Showing papers in "Nature in 1994"
TL;DR: The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.
Abstract: The mechanisms that balance food intake and energy expenditure determine who will be obese and who will be lean. One of the molecules that regulates energy balance in the mouse is the obese (ob) gene. Mutation of ob results in profound obesity and type II diabetes as part of a syndrome that resembles morbid obesity in humans. The ob gene product may function as part of a signalling pathway from adipose tissue that acts to regulate the size of the body fat depot.
12,394 citations
TL;DR: This in vivo model replicates many aspects of human AML and defines a new leukaemia-initiating cell which is less mature than colony-forming cells.
Abstract: Most human acute myeloid leukaemia (AML) cells have limited proliferative capacity, suggesting that the leukaemic clone may be maintained by a rare population of stem cells. This putative leukaemic stem cell has not been characterized because the available in vitro assays can only detect progenitors with limited proliferative and replating potential. We have now identified an AML-initiating cell by transplantation into severe combined immune-deficient (SCID) mice. These cells homed to the bone marrow and proliferated extensively in response to in vivo cytokine treatment, resulting in a pattern of dissemination and leukaemic cell morphology similar to that seen in the original patients. Limiting dilution analysis showed that the frequency of these leukaemia-initiating cells in the peripheral blood of AML patients was one engraftment unit in 250,000 cells. We fractionated AML cells on the basis of cell-surface-marker expression and found that the leukaemia-initiating cells that could engraft SCID mice to produce large numbers of colony-forming progenitors were CD34+ CD38-; however, the CD34+ CD38+ and CD34- fractions contained no cells with these properties. This in vivo model replicates many aspects of human AML and defines a new leukaemia-initiating cell which is less mature than colony-forming cells.
4,597 citations
TL;DR: It is demonstrated that the phenotype of APC resistance is associated with hetero-zygosity or homozygosity for a single point mutation in the factor V gene which predicts the synthesis of a factor V molecule that is not properly inactivated by APC.
Abstract: Activated protein C (APC) is a serine protease with potent anticoagulant properties, which is formed in blood on the endothelium from an inactive precursor During normal haemostasis, APC limits clot formation by proteolytic inactivation of factors Va and VIIIa (ref 2) To do this efficiently the enzyme needs a nonenzymatic cofactor, protein S (ref 3) Recently it was found that the anticoagulant response to APC (APC resistance) was very weak in the plasma of 21% of unselected consecutive patients with thrombosis and about 50% of selected patients with a personal or family history of thrombosis; moreover, 5% of healthy individuals show APC resistance, which is associated with a sevenfold increase in the risk for deep vein thrombosis Here we demonstrate that the phenotype of APC resistance is associated with heterozygosity or homozygosity for a single point mutation in the factor V gene (at nucleotide position 1,691, G-->A substitution) which predicts the synthesis of a factor V molecule (FV Q506, or FV Leiden) that is not properly inactivated by APC The allelic frequency of the mutation in the Dutch population is approximately 2% and is at least tenfold higher than that of all other known genetic risk factors for thrombosis (protein C (ref 8), protein S (ref 9), antithrombin10 deficiency) together
3,895 citations
TL;DR: In this article, a hybrid organic/inorganic electroluminescent device was constructed based on the recombination of holes injected into a layer of semiconducting p-paraphenylene vinylene (PPV) with electrons injected into the multilayer film of cadmium selenide nanocrystals.
Abstract: ELECTROLUMINESCENT devices have been developed recently that are based on new materials such as porous silicon1 and semiconducting polymers2,3. By taking advantage of developments in the preparation and characterization of direct-gap semiconductor nanocrystals4–6, and of electroluminescent polymers7, we have now constructed a hybrid organic/inorganic electroluminescent device. Light emission arises from the recombination of holes injected into a layer of semiconducting p-paraphenylene vinylene (PPV)8–10 with electrons injected into a multilayer film of cadmium selenide nanocrystals. Close matching of the emitting layer of nanocrystals with the work function of the metal contact leads to an operating voltage11 of only 4V. At low voltages emission from the CdSe layer occurs. Because of the quantum size effect19–24 the colour of this emission can be varied from red to yellow by changing the nanocrystal size. At higher voltages green emission from the polymer layer predominates. Thus this device has a degree of voltage tunability of colour.
3,783 citations
TL;DR: Production of interleukin-1 and tumour necrosis factor from stimulated human monocytes is inhibited by a new series of pyridinyl-imidazole compounds, suggesting that the CSBPs are critical for cytokine production.
Abstract: Production of interleukin-1 and tumour necrosis factor from stimulated human monocytes is inhibited by a new series of pyridinyl-imidazole compounds. Using radiolabelled and radio-photoaffinity-labelled chemical probes, the target of these compounds was identified as a pair of closely related mitogen-activated protein kinase homologues, termed CSBPs. Binding of the pyridinyl-imidazole compounds inhibited CSBP kinase activity and could be directly correlated with their ability to inhibit cytokine production, suggesting that the CSBPs are critical for cytokine production.
