Showing papers in "Nature in 1980"
TL;DR: It is demonstrated that relaxation of isolated preparations of rabbit thoracic aorta and other blood vessels by ACh requires the presence of endothelial cells, and that ACh, acting on muscarinic receptors of these cells, stimulates release of a substance(s) that causes relaxation of the vascular smooth muscle.
Abstract: Despite its very potent vasodilating action in vivo, acetylcholine (ACh) does not always produce relaxation of isolated preparations of blood vessels in vitro. For example, in the helical strip of the rabbit descending thoracic aorta, the only reported response to ACh has been graded contractions, occurring at concentrations above 0.1 muM and mediated by muscarinic receptors. Recently, we observed that in a ring preparation from the rabbit thoracic aorta, ACh produced marked relaxation at concentrations lower than those required to produce contraction (confirming an earlier report by Jelliffe). In investigating this apparent discrepancy, we discovered that the loss of relaxation of ACh in the case of the strip was the result of unintentional rubbing of its intimal surface against foreign surfaces during its preparation. If care was taken to avoid rubbing of the intimal surface during preparation, the tissue, whether ring, transverse strip or helical strip, always exhibited relaxation to ACh, and the possibility was considered that rubbing of the intimal surface had removed endothelial cells. We demonstrate here that relaxation of isolated preparations of rabbit thoracic aorta and other blood vessels by ACh requires the presence of endothelial cells, and that ACh, acting on muscarinic receptors of these cells, stimulates release of a substance(s) that causes relaxation of the vascular smooth muscle. We propose that this may be one of the principal mechanisms for ACh-induced vasodilation in vivo. Preliminary reports on some aspects of the work have been reported elsewhere.
11,871 citations
TL;DR: It is shown here that this morphological change is closely associated with excision of nucleosome chains from nuclear chromatin, apparently through activation of an intracellular, but non-lysosomal, endonuclease.
Abstract: In near-physiological concentrations, glucocorticoid hormones cause the death of several types of normal and neoplastic lymphoid cell, but the mechanisms involved are unknown. One of the earliest structural changes in the dying cell is widespread chromatin condensation, of the type characteristic of apoptosis, the mode of death frequently observed where cell deletion seems to be 'programmed'. It is shown here that this morphological change is closely associated with excision of nucleosome chains from nuclear chromatin, apparently through activation of an intracellular, but non-lysosomal, endonuclease.
4,605 citations
TL;DR: The phenotypes of the mutant embryos indicate that the process of segmentation involves at least three levels of spatial organization: the entire egg as developmental unit, a repeat unit with the length of two segments, and the individual segment.
Abstract: In systematic searches for embryonic lethal mutants of Drosophila melanogaster we have identified 15 loci which when mutated alter the segmental pattern of the larva. These loci probably represent the majority of such genes in Drosophila. The phenotypes of the mutant embryos indicate that the process of segmentation involves at least three levels of spatial organization: the entire egg as developmental unit, a repeat unit with the length of two segments, and the individual segment.
4,170 citations
TL;DR: The chemokinetic and aggregating activities released from rat and human PMNs exposed to ionophore A23187 are not due to the release of mono-HETEs but to that of 5,12-di- HETE (leukotriene B), which is active over the concentration range 10 pg ml−1 to 5 ng ml-1.
Abstract: Arachidonic acid is metabolised either by cyclooxygenases to produce prostaglandins and thromboxanes or by lipoxygenases to produce mono-, di- and trihydroxyeicosatetraenoic acids (HETEs). Polymorphonuclear leukocytes (PMNs) release HETEs, including mono- and dihydroxy fatty acids, when exposed to stimuli such as the calcium ionophore A23187 (refs 1, 2). The mono-HETEs are assumed to be of particular importance with respect to effects on leukocyte function because they have been shown to possess both chemotactic and chemokinetic activities towards PMNs and eosinophils. However, we have now shown that the chemokinetic and aggregating activities released from rat and human PMNs exposed to ionophore A23187 (ref. 5) are not due to the release of mono-HETEs but to that of 5, 12-di-HETE (leukotriene B). This compound is active over the concentration range 10 pg ml-1 to 5 ng ml-1.
2,010 citations
TL;DR: The DNA of higher organisms usually falls into two classes, one specific and the other comparatively nonspecific, and it seems plausible that most of the latter originated by the spreading of sequences which had little or no effect on the phenotype.
