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Showing papers in "Nature in 1991"


Journal ArticleDOI
Sumio Iijima1
01 Nov 1991-Nature
TL;DR: Iijima et al. as mentioned in this paper reported the preparation of a new type of finite carbon structure consisting of needle-like tubes, which were produced using an arc-discharge evaporation method similar to that used for fullerene synthesis.
Abstract: THE synthesis of molecular carbon structures in the form of C60 and other fullerenes1 has stimulated intense interest in the structures accessible to graphitic carbon sheets. Here I report the preparation of a new type of finite carbon structure consisting of needle-like tubes. Produced using an arc-discharge evaporation method similar to that used for fullerene synthesis, the needles grow at the negative end of the electrode used for the arc discharge. Electron microscopy reveals that each needle comprises coaxial tubes of graphitic sheets, ranging in number from 2 up to about 50. On each tube the carbon-atom hexagons are arranged in a helical fashion about the needle axis. The helical pitch varies from needle to needle and from tube to tube within a single needle. It appears that this helical structure may aid the growth process. The formation of these needles, ranging from a few to a few tens of nanometres in diameter, suggests that engineering of carbon structures should be possible on scales considerably greater than those relevant to the fullerenes. On 7 November 1991, Sumio Iijima announced in Nature the preparation of nanometre-size, needle-like tubes of carbon — now familiar as 'nanotubes'. Used in microelectronic circuitry and microscopy, and as a tool to test quantum mechanics and model biological systems, nanotubes seem to have unlimited potential.

39,086 citations


Journal ArticleDOI
24 Oct 1991-Nature
TL;DR: In this article, the authors describe a photovoltaic cell, created from low-to medium-purity materials through low-cost processes, which exhibits a commercially realistic energy-conversion efficiency.
Abstract: THE large-scale use of photovoltaic devices for electricity generation is prohibitively expensive at present: generation from existing commercial devices costs about ten times more than conventional methods1. Here we describe a photovoltaic cell, created from low-to medium-purity materials through low-cost processes, which exhibits a commercially realistic energy-conversion efficiency. The device is based on a 10-µm-thick, optically transparent film of titanium dioxide particles a few nanometres in size, coated with a monolayer of a charge-transfer dye to sensitize the film for light harvesting. Because of the high surface area of the semiconductor film and the ideal spectral characteristics of the dye, the device harvests a high proportion of the incident solar energy flux (46%) and shows exceptionally high efficiencies for the conversion of incident photons to electrical current (more than 80%). The overall light-to-electric energy conversion yield is 7.1-7.9% in simulated solar light and 12% in diffuse daylight. The large current densities (greater than 12 mA cm-2) and exceptional stability (sustaining at least five million turnovers without decomposition), as well as the low cost, make practical applications feasible.

26,457 citations


Journal ArticleDOI
21 Feb 1991-Nature
TL;DR: A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene as discussed by the authors, which suggests that some cases of AD could be caused by mutations in the APP gene.
Abstract: A locus segregating with familial Alzheimer's disease (AD) has been mapped to chromosome 21, close to the amyloid precursor protein (APP) gene. Recombinants between the APP gene and the AD locus have been reported which seemed to exclude it as the site of the mutation causing familial AD. But recent genetic analysis of a large number of AD families has demonstrated that the disease is heterogeneous. Families with late-onset AD do not show linkage to chromosome 21 markers. Some families with early-onset AD show linkage to chromosome 21 markers, but some do not. This has led to the suggestion that there is non-allelic genetic heterogeneity even within early onset familial AD. To avoid the problems that heterogeneity poses for genetic analysis, we have examined the cosegregation of AD and markers along the long arm of chromosome 21 in a single family with AD confirmed by autopsy. Here we demonstrate that in this kindred, which shows linkage to chromosome 21 markers, there is a point mutation in the APP gene. This mutation causes an amino-acid substitution (Val----Ile) close to the carboxy terminus of the beta-amyloid peptide. Screening other cases of familial AD revealed a second unrelated family in which this variant occurs. This suggests that some cases of AD could be caused by mutations in the APP gene.

4,416 citations


Journal ArticleDOI
06 Jun 1991-Nature
TL;DR: The cell cycle is composed of a series of steps which can be negatively or postively regulated by various factors, chief among the negative regulators is the p53 protein, which can lead to cancer.
Abstract: The cell cycle is composed of a series of steps which can be negatively or positively regulated by various factors. Chief among the negative regulators is the p53 protein. Alteration or inactivation of p53 by mutation, or by its interactions with oncogene products of DNA tumour viruses, can lead to cancer. These mutations seem to be the most common genetic change in human cancers.

