Showing papers in "Nature in 1983"
TL;DR: In the genome of a germ-line cell, the genetic information for an immunoglobulin polypeptide chain is contained in multiple gene segments scattered along a chromosome which are assembled by recombination which leads to the formation of a complete gene.
Abstract: In the genome of a germ-line cell, the genetic information for an immunoglobulin polypeptide chain is contained in multiple gene segments scattered along a chromosome. During the development of bone marrow-derived lymphocytes, these gene segments are assembled by recombination which leads to the formation of a complete gene. In addition, mutations are somatically introduced at a high rate into the amino-terminal region. Both somatic recombination and mutation contribute greatly to an increase in the diversity of antibody synthesized by a single organism.
3,679 citations
TL;DR: This paper found that children who are backward in reading are strikingly insensitive to rhyme and alliteration and are at a disadvantage when categorizing words on the basis of common sounds even in comparison with younger children who read no better than they do.
Abstract: Children who are backward in reading are strikingly insensitive to rhyme and alliteration1. They are at a disadvantage when categorizing words on the basis of common sounds even in comparison with younger children who read no better than they do. Categorizing words in this way involves attending to their constituent sounds, and so does learning to use the alphabet in reading and spelling. Thus the experiences which a child has with rhyme before he goes to school might have a considerable effect on his success later on in learning to read and to write. We now report the results of a large scale project which support this hypothesis.
2,960 citations
TL;DR: The embryo fibroblasts become tumorigenic if a second oncogene such as a viral or cellular myc gene or the gene for the polyoma large-T antigen is introduced together with the ras gene.
Abstract: Transfection of embryo fibroblasts by a human ras oncogene does not convert them into tumour cells unless the fibroblasts are established and immortalized before transfection. The embryo fibroblasts become tumorigenic if a second oncogene such as a viral or cellular myc gene or the gene for the polyoma large-T antigen is introduced together with the ras gene.
2,691 citations
TL;DR: It is reported here that micromolar concentrations of Ins1,4,5P3 release Ca2+ from a nonmitochondrial intracellular Ca2- store in pancreatic acinar cells, and the results strongly suggest that this is the same Ca1+ store that is released by acetylcholine.
Abstract: Activation of receptors for a wide variety of hormones and neurotransmitters leads to an increase in the intracellular level of calcium. Much of this calcium is released from intracellular stores but the link between surface receptors and this internal calcium reservoir is unknown. Hydrolysis of the phosphoinositides, which is another characteristic feature of these receptors, has been implicated in calcium mobilization. The primary lipid substrates for the receptor mechanism seem to be two polyphosphoinositides, phosphatidylinositol 4-phosphate (PtdIns4P) and phosphatidylinositol 4,5-bisphosphate (PtdIns4,5P2), which are rapidly hydrolysed following receptor activation in various cells and tissues. The action of phospholipase C on these polyphosphoinositides results in the rapid formation of the water-soluble products inositol 1,4-bisphosphate (Ins1,4P2) and inositol 1,4,5-trisphosphate (Ins1,4,5P3). In the insect salivary gland, where changes in Ins1,4P2 and Ins1,4,5P2 have been studied at early time periods, increases in these inositol phosphates are sufficiently rapid to suggest that they might mobilize internal calcium. We report here that micromolar concentrations of Ins1,4,5P3 release Ca2+ from a nonmitochondrial intracellular Ca2+ store in pancreatic acinar cells. Our results strongly suggest that this is the same Ca2+ store that is released by acetylcholine.
2,434 citations
TL;DR: In four of five patients studied, representing two histological types of cancer, substantial hypomethylation was found in genes of cancer cells compared with their normal counterparts, and was progressive in a metastasis from one of the patients.
Abstract: It has been suggested that cancer represents an alteration in DNA, heritable by progeny cells, that leads to abnormally regulated expression of normal cellular genes; DNA alterations such as mutations, rearrangements and changes in methylation have been proposed to have such a role. Because of increasing evidence that DNA methylation is important in gene expression (for review see refs 7, 9-11), several investigators have studied DNA methylation in animal tumours, transformed cells and leukaemia cells in culture. The results of these studies have varied; depending on the techniques and systems used, an increase, decrease, or no change in the degree of methylation has been reported. To our knowledge, however, primary human tumour tissues have not been used in such studies. We have now examined DNA methylation in human cancer with three considerations in mind: (1) the methylation pattern of specific genes, rather than total levels of methylation, was determined; (2) human cancers and adjacent analogous normal tissues, unconditioned by culture media, were analysed; and (3) the cancers were taken from patients who had received neither radiation nor chemotherapy. In four of five patients studied, representing two histological types of cancer, substantial hypomethylation was found in genes of cancer cells compared with their normal counterparts. This hypomethylation was progressive in a metastasis from one of the patients.