Abstract: The DNA of higher organisms usually falls into two classes, one specific and the other comparatively nonspecific. It seems plausible that most of the latter originates by the spreading of sequences which had little or no effect on the phenotype. We examine this idea from the point of view of the natural selection of preferred replicators within the genome.
1,927 citations
TL;DR: Five chemically distinct classes of intermediate filaments can be identified within higher eukaryotic cells and may function to integrate mechanically the various structures of the cytoplasmic space in a way that is tailored to the differentiated state of the cell.
Abstract: Five chemically distinct classes of intermediate filaments can be identified within higher eukaryotic cells. Each class is characteristic of a particular cell type. These filaments may function to integrate mechanically the various structures of the cytoplasmic space in a way that is tailored to the differentiated state of the cell.
1,904 citations
TL;DR: The cell lines with the highest incidence of spontaneous metastasis exhibit the greatest level of type IV collagen-degrading activity in two different assays using either living cells or media obtained from cell cultures.
Abstract: Tumour cells traverse epithelial and endothelial basement membranes during the successive stages of the metastatic process. At the transition from in situ to invasive carcinoma, local dissolution of the basement membrane is observed microscopically1,2, and coincides with tumour cell invasion of the underlying stroma. Tumour cells further traverse the endothelial basement membrane during entry into and egress from blood vessels3–5. Electron microscopic studies have shown local dissolution of basement membrane at its area of contact with invading tumour cells, suggesting an enzymatic mechanism3,6,7. Basement membranes are resilient structures which present a mechanical barrier to invasion8. Type IV collagen is a major structural protein of basement membranes and is chemically and genetically distinct from stroma collagen types I and III and cartilage collagen type II9,10. Previously characterised animal collagenases which cleave collagen types I; II and III fail to degrade type IV collagen11,12. We have recently purified about 1,000-fold and characterised a neutral protease activity preferential for type IV collagen from metastatic tumour cells and shown that it (1) produces specific degradation products, (2) has a molecular weight of 65,000, (3) is not plasmin or a cathepsin, by pH and inhibitor studies, and (4) does not significantly degrade other collagens or fibronectin12,13. Here we extend the relevance of this finding by quantitating the ability of several murine tumour cell lines of known metastatic potential to degrade type IV collagen. The cell lines with the highest incidence of spontaneous metastasis exhibit the greatest level of type IV collagen-degrading activity in two different assays using either living cells or media obtained from cell cultures.
1,805 citations
TL;DR: Metastases do not result from random survival of cells released from the primary tumour but from the selective growth of specialised subpopulations of highly metastatic cells endowed with specific properties that befit them to complete each step of the metastatic process.
Abstract: Metastases do not result from random survival of cells released from the primary tumour but from the selective growth of specialised subpopulations of highly metastatic cells endowed with specific properties that befit them to complete each step of the metastatic process.
1,724 citations
TL;DR: In this article, the authors explore the possibility that some active galactic nuclei may contain two massive black holes in orbit about each other, which suggests a new interpretation for the observed bending and apparent precession of radio jets emerging from these objects.
Abstract: Most theoretical discussions of active galactic nuclei (including quasars) attribute their energy production either to an accreting black hole or to a precursor stage—for instance a dense star cluster or a supermassive star—whose inevitable end point is a massive black hole1. We explore here the possibility that some active nuclei may contain two massive black holes in orbit about each other. This hypothesis suggests a new interpretation for the observed bending2 and apparent precession3 of radio jets emerging from these objects and may indeed be verified through detection of the direct consequences of orbital motion.
1,704 citations
TL;DR: Natural selection operating within genomes will inevitably result in the appearance of DNAs with no phenotypic expression whose only ‘function’ is survival within genomes.
Abstract: Natural selection operating within genomes will inevitably result in the appearance of DNAs with no phenotypic expression whose only ‘function’ is survival within genomes. Prokaryotic transposable elements and eukaryotic middle-repetitive sequences can be seen as such DNAs, and thus no phenotypic or evolutionary function need be assigned to them.
1,694 citations
TL;DR: Cell membrane receptors for hormones and neurotransmitters form oligomeric complexes with GTP-regulatory proteins and inhibit the latter from reacting with G TP, and this theory may apply generally to membrane signal transduction involving surface receptors.