3,665 citations


Journal ArticleDOI
20 Jun 1991-Nature
TL;DR: A simple statistical test of the neutral protein evolution hypothesis is proposed based on a comparison of the number of amino-acid replacement substitutions to synonymous substitutions in the coding region of a locus, finding that there are more fixed replacement differences between species than expected.
Abstract: Proteins often differ in amino-acid sequence across species. This difference has evolved by the accumulation of neutral mutations by random drift, the fixation of adaptive mutations by selection, or a mixture of the two. Here we propose a simple statistical test of the neutral protein evolution hypothesis based on a comparison of the number of amino-acid replacement substitutions to synonymous substitutions in the coding region of a locus. If the observed substitutions are neutral, the ratio of replacement to synonymous fixed differences between species should be the same as the ratio of replacement to synonymous polymorphisms within species. DNA sequence data on the Adh locus (encoding alcohol dehydrogenase, EC 1.1.1.1) in three species in the Drosophila melanogaster species subgroup do not fit this expectation; instead, there are more fixed replacement differences between species than expected. We suggest that these excess replacement substitutions result from adaptive fixation of selectively advantageous mutations.

3,268 citations


Journal ArticleDOI
10 Jan 1991-Nature
TL;DR: GTPases are conserved molecular switches, built according to a common structural design, and rapidly accruing knowledge of individual GTPases—crystal structures, biochemical properties, or results of molecular genetic experiments—support and generate hypotheses relating structure to function in other members of the diverse family of GTPase.
Abstract: GTPases are conserved molecular switches, built according to a common structural design. Rapidly accruing knowledge of individual GTPases--crystal structures, biochemical properties, or results of molecular genetic experiments--support and generate hypotheses relating structure to function in other members of the diverse family of GTPases.

3,236 citations


Journal ArticleDOI
18 Apr 1991-Nature
TL;DR: The DNA of telomeres—the terminal DNA-protein complexes of chromosomes—differs notably from other DNA sequences in both structure and function, and has been shown to be essential for telomere maintenance and long-term viability.
Abstract: The DNA of telomeres--the terminal DNA-protein complexes of chromosomes--differs notably from other DNA sequences in both structure and function. Recent work has highlighted its remarkable mode of synthesis by the ribonucleoprotein reverse transcriptase, telomerase, as well as its ability to form unusual structures in vitro. Moreover, telomere synthesis by telomerase has been shown to be essential for telomere maintenance and long-term viability.

3,139 citations


Journal ArticleDOI
04 Jul 1991-Nature
TL;DR: It is concluded that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of X-LINKED spinal and bulbar muscular atrophy.
Abstract: X-linked spinal and bulbar muscular atrophy (Kennedy's disease) is an adult-onset form of motorneuron disease which may be associated with signs of androgen insensitivity. We have now investigated whether the androgen receptor gene on the proximal long arm of the X chromosome is a candidate gene for this disease. In patient samples we found androgen receptor gene mutations with increased size of a polymorphic tandem CAG repeat in the coding region. These amplified repeats were absolutely associated with the disease, being present in 35 unrelated patients and none of 75 controls. They segregated with the disease in 15 families, with no recombination in 61 meioses (the maximum log likelihood ratio (lod score) is 13.2 at a recombination rate of 0). The association is unlikely to be due to linkage disequilibrium, because 11 different disease alleles were observed. We conclude that enlargement of the CAG repeat in the androgen receptor gene is probably the cause of this disorder.

2,704 citations


Journal ArticleDOI
05 Sep 1991-Nature
TL;DR: The analysis of mutations affecting flower structure has led to the identification of some of the genes that direct flower development, and has shown that the distantly related flowering plants Arabidopsis thaliana and Antirrhinum majus use homologous mechanisms in floral pattern formation.
Abstract: The analysis of mutations affecting flower structure has led to the identification of some of the genes that direct flower development. Cloning of these genes has allowed the formulation of molecular models of how floral meristem and organ identity may be specified, and has shown that the distantly related flowering plants Arabidopsis thaliana and Antirrhinum majus use homologous mechanisms in floral pattern formation.