2,358 citations
TL;DR: Application of the patch-clamp technique to CN-treated mammalian heart cells reveals specific K+ channels which are depressed by intracellular ATP (ATPi) at levels greater than 1 mM, which seems to be important for regulation of cellular energy metabolism in the control of membrane excitability.
Abstract: An outward current of unknown nature increases significantly when cardiac cells are treated with cyanide or subjected to hypoxia, and decreases on intracellular injection of ATP. We report here that application of the patch-clamp technique to CN-treated mammalian heart cells reveals specific K+ channels which are depressed by intracellular ATP (ATPi) at levels greater than 1 mM. For these channels, conductance in the outward direction is much larger than the inward rectifier K+ channel which is insensitive to ATP. AMP had no effect on the ATP-sensitive K+ channel, and ADP was less effective than ATP. Thus, the ATP-sensitive K+ channel seems to be important for regulation of cellular energy metabolism in the control of membrane excitability.
2,343 citations
TL;DR: The approach described here permits the application of recombinant DNA technology to analyses of complex neurobiological systems in the absence of prior structural or biological information.
Abstract: Alternative processing of the RNA transcribed from the calcitonin gene appears to result in the production of a messenger RNA in neural tissue distinct from that in thyroidal 'C' cells The thyroid mRNA encodes a precursor to the hormone calcitonin whereas that in neural tissues generates a novel neuropeptide, referred to as calcitonin gene-related peptide (CGRP) The distribution of CGRP-producing cells and pathways in the brain and other tissues suggests functions for the peptide in nociception, ingestive behaviour and modulation of the autonomic and endocrine systems The approach described here permits the application of recombinant DNA technology to analyses of complex neurobiological systems in the absence of prior structural or biological information
2,243 citations
TL;DR: The chromosomal localization of the Huntington's disease gene is the first step in using recombinant DNA technology to identify the primary genetic defect in this disorder.
Abstract: Family studies show that the Huntington's disease gene is linked to a polymorphic DNA marker that maps to human chromosome 4. The chromosomal localization of the Huntington's disease gene is the first step in using recombinant DNA technology to identify the primary genetic defect in this disorder.
2,211 citations
TL;DR: Mice homozygous for this mutation have few if any lymphocytes; consequently they are hypogammaglobulinaemic and deficient for immune functions mediated by T and B lymphocytes and represent a new model for investigating how lymphoid differentiation may be impaired in the disease state and regulated in the normal state.
Abstract: The most debilitating human lymphoid deficiency disease, known as severe combined immunodeficiency (SCID), impairs the differentiation of both T and B lymphocytes. Affected infants are highly susceptible to recurring infections of viruses, fungi and bacteria and invariably die within 2 yr of birth. Inheritance of this congenital syndrome may show X-linked or autosomal recessive control. To date autosomal recessive inheritance of SCID has been observed in Arabian foals which represent the only known animal model of this disease syndrome but here we report an autosomal recessive mutation in mice that severely impairs lymphopoiesis. Mice homozygous for this mutation have few if any lymphocytes; consequently they are hypogammaglobulinaemic and deficient for immune functions mediated by T and B lymphocytes. These mice, therefore, represent a new model for investigating how lymphoid differentiation may be impaired in the disease state and regulated in the normal state.
2,129 citations
TL;DR: An animal model is developed where changes occur in the threshold and responsiveness of the flexor reflex following peripheral injury that are analogous to the sensory changes found in man, and shows that it in part arises from changes in the activity of the spinal cord.
Abstract: Noxious skin stimuli which are sufficiently intense to produce tissue injury, characteristically generate prolonged post-stimulus sensory disturbances that include continuing pain, an increased sensitivity to noxious stimuli and pain following innocuous stimuli. This could result from either a reduction in the thresholds of skin nociceptors (sensitization)1,2 or an increase in the excitability of the central nervous system so that normal inputs now evoke exaggerated responses3,4. Because sensitization of peripheral receptors occurs following injury5–7, a peripheral mechanism is widely held to be responsible for post-injury hypersensitivity. To investigate this I have now developed an animal model where changes occur in the threshold and responsiveness of the flexor reflex following peripheral injury that are analogous to the sensory changes found in man. Electrophysiological analysis of the injury-induced increase in excitability of the flexion reflex shows that it in part arises from changes in the activity of the spinal cord. The long-term consequences of noxious stimuli result, therefore, from central as well as from peripheral changes.