Abstract: Cell membrane receptors for hormones and neurotransmitters form oligomeric complexes with GTP-regulatory proteins and inhibit the latter from reacting with GTP. Hormones and neurotransmitters act by releasing the inhibitory constraints imposed by the receptors, thus allowing the GTP-regulatory proteins to interact with and control the activity of enzymes such as adenylate cyclase. This theory may apply generally to membrane signal transduction involving surface receptors.
TL;DR: Evidence is presented that PGPR exert their plant growth-promoting activity by depriving native microflora of iron by producing extracellular siderophores (microbial iron transport agents) which efficiently complex environmental iron, making it less available to certain nativemicroflora.
Abstract: Specific strains of the Pseudomonas fluorescens-putida group have recently been used as seed inoculants on crop plants to promote growth and increase yields. These pseudomonads, termed plant growth-promoting rhizobacteria (PGPR), rapidly colonize plant roots of potato, sugar beet and radish, and cause statistically significant yield increases up to 144% in field tests1–5. These results prompted us to investigate the mechanism by which plant growth was enhanced. A previous study indicated that PGPR increase plant growth by antagonism to potentially deleterious rhizoplane fungi and bacteria, but the nature of this antagonism was not determined6. We now present evidence that PGPR exert their plant growth-promoting activity by depriving native microflora of iron. PGPR produce extracellular siderophores (microbial iron transport agents)7 which efficiently complex environmental iron, making it less available to certain native microflora.
TL;DR: Using voltage-clamped frog sympathetic neurones, this work has identified a distinctive voltage-sensitive K+ -current, separate from the delayed rectifier current, as the prime target for muscarinic agonists, and termed this current the M-current, IM.
Abstract: Cholinergic excitation of vertebrate neurones is frequently mediated through the action of acetylcholine on muscarinic (atropine-sensitve) receptors. This type of excitation differs substantially from the better known nicotinic excitation. One difference is that, instead of an increased membrane conductance, a decreased conductance (to K+ ions) frequently accompanies muscarinic depolarisation. This has been detected in sympathetic, cortical and hippocampal neurones. Using voltage-clamped frog sympathetic neurones we have now identified a distinctive voltage-sensitive K+-current, separate from the delayed rectifier current, as the prime target for muscarinic agonists. We have termed this current the M-current, IM.
TL;DR: In this paper, an empirical relationship was established that predicts organic carbon flux at any depth in the oceans below the base of the euphotic zone as a function of the mean net primary production rate at the surface and depth-dependent consumption.
Abstract: Organic detritus passing from the sea surface through the water column to the sea floor controls nutrient regeneration, fuels benthic life and affects burial of organic carbon in the sediment record1–3. Particle trap systems have enabled the first quantification of this important process. The results suggest that the dominant mechanism of vertical transport is by rapid settling of rare large particles, most likely of faecal pellets or marine snow of the order of >200 μm in diameter, whereas the more frequent small particles have an insignificant role in vertical mass flux4–6. The ultimate source of organic detritus is biological production in surface waters of the oceans. I determine here an empirical relationship that predicts organic carbon flux at any depth in the oceans below the base of the euphotic zone as a function of the mean net primary production rate at the surface and depth-dependent consumption. Such a relationship aids in estimating rates of decay of organic matter in the water column, benthic and water column respiration of oxygen in the deep sea and burial of organic carbon in the sediment record.
TL;DR: Binding studies using a new anti-muscarinic drug, pirenzepine, are used, in which heterogeneity of binding is found that correlates well with the pharmacological activity and cannot be taken as evidence for different receptor subtypes.
Abstract: Some antagonists exhibit tissue selectivity in their pharmacological antagonism of muscarinic responses. However, the affinity constants for equilibrium binding of classical antagonists to muscarinic receptors in subcellular preparations have shown only small variations in different peripheral tissues and regions of the brain. The binding curves do not deviate significantly from the simple Langmuir isotherm, indicating apparent homogeneity of the receptor population in any given region. In contrast, heterogeneity has been detected by agonist binding studies but this may arise from different environmental or coupling restraints on the agonist-induced conformational change and cannot be taken as evidence for different receptor subtypes. We report here binding studies using a new anti-muscarinic drug, pirenzepine, in which we found heterogeneity of binding that correlates well with the pharmacological activity.