2,602 citations


Journal ArticleDOI
23 May 1991-Nature
TL;DR: Each MHC class I allele has its individual rules to which peptides presented in the groove adhere, and this information about the contents of MHC grooves is now provided.
Abstract: The crystal structures of major histocompatibility complex (MHC) molecules contain a groove occupied by heterogeneous material thought to represent peptides central to immune recognition, although until now relatively little characterization of the peptides has been possible. Exact information about the contents of MHC grooves is now provided. Moreover, each MHC class I allele has its individual rules to which peptides presented in the groove adhere.

2,577 citations


Journal ArticleDOI
18 Apr 1991-Nature
TL;DR: In this paper, low-temperature studies of potassium-doped C60 both as films and bulk samples, and demonstrate that this material becomes superconducting is demonstrated by microwave, resistivity and Meissner-effect measurements.
Abstract: THE synthesis of macroscopic amounts of C60 and C70 (fullerenes)1 has stimulated a variety of studies on their chemical and physical properties2,3. We recently demonstrated that C60 and C70 become conductive when doped with alkali metals4. Here we describe low-temperature studies of potassium-doped C60 both as films and bulk samples, and demonstrate that this material becomes superconducting. Superconductivity is demonstrated by microwave, resistivity and Meissner-effect measurements. Both polycrystalline powders and thin-film samples were studied. A thin film showed a resistance transition with an onset temperature of 16 K and essentially zero resistance near 5 K. Bulk samples showed a well-defined Meissner effect and magnetic-field-dependent microwave absorption beginning at 18 K. The onset of superconductivity at 18 K is the highest yet observed for a molecular superconductor.

Journal ArticleDOI
10 Jan 1991-Nature
TL;DR: Cyclin degradation is the key step governing exit from mitosis and progress into the next cell cycle, and anaphase may be triggered by the recognition of cyclin by the ubiquitin-conjugating system.
Abstract: Cyclin degradation is the key step governing exit from mitosis and progress into the next cell cycle. When a region in the N terminus of cyclin is fused to a foreign protein, it produces a hybrid protein susceptible to proteolysis at mitosis. During the course of degradation, both cyclin and the hybrid form conjugates with ubiquitin. The kinetic properties of the conjugates indicate that cyclin is degraded by ubiquitin-dependent proteolysis. Thus anaphase may be triggered by the recognition of cyclin by the ubiquitin-conjugating system.

Journal ArticleDOI
27 Jun 1991-Nature
TL;DR: Cloning of a complementary DNA for brain nitric oxide synthase reveals recognition sites for NADPH, FAD, flavin mononucleotide and calmodulin as well as phosphorylation sites, indicating that the synthase is regulated by many different factors.
Abstract: Nitric oxide is a messenger molecule, mediating the effect of endothelium-derived relaxing factor in blood vessels and the cytotoxic actions of macrophages, and playing a part in neuronal communication in the brain. Cloning of a complementary DNA for brain nitric oxide synthase reveals recognition sites for NADPH, FAD, flavin mononucleotide and calmodulin as well as phosphorylation sites, indicating that the synthase is regulated by many different factors. The only known mammalian enzyme with close homology is cytochrome P-450 reductase.

Journal ArticleDOI
31 Jan 1991-Nature
TL;DR: DCMP and dAMP are incorporated selectively opposite 8-oxodG with transient inhibition of chain extension occurring 3' to the modified base, and the potentially mutagenic insertion of dAMP is targeted exclusively to the site of the lesion.
Abstract: Oxidative damage to DNA, reflected in the formation of 8-oxo-7-hydrodeoxyguanosine (8-oxodG), may be important in mutagenesis, carcinogenesis and the ageing process. Kuchino et al. studied DNA synthesis on oligodeoxynucleotide templates containing 8-oxodG, concluding that the modified base lacked base pairing specificity and directed misreading of pyrimidine residues neighbouring the lesion. Here we report different results, using an approach in which the several products of a DNA polymerase reaction can be measured. In contrast to the earlier report, we find that dCMP and dAMP are incorporated selectively opposite 8-oxodG with transient inhibition of chain extension occurring 3' to the modified base. The potentially mutagenic insertion of dAMP is targeted exclusively to the site of the lesion. The ratio of dCMP to dAMP incorporated varies, depending on the DNA polymerase involved. Chain extension from the dA.8-oxodG pair was efficiently catalysed by all polymerases tested.