2,055 citations
TL;DR: It is suggested that fibrous astrocytes and oligodendrocyte develop from a common progenitor cell and provide a striking example of developmental plasticity and environmental influence in the differentiation of CNS glial cells.
Abstract: We have identified a cell type in 7-day-old rat optic nerve that differentiates into a fibrous astrocyte if cultured in the presence of fetal calf serum and into an oligodendrocyte if cultured in the absence of serum. In certain culture conditions some of these cells acquire a mixed phenotype, displaying properties of both astrocytes and oligodendrocytes. These observations suggest that fibrous astrocytes and oligodendrocytes develop from a common progenitor cell and provide a striking example of developmental plasticity and environmental influence in the differentiation of CNS glial cells.
TL;DR: A comparison of constitutional and tumour genotypes from several cases indicates that tumorigenesis may result from the development of homozygosity for the mutant allele at the Rb-1 locus.
Abstract: Inheritance of a mutation at the Rb-1 locus, which has been mapped to band q14 of human chromosome 13, results in predisposition to retinoblastoma. Cloned DNA segments homologous to arbitrary loci of human chromosome 13 and which reveal polymorphic restriction endonuclease recognition sequences, have been used to look for somatic genetic events that might occur during tumorigenesis. A comparison of constitutional and tumour genotypes from several cases indicates that tumorigenesis may result from the development of homozygosity for the mutant allele at the Rb-1 locus. The homozygosity in these cases results from mitotic nondisjunction, resulting in loss of the homologous wild-type chromosome, or from a mitotic recombination event.
TL;DR: The interaction of two compatible plasmids, one containing the vir-region, the other carrying the T-DNA on a wide host-range replicon are reported, which allows introduction of the manipulated T- DNA into plant cells.
Abstract: The soil bacterium Agrobacterium tumefaciens is a plant pathogen that causes crown-gall tumours after infection of wounded dicotyledonous plants. Large plasmids (Ti-plasmids) are responsible for the oncogenicity of the bacterium1–3. Crown-gall tumours contain a DNA segment, called the T-DNA, which is homologous with a defined part of the Ti-plasmid present in the tumour-inducing bacterium, and is stably integrated into the plant genome4–7. Apart from the T-DNA another region of the Ti-plasmid-called the vir-region, is essential for tumour induction8–11. We report here the interaction of two compatible plasmids, one containing the vir-region, the other carrying the T-DNA on a wide host-range replicon. An A. tumefaciens strain harbouring both plasmids has a normal tumour-inducing capacity, although neither plasmid is functional alone. With this approach, the T-DNA on one plasmid can, because of its size, be easily genetically manipulated using Escherichia coli as a host. Transfer of this plasmid into an A. tumefaciens strain harbouring the plasmid with the vir-region allows introduction of the manipulated T-DNA into plant cells. In this way, sophisticated binary vector systems for plant genetic engineering can be developed.
TL;DR: It is shown here that histamine inhibits its own release from depolarized slices of rat cerebral cortex, an action apparently mediated by a class of receptor (H3) pharmacologically distinct from those previously characterized, that is, the H1 and H2 receptors.
Abstract: Although histaminergic neurones have not yet been histochemically visualized, there is little doubt that histamine (HA) has a neurotransmitter role in the invertebrate and mammalian central nervous system. For example, a combination of biochemical, electrophysiological and lesion studies in rats have shown that histamine is synthesized in and released from a discrete set of neurones ascending through the lateral hypothalamic area and widely projecting in the telencephalon. Histamine acts on target cells in mammalian brain via stimulation of two classes of receptor (H1 and H2) previously characterized in peripheral organs and probably uses Ca2+ and cyclic AMP, respectively, as second messengers. It is well established that several neurotransmitters affect neuronal activity in the central nervous system through stimulation not only of postsynaptic receptors, but also of receptors located presynaptically which often display distinct pharmacological specificity and by which they may control their own release. Such 'autoreceptors' have been demonstrated (or postulated) in the case of noradrenaline, dopamine, serotonin, acetylcholine and gamma-aminobutyric acid (GABA) neurones but have never been demonstrated for histamine. We show here that histamine inhibits its own release from depolarized slices of rat cerebral cortex, an action apparently mediated by a class of receptor (H3) pharmacologically distinct from those previously characterized, that is, the H1 and H2 receptors.