TL;DR: The North American Cordillera is made up of "suspect terranes" as discussed by the authors, which are allochthonous to the North American continent and seem to have been swept from far reaches of the Pacific Ocean before collision and accretion into the Cordilleran margin mostly in Mesozoic to early Cenozoic time.
Abstract: Over 70% of the North American Cordillera is made up of ‘suspect terranes’. Many of these geological provinces are certainly allochthonous to the North American continent and seem to have been swept from far reaches of the Pacific Ocean before collision and accretion into the Cordilleran margin mostly in Mesozoic to early Cenozoic time.
TL;DR: It is demonstrated that one function of (ADP–ribose)n is to participate in the cellular recovery from DNA damage, and specific inhibitors of poly(ADP-ribose] polymerase prevent rejoining of DNA strand breaks caused by dimethyl sulphate and cytotoxicity is enhanced thereby.
Abstract: Chromatin proteins are covalently modified by at least five different processes; in no case has the precise physiological function been established. One of these post-synthetic, covalent modifications is effected by the enzyme poly(ADP-ribose) polymerase, which uses the coenzyme NAD+ to ADP-ribosylate chromatin proteins. The modification consists largely of mono(ADP-ribose), but long, homopolymer chains of (ADP-ribose) are also present. Various physiological functions have been suggested for (ADP-ribose)n. Here we demonstrate that one function of (ADP-ribose)n is to participate in the cellular recovery from DNA damage. Specific inhibitors of poly(ADP-ribose) polymerase prevent rejoining of DNA strand breaks caused by dimethyl sulphate and cytotoxicity is enhanced thereby. The rejoining of strand breaks is prevented also by nutritionally depleting the cells of NAD.
TL;DR: This first demonstration of angiogenesis in vitro shows that all the information necessary to develop an entire capillary network in vitro is expressed by one cell type, suggests a mechanism for lumen formation, and offers a possibility of distinguishing between direct and indirectAngiogenesis factors.
Abstract: Cloned capillary endothelial cells, cultured in tumour-conditioned medium, form capillary tubes. By light and electron microscopy these tubes resemble capillaries in vivo. This first demonstration of angiogenesis in vitro: (1) shows that all the information necessary to develop an entire capillary network in vitro is expressed by one cell type; (2) suggests a mechanism for lumen formation; and (3) offers a possibility of distinguishing between direct and indirect angiogenesis factors.
TL;DR: GABA clearly decreased the evoked release of accumulated 3H-noradrenaline from rat atria in vitro and3H-acetylcholine from preganglionic terminals in the rat superior cervical ganglion in vitro without affecting the basal release of tritium.
Abstract: The existence of a receptor for γ-aminobutyric acid (GABA) on neurones of the mammalian central nervous system (CNS) is now firmly established1–3. It is generally accepted that bicuculline (and its methohalide salts) is an antagonist of the actions of GABA4,5, although resistance to bicuculline has been described6,7. The view that bicuculline prevents GABA from interacting with a membrane recognition site is supported by results obtained in radiolabelled ligand binding studies8,9. Bicuculline-sensitive GABA receptors are not confined to neurones in the CNS but are also present on neurones and axons of the peripheral nervous system10,11. Their existence on neurones in sympathetic ganglia made us consider the possibility that they are also present on the terminals of such neurones. This has recently been tested12,13 by assuming that if GABA depolarises the terminals in a manner similar to the cell bodies, evoked transmitter output might be decreased (see ref. 14). GABA (ED50, 4µM) clearly decreased the evoked release of accumulated 3H-noradrenaline from rat atria in vitro and 3H-acetylcholine from preganglionic terminals in the rat superior cervical ganglion in vitro without affecting the basal release of tritium. In neither system was the effect of GABA antagonised by bicuculline methobromide, even though the ganglion terminal depolarisation was13. This suggested that the two phenomena, depolarisation and inhibition of transmitter release, were separate. The decrease in transmitter release not surprisingly leads to a decrease in the postsynaptic response15. Again, the decrease in response was not prevented by bicuculline or other GABA antagonists. We believe that these results indicate the presence of a novel GABA receptor on nerve terminals, a theory supported by results obtained with a variety of GABA analogues. For example, 3-aminopropane sulphonic acid (3-APS) which is at least as active as GABA at bicuculline sensitive sites10,16,17 is inactive at the terminal receptor. By contrast, the analogue baclofen (β-chlorophenyl GABA) is inactive at bicuculline-sensitive sites18,19 but is as active as GABA in reducing evoked transmitter output15. This effect of baclofen is stereospecific, the (−) isomer being > 100-fold more active than the (+) isomer15. We now report the presence of the novel GABA receptor within the mammalian CNS.