Journal ArticleDOI
25 Jul 1991-Nature
TL;DR: In this article, wild-type p53 protein has many properties consistent with its being the product of a tumour suppressor gene, which could be involved in promoting cell differentiation as well as in mediating growth arrest by growthinhibitory cytokines.
Abstract: Wild-type p53 protein has many properties consistent with its being the product of a tumour suppressor gene. Although the normal roles of tumour suppressor genes are still largely unknown, it seems that they could be involved in promoting cell differentiation as well as in mediating growth arrest by growth-inhibitory cytokines. Hence, the abrogation of wild-type p53 expression, which is a common feature of many tumours, could eliminate these activities. We have now tested this notion by restoring the expression of p53 in a murine myeloid leukaemic cell line that normally lacks p53. The use of a temperature-sensitive p53 mutant allowed us to analyse cells in which the introduced p53 had either wild-type or mutant properties. Although there seemed to be no effect on differentiation, the introduction of wild-type p53 resulted in rapid loss of cell viability in a way characteristic of apoptosis (programmed cell death). The effect of wild-type p53 was counteracted by interleukin-6. Thus products of tumour suppressor genes could be involved in restricting precursor cell populations by mediating apoptosis.

Journal ArticleDOI
15 Aug 1991-Nature
TL;DR: Using a random combinatorial library of the rearranged heavy and kappa light chains from mice immune to the hapten 2-phenyloxazol-5-one (phOx), diverse libraries of antibody fragments are displayed on the surface of fd phage and elicited many more pairings with strong binding activities.
Abstract: To by-pass hybridoma technology and animal immunization, we are trying to build antibodies in bacteria by mimicking features of immune selection. Recently we used fd phage to display antibody fragments fused to a minor coat protein, allowing enrichment of phage with antigen. Using a random combinatorial library of the rearranged heavy (VH) and kappa (V kappa) light chains from mice immune to the hapten 2-phenyloxazol-5-one (phOx), we have now displayed diverse libraries of antibody fragments on the surface of fd phage. After a single pass over a hapten affinity column, fd phage with a range of phOx binding activities were detected, at least one with high affinity (dissociation constant, Kd = 10(-8) M). A second pass enriched for the strong binders at the expense of the weak. The binders were encoded by V genes similar to those found in anti-phOx hybridomas but in promiscuous combinations (where the same V gene is found with several different partners). By combining a promiscuous VH or V kappa gene with diverse repertoires of partners to create hierarchical libraries, we elicited many more pairings with strong binding activities. Phage display offers new ways of making antibodies from V-gene libraries, altering V-domain pairings and selecting for antibodies with good affinities.

Journal ArticleDOI
09 May 1991-Nature
TL;DR: It is shown that Sry on a 14-kilobase genomic DNA fragment is sufficient to induce testis differentiation and subsequent male development when introduced into chromosomally female mouse embryos.
Abstract: The initiation of male development in mammals requires one or more genes on the Y chromosome. A recently isolated gene, termed SRY in humans and Sry in mouse, has many of the genetic and biological properties expected of a Y-located testis-determining gene. It is now shown that Sry on a 14-kilobase genomic DNA fragment is sufficient to induce testis differentiation and subsequent male development when introduced into chromosomally female mouse embryos.

Journal ArticleDOI
18 Apr 1991-Nature
TL;DR: The cloning of a gene that encodes a dopamine receptor gene that has high homology to the human dopamine D2 and D3 receptor genes is reported, which suggests the existence of other types of dopamine receptors which are more sensitive to clozapine.
Abstract: DOPAMINE receptors belong to the family of G protein-coupled receptors. On the basis of the homology between these receptors, three different dopamine receptors (D1,D2,D3) have been cloned1–7. Dopamine receptors are primary targets for drugs used in the treatment of psychomotor disorders such as Parkinson's disease and schizophrenia8,9. In the management of socially withdrawn and treatment-resistant schizophrenics, clozapine10 is one of the most favoured antipsychotics because it does not cause tardive dyskinesia11. Clozapine, however, has dissociation constants for binding to D2 and D3 that are 4 to 30 times the therapeutic free concentration of clozapine in plasma water12,13. This observation suggests the existence of other types of dopamine receptors which are more sensitive to clozapine. Here we report the cloning of a gene that encodes such a receptor (D4). The D4 receptor gene has high homology to the human dopamine D2 and D3 receptor genes. The pharmacological characteristics of this receptor resembles that of the D2 and D3 receptors, but its affinity for clozapine is one order of magnitude higher. Recognition and characterization of this clozapine neuroleptic site may prove useful in the design of new types of drugs.