3,348 citations
TL;DR: In this paper, a topological analysis of local quantum-mechanical functions related to the Pauli exclusion principle is presented, where the local maxima of these functions define "localization attractors", of which there are only three basic types: bonding, non-bonding and core.
Abstract: THE definitions currently used to classify chemical bonds (in terms of bond order, covalency versus ionicity and so forth) are derived from approximate theories1–3 and are often imprecise. Here we outline a first step towards a more rigorous means of classification based on topological analysis of local quantum-mechanical functions related to the Pauli exclusion principle. The local maxima of these functions define 'localization attractors', of which there are only three basic types: bonding, non-bonding and core. Bonding attractors lie between the core attractors (which themselves surround the atomic nuclei) and characterize the shared-electron interactions. The number of bond attractors is related to the bond multiplicity. The spatial organization of localization attractors provides a basis for a well-defined classification of bonds, allowing an absolute characterization of covalency versus ionicity to be obtained from observable properties such as electron densities.
3,146 citations
TL;DR: The crystal structure of bovine mitochondrial F1-ATPase determined at 2.8 Å resolution supports a catalytic mechanism in intact ATP synthase in which the three catalytic subunits are in different states of the catalytic cycle at any instant.
Abstract: In the crystal structure of bovine mitochondrial F1-ATPase determined at 2.8 A resolution, the three catalytic beta-subunits differ in conformation and in the bound nucleotide. The structure supports a catalytic mechanism in intact ATP synthase in which the three catalytic subunits are in different states of the catalytic cycle at any instant. Interconversion of the states may be achieved by rotation of the alpha 3 beta 3 subassembly relative to an alpha-helical domain of the gamma-subunit.
2,878 citations
TL;DR: A novel protease resembling ICE (prICE) that is active in a cell-free system that reproduces the morphological and biochemical events of apoptosis in the extracts including morphological changes, cleavage of PARP and production of an oligonucleosomal ladder.
Abstract: Recent studies suggest that proteases of the interleukin 1-beta-converting enzyme (ICE)/ced-3 family are involved in initiating the active phase of apoptosis. Here we identify a novel protease resembling ICE (prICE) that is active in a cell-free system that reproduces the morphological and biochemical events of apoptosis. prICE cleaves the nuclear enzyme poly(ADP-ribose) polymerase (PARP) at a tetrapeptide sequence identical to one of two ICE sites in pro-interleukin-1-beta. However, prICE does not cleave purified pro-interleukin-1-beta, and purified ICE does not cleave PARP, indicating that the two activities are distinct. Inhibition of prICE abolishes all manifestations of apoptosis in the extracts including morphological changes, cleavage of PARP and production of an oligonucleosomal ladder. These studies suggest that prICE might be pivotal in initiating the active phase of apoptosis in vitro and in intact cells.
2,631 citations
TL;DR: The kinase p54s are the principal c-Jun N-terminal kinases activated by cellular stress and tumour necrosis factor (TNF)-α, hence they are designated stress-activated protein kinases, or SAPKs.
Abstract: The mitogen-activated protein (MAP) kinases Erk-1 and Erk-2 are proline-directed kinases that are themselves activated through concomitant phosphorylation of tyrosine and threonine residues. The kinase p54 (M(r) 54,000), which was first isolated from cycloheximide-treated rats, is proline-directed like Erks-1/2, and requires both Tyr and Ser/Thr phosphorylation for activity. p54 is, however, distinct from Erks-1/2 in its substrate specificity, being unable to phosphorylate pp90rsk but more active in phosphorylating the c-Jun transactivation domain. Molecular cloning of p54 reveals a unique subfamily of extracellularly regulated kinases. Although they are 40-45% identical in sequence to Erks-1/2, unlike Erks-1/2 the p54s are only poorly activated in most cells by mitogens or phorbol esters. However, p54s are the principal c-Jun N-terminal kinases activated by cellular stress and tumour necrosis factor (TNF)-alpha, hence they are designated stress-activated protein kinases, or SAPKs. SAPKs are also activated by sphingomyelinase, which elicits a subset of cellular responses to TNF-alpha (ref. 9). SAPKs therefore define a new TNF-alpha and stress-activated signalling pathway, possibly initiated by sphingomyelin-based second messengers, which regulates the activity of c-Jun.
2,628 citations
TL;DR: The cloning of the complemen-tary DNA encoding a new matrix metalloproteinase with a potential transmembrane domain is reported, which may trigger invasion by tumour cells by activating pro-gelatinase A on the tumour cell surface.
Abstract: GELATINASE A (type-IV collagenase; Mr 72,000) is produced by tumour stroma cells and is believed to be crucial for their invasion and metastasis, acting by degrading extracellular matrix macro-molecules such as type IV collagen1–3. An inactive precursor of gelatinase A (pro-gelatinase A) is secreted and activated in invasive tumour tissue4–7 as a result of proteolysis which is mediated by a fraction of tumour cell membrane that is sensitive to metallopro-teinase inhibitors4,5. Here we report the cloning of the complemen-tary DNA encoding a new matrix metalloproteinase with a potential transmembrane domain. Expression of the gene product on the cell surface induces specific activation of pro-gelatinase A in vitro and enhances cellular invasion of the reconstituted basement membrane. Tumour cells of invasive lung carcinomas, which con-tain activated forms of gelatinase A, were found to express the transcript and the gene product. The new metalloproteinase may thus trigger invasion by tumour cells by activating pro-gelatinase A on the tumour cell surface.