TL;DR: Several lines of evidence are presented that suggest a direct involvement of snRNPs in the splicing of hnRNA molecules, including the observation that the nucleotide sequence at the 5′ end of U1 RNA exhibits extensive complementarity to those across splice junctions in hn RNA molecules.
Abstract: Discrete, stable small RNA molecules are found in the nuclei of cells1 from a wide variety of eukaryotic organisms2. Many of these small nuclear RNA (snRNA) species, which range in size from about 90 to 220 nucleotides, have been well-characterised biochemically3–6, and some sequenced7,8. However, their function has remained obscure. The most abundant snRNA species exist as a closely related set of RNA–protein complexes called small nuclear ribonucleoproteins (snRNPs)9. snRNPs are the antigens recognised by antibodies from some patients with lupus erythematosus (LE), an autoimmune rheumatic disease10,11. Anti-RNP antibodies from lupus sera selectively precipitate snRNP species containing Ula7 and Ulb9 RNAs from mouse Ehrlich ascites cell nuclei, whereas anti-Sm antibodies bind these snRNPs and four others containing U2 (ref. 8), U4, US and U6 (ref. 9) RNAs. Both antibody systems precipitate the same seven prominent nuclear proteins (molecular weight 12,000–32,000). All molecules of the snRNAs U1, U2, U4, U5 and U6 appear to exist in the form of antigenic snRNPs9. The particles sediment at about 10S and each probably contains a single snRNA molecule. Indirect immunofluorescence studies (refs 12, 13, and unpublished observations) using anti-RNP and anti-Sm sera confirm the nuclear (but non-nucleolar) location of the antigenic snRNPs. Here we present several lines of evidence that suggest a direct involvement of snRNPs in the splicing of hnRNA. Most intriguing is the observation that the nucleotide sequence at the 5′ end of U1 RNA exhibits extensive complementarity to those across splice junctions in hnRNA molecules.
TL;DR: The induction of polyarthritis in rats by intradermal immunisation with homologous or heterologous type II collagen in complete or incomplete Freund's adjuvant was reported recently and a similar disease in certain strains of mice is produced.
Abstract: The induction of polyarthritis in rats by intradermal immunisation with homologous or heterologous type II collagen incomplete or incomplete Freund's adjuvant was reported recently by Trentham et al. We have now produced a similar disease in certain strains of mice.
TL;DR: It has now been found that, on stimulating muscles in the human hand without any special preparation of the skin, the effective resistance fell to low values if brief but very high voltage shocks were used.
Abstract: One of the most fertile methods of investigating the brain is to stimulate a part of it electrically and observe the results. So far, however, use of the method in man has been restricted by the necessity of opening the skull surgically to apply the electrodes. Much could be done, both with healthy subjects and with neurological patients, if it were feasible to stimulate through electrodes on the scalp, although the localization of the stimulus on the cortex will always be much less sharp than with electrodes on the brain surface. In an intact man, however, the brain is protected from electricity by the skull and by the scalp, both of which normally offer considerable resistance. Furthermore, the cerebral cortex does not have a particularly low electrical threshold. It is probably for these reasons (despite an occasional contrary claim1) that attempts to stimulate the brain by applying stimuli from conventional stimulators to the scalp have been stopped by pain or have otherwise failed. These obstacles have now begun to yield. Recently, it was found that, on stimulating muscles in the human hand2 without any special preparation of the skin, the effective resistance fell to low values if brief but very high voltage shocks were used. Applying the same technique to the head, it has now proved possible at the first attempt to stimulate two areas of the human cortex, without undue discomfort.
TL;DR: The metabolic state of skeletal muscle and brain within intact rats is monitored using high resolution phosphorus nuclear magnetic resonance, indicating the diagnostic possibilities of the method.