Journal ArticleDOI
01 Sep 1991-Nature
TL;DR: In this article, the authors used the atomic force microscope to measure the forces between a planar surface and an individual colloid particle, a silica sphere of radius 3.5 µm, attached to the force sensor in the microscope and measured in solutions of sodium chloride.
Abstract: THE forces between colloidal particles dominate the behaviour of a great variety of materials, including paints, paper, soil, clays and (in some circumstances) cells. Here we describe the use of the atomic force microscope to measure directly the force between a planar surface and an individual colloid particle. The particle, a silica sphere of radius 3.5 µm, was attached to the force sensor in the microscope and the force between the particle and the surface was measured in solutions of sodium chloride. The measurements are consistent with the double-layer theory1,2 of colloidal forces, although at very short distances there are deviations that may be attributed to hydration forces3–6 or surface roughness, and with previous studies on macroscopic systems4–6. Similar measurements should be possible for a wide range of the particulate and fibrous materials that are often encountered in industrial contexts, provided that they can be attached to the microscope probe.

Journal ArticleDOI
25 Jul 1991-Nature
TL;DR: Fibrillin is implicate as the protein defective in patients with the Marfan syndrome and a de novo missense mutation in the fibrillin gene is described in two patients with sporadic disease.
Abstract: Marfan syndrome is an inherited disorder of connective tissue manifested in the ocular, skeletal and cardiovascular systems. It is inherited as an autosomal dominant with high penetrance, but has great clinical variability. Linkage studies have mapped the Marfan locus to chromosome 15q15-21.3. There have been no reports of genetic heterogeneity in the syndrome. Following the identification of fibrillin (a glycoprotein component of the extracellular microfibril), immunohistopathological quantification of the protein in skin and fibroblast culture, and examination of fibrillin synthesis, extracellular transport, and incorporation into the extracellular matrix (D. M. Milewicz, R.E.P., E. S. Crawford and P. H. Byers, manuscript in preparation) have demonstrated abnormalities of fibrillin metabolism in most patients. A portion of the complementary DNA encoding fibrillin has been cloned and mapped by in situ hybridization to chromosome 15. Here we report that the fibrillin gene is linked to the Marfan phenotype (theta = 0.00; logarithm of the odds (lod) = 3.9) and describe a de novo missense mutation in the fibrillin gene in two patients with sporadic disease. We thus implicate fibrillin as the protein defective in patients with the Marfan syndrome.

Journal ArticleDOI
04 Apr 1991-Nature
TL;DR: The importance of the membrane form of the μ chain in B-cell development is assessed by generating mice lacking this chain by disrupting one of the membranes exons of the gene encoding the μ-chain constant region by gene targeting in mouse embryonic stem cells.
Abstract: OF the various classes of antibodies that B lymphocytes can produce, class M (IgM) is the first to be expressed on the membrane of the developing cells. Pre-B cells, the precursors of B-lymphocytes, produce the heavy chain of IgM (μ chain), but not light chains1. Recent data suggest that pre-B cells express μ chains on the membrane together with the 'surrogate' light chains λ5 and VpreB (refs 2–7). This complex could control pre-B-cell differentiation, in particular the rearrangement of the light-chain genes8. We have now assessed the importance of the membrane form of the μ chain in B-cell development by generating mice lacking this chain. We disrupted one of the membrane exons of the gene encoding the μ-chain constant region by gene targeting9 in mouse embryonic stem cells10. From these cells we derived mice heterozygous or homozygous for the mutation. B-cell development in the heterozygous mice seemed to be normal, but in homozygous animals B cells were absent, their development already being arrested at the stage of pre-B-cell maturation.

Journal ArticleDOI
07 Nov 1991-Nature
TL;DR: A complementary DNA encoding the rat NMDA receptor has been cloned and characterized and it has been found that this protein has a significant sequence similarity to the AMPA/kainate receptors.
Abstract: A complementary DNA encoding the rat NMDA receptor has been cloned and characterized. The single protein encoded by the cDNA forms a receptor-channel complex that has electrophysiological and pharmacological properties characteristic of the NMDA receptor. This protein has a significant sequence similarity to the AMPA/kainate receptors and contains four putative transmembrane segments following a large extracellular domain. The NMDA receptor messenger RNA is expressed in neuronal cells throughout the brain regions, particularly in the hippocampus, cerebral cortex and cerebellum.