TL;DR: A monoclonal antibody specific for a lymphocyte surface molecule that appears to mediate recognition of lymph node HEV and to be required for lymphocyte homing into lymph nodes in vivo is described.
Abstract: Lymphocytes migrate from the bloodstream by recognizing and binding to specialized endothelial cells lining the high endothelial venules (HEV) in lymph nodes and Peyer's patches. We describe here a monoclonal antibody, MEL-14, specific for a lymphocyte surface molecule that appears to mediate recognition of lymph node HEV, and to be required for lymphocyte homing into lymph nodes in vivo.
TL;DR: A partial amino acid sequence of human platelet-derived growth factor, the major mitogen in serum for cells of mesenchymal origin, shows virtual identity with the predicted sequence of p28sis, the putative transforming protein of simian sarcoma virus (SSV).
Abstract: A partial amino acid sequence of human platelet-derived growth factor, the major mitogen in serum for cells of mesenchymal origin, has been determined. A region of 104 contiguous amino acids shows virtual identity with the predicted sequence of p28sis, the putative transforming protein of simian sarcoma virus (SSV). This similarity suggests a mechanism for transformation by SSV and other agents, involving expression of growth factors.
TL;DR: The properties of a unique set of quantum states of the electromagnetic field are reviewed in this article, and proposed schemes for the generation and detection of squeezed states as well as potential applications are discussed.
Abstract: The properties of a unique set of quantum states of the electromagnetic field are reviewed. These ‘squeezed states’ have less uncertainty in one quadrature than a coherent state. Proposed schemes for the generation and detection of squeezed states as well as potential applications are discussed.
TL;DR: It is shown here that a DNA domain detectable by partial homology to the myc oncogene is amplified up to 140-fold in cell lines derived from different human neuroblastomas and in a neuroblastoma tumour, but not in other tumour cells showing cytological evidence for gene amplification.
Abstract: Amplified cellular genes in mammalian cells frequently manifest themselves as double minute chromosomes (DMs) and homogeneously staining regions of chromosomes (HSRs). With few exceptions both karyotypic abnormalities appear to be confined to tumour cells. All vertebrates possess a set of cellular genes homologous to the transforming genes of RNA tumour viruses, and there is circumstantial evidence that these cellular oncogenes are involved in tumorigenesis. We have recently shown that DMs and HSRs in cells of the mouse adrenocortical tumour Y1 and an HSR in the human colon carcinoma COLO320 contain amplified copies of the cellular oncogenes c-Ki-ras and c-myc, respectively. Both DMs and HSRs are found with remarkable frequency in cells of human neuroblastomas. We show here that a DNA domain detectable by partial homology to the myc oncogene is amplified up to 140-fold in cell lines derived from different human neuroblastomas and in a neuroblastoma tumour, but not in other tumour cells showing cytological evidence for gene amplification. By in situ hybridization we found that HSRs are the chromosomal sites of the amplified DNA. The frequency with which this amplification appears in cells from neuroblastomas and its apparent specificity raise the possibility that one or more of the genes contained within the amplified domain contribute to tumorigenesis.
TL;DR: It is shown here that TSSE is not demonstrably transferred by lysogeny; moreover, the gene is cloned and the cloned product is serologically and biologically indistinguishable from the native protein, and that the TSSE determinant is associated with a larger DNA segment that is absent or rearranged in TSSE− strains.
Abstract: Toxic shock syndrome (TSS) is a complex of generalized symptoms caused by a local staphylococcal infection, and a circulating toxin is thought to be involved. Indeed, nearly 100% of TSS isolates produce an exoprotein, TSSE, that is thought to have an aetiological role on the basis of positive animal tests (refs 1,2 and F. Quimby, personal communication) and human serological data3. Although the precise role of TSSE in TSS remains unclear (E. Kass, personal communication), no other staphylococcal factor has been implicated. Our preliminary studies of the genetics of TSSE production failed to demonstrate plasmid or phage involvement or linkage with known chromosomal genes (ref. 4 and B.N.K. et al., unpublished data); however, Schutzer et al. have found that most TSS strains harbour prophages with common plating characteristics and suggest that the toxin(s) involved in TSS are transmitted by lysogenic conversion5. We show here that TSSE is not demonstrably transferred by lysogeny; moreover, we have cloned the gene and found that the cloned product is serologically and biologically indistinguishable from the native protein, and that the TSSE determinant is associated with a larger DNA segment that is absent or rearranged in TSSE− strains.