Abstract: The metabolic state of skeletal muscle and brain within intact rats is monitored using high resolution phosphorus nuclear magnetic resonance. Regional disturbances in metabolism (for example, localised ischaemia) are easily observed, indicating the diagnostic possibilities of the method. Measurements are made using 'surface' radiofrequency coils, which we discuss in detail.
TL;DR: Many specific sites in Drosophila chromatin are hypersensitive to DNase I and the positions of such sites were mapped along the regions of the genome coding for two heat shock proteins.
Abstract: Many specific sites in Drosophila chromatin are hypersensitive to DNase I. The positions of such sites were mapped along the regions of the genome coding for two heat shock proteins. Such sites lie at the 5' ends of heat shock genes and may function as elements for recognition by molecules which regulate gene activity.
TL;DR: The capacity of transected axons originating in the CNS to regrow into nerve grafts containing Schwann cells is examined and it is found that these axonal sprouts form sprouts after injury in mammals and some fish and amphibians.
Abstract: Axons in the peripheral nervous system (PNS) and central nervous system (CNS) form sprouts after injury. Elongation of regenerating axonal sprouts has been observed as the exception within the adult mammalian CNS but is the rule in the PNS of mammals as well as in the CNS of some fish and amphibians. The relative importance of intrinsic neuronal properties and axonal environment in determining the extent of axonal regrowth is unknown. Neuroglial cells, nerve growth factor and target tissues such as smooth muscle are known to influence neuronal responses to injury. Here we have examined the capacity of transected axons originating in the CNS to regrow into nerve grafts containing Schwann cells.
TL;DR: The remarkable contractile activity of both LTC4 and LTD4 on isolated human bronchi is reported, which further emphasizes the possibility that leukotrienes are potent mediators of ronchoconstriction in man.
Abstract: Slow reacting substance of anaphylaxis (SRS-A) is released by various stimuli, including immunological challenge, and has long been considered an important mediator of immediate hypersensitivity reactions, such as bronchoconstriction in allergic asthma1–3. Recently, slow reacting substances from several tissues have been identified and characterized as members of a newly discovered group of substances, the leukotrienes4. Leukotrienes are generated from arachidonic acid and other polyunsaturated fatty acids in a pathway initially involving a lipoxygenase-catalysed oxygenation at C-5 (Fig. 1). This differs from the synthesis of prostaglandins and thromboxanes, where the initial transformation of arachidonic acid is catalysed by a cyclo oxygenase (Fig. 1). Recently, leukotriene C4(LTC4:5(s)-hydroxy,6(R)-S-glutathionyl-7,9-trans,11,14-cis-eicosatetraenoic acid) and D4(LTD4:5(S)-hydroxy,6(R)-S-cysteinylglycyl-7,9-trans,11,14-cis-eicosatetraenoic acid) were found to have biological effects in several bioassay systems, which are strikingly similar to those previously reported for impure extracts of SRS-A5,6. Here we report the remarkable contractile activity of both LTC4 and LTD4 on isolated human bronchi, which further emphasizes the possibility that leukotrienes are potent mediators of ronchoconstriction in man.
TL;DR: Many naturally deformed crustal rocks contain mineral-filled extension veins and the crystals making up the vein filling often show a fibrous habit and seem to be built up by a succession of "crack-seal" increments: the elastically deforming rock fails by fracture, and the walls of the open micro-crack are sealed together by crystalline material derived by pressure solution in the rock matrix as mentioned in this paper.
Abstract: Many naturally deformed crustal rocks contain mineral-filled extension veins. The crystals making up the vein filling often show a fibrous habit and seem to be built up by a succession of ‘crack–seal’ increments: the elastically deforming rock fails by fracture, and the walls of the open micro-crack are sealed together by crystalline material derived by pressure solution in the rock matrix.
TL;DR: Calmodulin, a protein that binds calcium with high affinity and specificity, is structurally conserved and functionally preserved throughout the animal and plant kingdoms.
Abstract: Calmodulin, a protein that binds calcium with high affinity and specificity, is structurally conserved and functionally preserved throughout the animal and plant kingdoms. It serves as an intracellular Ca2+-receptor and mediates the Ca2+ regulation of cyclic nucleotide and glycogen metabolism, secretion, motility and Ca2+ transport. Calmodulin is also a dynamic component of the mitotic apparatus.