Journal ArticleDOI
27 Jun 1991-Nature
TL;DR: The functional properties of the channels corresponding to the two receptors are compared by incorporating endoplasmic reticulum vesicles from canine cerebellum into planar bilayers to provide a basis for complex patterns of intracellular calcium regulation.
Abstract: RELEASE of calcium from intracellular stores occurs by two pathways, an inositol 1,4,5-trisphosphate (InsP3)-gated channel1–3 and a calcium-gated channel (ryanodine receptor)4–6. Using specific antibodies, both receptors were found in Purkinje cells of cerebellum7,8. We have now compared the functional properties of the channels corresponding to the two receptors by incorporating endoplasmic reticulum vesicles from canine cerebellum into planar bilayers. InsP3-gated channels were observed most frequently. Another channel type was activated by adenine nucleotides or caffeine, inhibited by ruthenium red, and modified by ryanodine, characteristics of the ryanodine receptor/channel6. The open probability of both channel types displayed a bell-shaped curve for dependence on calcium. For the InsP3-gated channel, the maximum probability of opening occurred at 0.2 µM free calcium, with sharp decreases on either side of the maximum. Maximum activity for the ryanodine receptor/channel was maintained between 1 and 100 µM calcium. Thus, within the physiological range of cytoplasmic calcium, the InsP3-gated channel itself allows positive feed-back and then negative feedback for calcium release, whereas the ryanodine receptor/channel behaves solely as a calcium-activated channel. The existence in the same cell of two channels with different responses to calcium and different ligand sensitivities provides a basis for complex patterns of intracellular calcium regulation.

Journal ArticleDOI
04 Jul 1991-Nature
TL;DR: During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS–1 acts as a multisite Mocking' protein to bind signal-transducing molecules containing Src-homology 2 and SRC-Homology-3 domains, which may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism.
Abstract: Since the discovery of insulin nearly 70 years ago, there has been no problem more fundamental to diabetes research than understanding how insulin works at the cellular level. Insulin binds to the alpha subunit of the insulin receptor which activates the tyrosine kinase in the beta subunit, but the molecular events linking the receptor kinase to insulin-sensitive enzymes and transport processes are unknown. Our discovery that insulin stimulates tyrosine phosphorylation of a protein of relative molecular mass between 165,000 and 185,000, collectively called pp185, showed that the insulin receptor kinase has specific cellular substrates. The pp185 is a minor cytoplasmic phosphoprotein found in most cells and tissues; its phosphorylation is decreased in cells expressing mutant receptors defective in signalling. We have now cloned IRS-1, which encodes a component of the pp185 band. IRS-1 contains over ten potential tyrosine phosphorylation sites, six of which are in Tyr-Met-X-Met motifs. During insulin stimulation, the IRS-1 protein undergoes tyrosine phosphorylation and binds phosphatidylinositol 3-kinase, suggesting that IRS-1 acts as a multisite 'docking' protein to bind signal-transducing molecules containing Src-homology 2 and Src-homology-3 domains. Thus IRS-1 may link the insulin receptor kinase and enzymes regulating cellular growth and metabolism.

Journal ArticleDOI
15 Aug 1991-Nature
TL;DR: Data support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens.
Abstract: A large case-control study of malaria in West African children shows that a human leucocyte class I antigen (HLA-Bw53) and an HLA class II haplotype (DRB1*1302-DQB1*0501), common in West Africans but rare in other racial groups, are independently associated with protection from severe malaria. In this population they account for as great a reduction in disease incidence as the sickle-cell haemoglobin variant. These data support the hypothesis that the extraordinary polymorphism of major histocompatibility complex genes has evolved primarily through natural selection by infectious pathogens.

Journal ArticleDOI
07 Nov 1991-Nature
TL;DR: The precise identification of an antigenic determinant recognized by a monoclonal antibody as well as the straightforward development of new potent antimicrobial peptides are presented.
Abstract: Existing methods for the synthesis and screening of large numbers of peptides are limited by their inability to generate and screen the requisite number (millions) of individual peptides and/or their inability to generate unmodified free peptides in quantities able to interact in solution. We have circumvented these limitations by developing synthetic peptide combinatorial libraries composed of mixtures of free peptides in quantities which can be used directly in virtually all existing assay systems. The screening of these heterogeneous libraries, along with an iterative selection and synthesis process, permits the systematic identification of optimal peptide ligands. Starting with a library composed of more than 34 million hexa-peptides, we present here the precise identification of an antigenic determinant recognized by a monoclonal antibody as well as the straightforward development of new potent antimicrobial peptides.