TL;DR: Treatment of parietal yolk sacs cells with biologically active 12-O-tetradecanoyl phorbol-13-acetate (TPA) provokes a rapid decrease in cytosolic Ca,PL-PK activity that is accompanied by a significant increase in the amount of Ca, PL- PK activity associated with the plasma membrane fraction.
Abstract: Although the biochemical mechanism of action of phorbol ester tumour promoters is not fully understood, it is known that phorbol ester binding to the cell surface causes rapid changes in calcium flux1,2 and phospholipid metabolism3–7. A protein kinase activity has recently been described which is dependent on calcium and acidic phospholipids and is further enhanced by diacylglycerol8–10. Previously, we have observed that phorbol ester treatment of EL4 mouse thymoma cells causes a rapid decrease in cytosolic calcium, phospholipid-dependent protein kinase (Ca, PL-PK) activity, which is mediated through the specific phorbol ester cell-surface receptors identified on EL4 cells11. We now show that treatment of parietal yolk sacs (PYS-2) cells with biologically active 12-O-tetradecanoyl phorbol-13-acetate (TPA) provokes a rapid decrease in cytosolic Ca, PL-PK activity that is accompanied by a significant increase in the amount of Ca, PL-PK activity associated with the plasma membrane fraction. These results suggest that the rapid and tight association of Ca, PL-PK activity with the plasma membrane may be an early event in mediating some of the effects of phorbol esters.
TL;DR: The polyoma virus middle-T and the T24 Harvey ras1 genes are individually unable to transform primary baby rat kidney cells and separate establishment and transforming functions are required for oncogenic transformation of primary cells in culture.
Abstract: The polyoma virus middle-T and the T24 Harvey ras1 genes are individually unable to transform primary baby rat kidney cells. Adenovirus early region 1A provides functions required by these genes to transform primary cells following DNA-mediated gene transfer. These results suggest that separate establishment and transforming functions are required for oncogenic transformation of primary cells in culture.
TL;DR: Calcium channels in excitable membranes are of great importance for many cellular functions and modulation by neurotransmitters and drugs regulates calcium influx into the cell and thereby alters the functional state of the cell.
Abstract: Calcium channels in excitable membranes are of great importance for many cellular functions. Modulation of these channels by neurotransmitters and drugs regulates calcium influx into the cell and thereby alters the functional state of the cell. Recently it has become possible to measure properties of single calcium channels directly and to obtain evidence on mechanisms of their modulation.
TL;DR: Bacterial clones containing human tissue-type plasminogen activator cDNA sequences were identified in a cDNA library prepared using gel-fractionated mRNA from human melanoma cells and a polypeptide was produced having the fibrinolytic properties characteristic of authentic human t-PA.
Abstract: Bacterial clones containing human tissue-type plasminogen activator (t-PA) cDNA sequences were identified in a cDNA library prepared using gel-fractionated mRNA from human melanoma cells. A plasmid containing the Escherichia coli trp promoter and the cDNA sequence coding f or the 527-amino acid mature t-PA protein was constructed for expression in E. coli. A polypeptide was produced having the fibrinolytic properties characteristic of authentic human t-PA.
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TL;DR: A cDNA coding for human interleukin-2 (IL-2) has been cloned from a cDNA library prepared from partially purified IL-2 mRNA, which consists of 153 amino acids including a putative signal sequence.
Abstract: A cDNA coding for human interleukin-2 (IL-2) has been cloned from a cDNA library prepared from partially purified IL-2 mRNA. The DNA sequence codes for a polypeptide which consists of 153 amino acids including a putative signal sequence. A biologically active polypeptide, characteristic of human IL-2, was produced when the cDNA was fused to a simian virus 40 promoter sequence and used to transfect cultured monkey COS cells.
TL;DR: It is reported that intracellular injections of the calcium chelator EGTA block the development of LTP and this results strongly suggest that LTP is caused by a modification of the postsynaptic neurone and that its induction depends on the level of free calcium.
Abstract: Hippocampal long-term potentiation (LTP) is a remarkably stable facilitation of synaptic responses resulting from very brief trains of high-frequency stimulation. Because of its persistence and modest induction conditions, LTP represents a promising candidate for a substrate of memory. Some progress has been made in localizing the changes responsible for the effect; for example, it has been shown that LTP is not accompanied by changes in the fibre volleys of the test afferents or by generalized alterations of the dendrites of their target cells. However, it is unknown whether the potentiation is due to pre- or postsynaptic changes and there is evidence in favour of each (for example, see refs 5, 6). We now report that intracellular injections of the calcium chelator EGTA block the development of LTP. These results strongly suggest that LTP is caused by a modification of the postsynaptic neurone and that its induction depends on the level of free calcium.
