IVF), but more importantly for the successful development of techniques for the preimplantation diagnosis of certain inherited genetic diseases. We describe here changes in the pattern of polypeptides synthesized during the pre-implantation stages of human development, and demonstrate that some of the major qualitative changes which occur between the four- and eight-cell stages are dependent on transcription. In addition, it appears that cleavage is not sensitive to transcriptional inhibition until after the four-cell stage.