Journal ArticleDOI
06 Jun 1991-Nature
TL;DR: Extrachromosomal and integrative expression vectors carrying the regulatory sequences for major BCG heat-shock proteins have been developed and can elicit long-lasting humoral and cellular immune responses to foreign antigens in mice.
Abstract: BCG, a live attenuated tubercle bacillus, is the most widely used vaccine in the world and is also a useful vaccine vehicle for delivering protective antigens of multiple pathogens. Extrachromosomal and integrative expression vectors carrying the regulatory sequences for major BCG heat-shock proteins have been developed to allow expression of foreign antigens in BCG. These recombinant BCG strains can elicit long-lasting humoral and cellular immune responses to foreign antigens in mice.

Journal ArticleDOI
21 Mar 1991-Nature
TL;DR: BRAIN-derived neurotrophic factor seems to be a trophic factor for mesencephalic dopaminergic neurons, increasing their survival, including that of neuronal cells which degenerate in Parkinson's disease.
Abstract: Brain-derived neurotrophic factor (BDNF), present in minute amounts in the adult central nervous system, is a member of the nerve growth factor (NGF) family, which includes neurotrophin-3 (NT-3). NGF, BDNF and NT-3 all support survival of subpopulations of neural crest-derived sensory neurons; most sympathetic neurons are responsive to NGF, but not to BDNF; NT-3 and BDNF, but not NGF, promote survival of sensory neurons of the nodose ganglion. BDNF, but not NGF, supports the survival of cultured retinal ganglion cells but both NGF and BDNF promote the survival of septal cholinergic neurons in vitro. However, knowledge of their precise physiological role in development and maintenance of the nervous system neurons is still limited. The BDNF gene is expressed in many regions of the adult CNS, including the striatum. A protein partially purified from bovine striatum, a target of nigral dopaminergic neurons, with characteristics apparently similar to those of BDNF, can enhance the survival of dopaminergic neurons in mesencephalic cultures. BDNF seems to be a trophic factor for mesencephalic dopaminergic neurons, increasing their survival, including that of neuronal cells which degenerate in Parkinson's disease. Here we report the effects of BDNF on the survival of dopaminergic neurons of the developing substantia nigra.

Journal ArticleDOI
17 Oct 1991-Nature
TL;DR: Evidence is presented that mitogen-activated protein-serine (MAP) kinases (pp54 and pp42/44) specifically phosphorylate these sites and that their phosphorylation positively regulates the transacting activity of c-jun.
Abstract: THE proto-oncogene c-jun is a component of the AP-1 transcription factor family involved in the mediation of nuclear events elicited by extracellular stimuli1–3. The c-jun protein is negatively regulated by phosphorylation of residues near the carboxy terminus which are dephosphorylated in response to phorbol esters4. Here we identify two serine residues in the amino terminal Al transactivation domain which are phosphorylated in response to a variety of mitogens, phorbol esters and activated ras (ref. 5). We present evidence that mitogen-activated protein-serine (MAP) kinases (pp54 and pp42/44) specifically phosphorylate these sites and that their phosphorylation positively regulates the transacting activity of c-jun. The MAP kinase enzymes pp54 and pp42/44 are regulated by tyrosine as well as serine/threonine phosphorylation6,7. MAP kinase activation of c-jun may underlie the common stimulation of this transcription factor by mitogens, growth factors and oncogenes.

Journal ArticleDOI
14 Nov 1991-Nature
TL;DR: The results suggest that FtsZ self-assembles into a ring structure at the future division site and may function as a cytoskeletal element and the formation of this ring may be the point at which division is regulated.
Abstract: Genes for cell division have been identified in Escherichia coli by the isolation of conditional lethal mutations that block cell division, but do not affect DNA replication or segregation. Of these genes, ftsZ is of great interest as it acts earliest in the division pathway, is essential, its level dictates the frequency of division, and it is thought to be the target of two cell-division inhibitors, SulA, produced in response to DNA damage, and MinCD, which prevents division at old sites. Here we have used immunoelectronmicroscopy to localize the FtsZ protein to the division site. The results suggest that FtsZ self-assembles into a ring structure at the future division site and may function as a cytoskeletal element. The formation of this ring may be the point at which division is regulated.