TL;DR: The benefits of strength of numbers for defence of kills and territory, and in the hunting and killing of large prey, have contributed to the evolution of varied social groups of carnivores as mentioned in this paper.
Abstract: Diverse selective pressures have contributed to the evolution of the varied social groups of carnivores: the benefits of strength of numbers for defence of kills and territory, and in the hunting and killing of large prey; the ability to intimidate predators and to be vigilant against their approaches; the potential for information transfer and social learning, and a suite of alloparental behaviour patterns. Each of these may operate within the constraints upon group size and home range size set by patterns of resource dispersion. Between and within species, the magnitudes of costs and benefits attendant upon group life vary with circumstances and between individuals
TL;DR: To determine whether purified IL-1 could stimulate connective tissue breakdown in vitro, preliminary experiments with monocyte-conditioned medium indicated that MCF could stimulate bone resorption, and this study undertook this study to verify these observations.
Abstract: Many activities are now ascribed to the monokine interleukin 1 including enhancement of immune responses, stimulation of thymocyte proliferation, activation of B cells, stimulation of proteinase and prostaglandin production by connective tissue cells, stimulation of the production of acute phase proteins, induction of fever and the induction of neutrophilia. These activities were thought to be due to various different factors, but are now considered probably due to very similar, if not identical, molecules. The term interleukin 1 (IL-1) was coined to describe the factor released by monocyte/macrophages which acts on T and B lymphocytes. Only after this definition had been accepted was it shown that target cells other than lymphocytes were affected by IL-1. Products of human blood monocytes (mononuclear cell factor, MCF) have been implicated in the pathogenesis of inflammatory diseases such as rheumatoid arthritis and periodontal disease. Bone resorption is often a feature of such diseases, and monocytes are frequently found at sites of localized bone resorption. Preliminary experiments with monocyte-conditioned medium indicated that MCF could stimulate bone resorption. We therefore undertook this study to verify these observations and to determine whether purified IL-1 could stimulate connective tissue breakdown in vitro.
TL;DR: Cryopreservation procedures that allow a high survival rate of four- and eight-cell human embryos and the establishment of a pregnancy following the freezing and storage of an eight- cell embryo for 4 months in liquid nitrogen are reported.
Abstract: The widespread use of clomiphene citrate and exogenous gonadotrophins for in vitro fertilization (IVF) in human frequently results in the production of multiple embryos. Replacement of more than two embryos increases pregnancy rate but may result in multiple pregnancies with increased pre- and post-natal abnormality. Preservation of embryos for a limited time allows fewer embryos to be replaced on several different occasions and thus the problems of multiple pregnancy can be minimized, the effectiveness of a single IVF procedure increased and embryo replacement in adverse maternal conditions avoided. Preimplantation embryos have been successfully cryopreserved in many animal species. The sensitivity of embryos to cooling and freezing varies between species and stages of embryo development. We report here the cryopreservation procedures that allow a high survival rate of four- and eight-cell human embryos and the establishment of a pregnancy following the freezing and storage of an eight-cell embryo for 4 months in liquid nitrogen. The pregnancy terminated at 24 weeks' gestation due to development of a septic Streptomyces agalactiae chorion amnionitis after premature membrane rupture.
TL;DR: The properties of BAY K 8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-pyridine-5-carboxylate), one of the most potent of these novel compounds, are reported here.
Abstract: Transmembrane influx of extracellular calcium through specific calcium channels is now accepted to have an important role in the excitation-contraction coupling of cardiac and smooth muscle. The importance of such slow calcium channels has been underlined by the development of specific calcium channel blocking agents, the 'calcium antagonists', typified by verapamil, nifedipine and diltiazem. These drugs have been used to investigate the properties of slow calcium channels in a variety of tissues. We have found that small modifications to the nifedipine molecule produce other dihydropyridine derivatives (see Fig. 1) with effects diametrically opposite to those of the calcium antagonists: cardiac contractility is stimulated and smooth muscle is contracted. These effects are competitively antagonized by nifedipine. Apparently, nifedipine and the novel compounds bind to the same specific dihydropyridine binding sites in or near the calcium channel. In contrast to nifedipine, however, the new compounds promote--instead of inhibiting--the influx of Ca2+ ions. We report here the properties of BAY K 8644 (methyl 1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)- pyridine-5-carboxylate), one of the most potent of these novel compounds.