2,615 citations
TL;DR: It is reported here that selected mutants had a minimum inhibitory concentration of 640 μg ml-1, a 32,000-fold increase and 64-fold greater than any published TEM-1 derived enzyme.
Abstract: DNA SHUFFLING is a method for in vitro homologous recombination of pools of selected mutant genes by random fragmentation and polymerase chain reaction (PCR) reassembly1. Computer simulations called genetic algorithms2–4have demonstrated the importance of iterative homologous recombination for sequence evolution. Oligonucleotide cassette mutagenesis5–11 and error-prone PCR12,13 are not combinatorial and thus are limited in searching sequence space1,14. We have tested mutagenic DNA shuffling for molecular evolution14–18 in a p-lactamase model system9,19. Three cycles of shuffling and two cycles of backcrossing with wild-type DNA, to eliminate non-essential mutations, were each followed by selection on increasing concentrations of the antibiotic cefotaxime. We report here that selected mutants had a minimum inhibitory concentration of 640 μg ml-1, a 32,000-fold increase and 64-fold greater than any published TEM-1 derived enzyme. Cassette mutagenesis and error-prone PCR resulted in only a 16-fold increase9.
TL;DR: A model is described that explains multispecies coexistence in patchy habitats and which predicts that their abundance may be fleeting, a future ecological cost of current habitat destruction.
Abstract: HABITAT destruction is the major cause of species extinctions1–3. Dominant species often are considered to be free of this threat because they are abundant in the undisturbed fragments that remain after destruction. Here we describe a model that explains multispecies coexistence in patchy habitats4 and which predicts that their abundance may be fleeting. Even moderate habitat destruction is predicted to cause time-delayed but deterministic extinction of the dominant competitor in remnant patches. Further species are predicted to become extinct, in order from the best to the poorest competitors, as habitat destruction increases. More-over, the more fragmented a habitat already is, the greater is the number of extinctions caused by added destruction. Because such extinctions occur generations after fragmentation, they represent a debt—a future ecological cost of current habitat destruction.
TL;DR: The role of TGF-β binds directly to receptor II, which is a constitutively active kinase, and phosphorylation allows receptor I to propagate the signal to downstream substrates, providing a mechanism by which a cytokine can generate the first step of a signalling cascade.
Abstract: Transforming growth factor-β (TGF-β) signals by contacting two distantly related transmem-brane serine/threonine kinases called receptors I and II. The role of these molecules in signalling has now been determined. TGF-β binds directly to receptor II, which is a constitutively active kinase. Bound TGF-β is then recognized by receptor I which is recruited into the complex and becomes phosphorylated by receptor II. Phosphorylation allows receptor I to propagate the signal to downstream substrates. This provides a mechanism by which a cytokine can generate the first step of a signalling cascade.
TL;DR: Findings suggest the human amygdala may be indispensable to recognize fear in facial expressions, but is not required to recognize personal identity from faces, and constrains the broad notion that the amygdala is involved in emotion.
Abstract: Studies in animals have shown that the amygdala receives highly processed visual input, contains neurons that respond selectively to faces, and that it participates in emotion and social behaviour Although studies in epileptic patients support its role in emotion, determination of the amygdala's function in humans has been hampered by the rarity of patients with selective amygdala lesions Here, with the help of one such rare patient, we report findings that suggest the human amygdala may be indispensable to: (1) recognize fear in facial expressions; (2) recognize multiple emotions in a single facial expression; but (3) is not required to recognize personal identity from faces These results suggest that damage restricted to the amygdala causes very specific recognition impairments, and thus constrains the broad notion that the amygdala is involved in emotion
TL;DR: It is reported that a human gene encoding a protein, hMLHl (human MutL homologue), homologous to the bacterial DNA mismatch repair protein MutL, is located on human chromosome 3p21.3-23.
Abstract: The human DNA mismatch repair gene homologue hMSH2, on chromosome 2p is involved in hereditary non-polyposis colon cancer (HNPCC) On the basis of linkage data, a second HNPCC locus was assigned to chromosome 3p21-23 (ref 3) Here we report that a human gene encoding a protein, hMLH1 (human MutL homologue), homologous to the bacterial DNA mismatch repair protein MutL, is located on human chromosome 3p213-23 We propose that hMLH1 is the HNPCC gene located on 3p because of the similarity of the hMLH1 gene product to the yeast DNA mismatch repair protein, MLH1, the coincident location of the hMLH1 gene and the HNPCC locus on chromosome 3, and hMLH1 missense mutations in affected individuals from a chromosome 3-linked HNPCC family
TL;DR: In vivo, dominant negative Ras mutant N17 inhibits growth factor induced production of 3′ hosphorylated phosphoinositides in PC12 cells, and transfection of Ras, but not Raf, into COS cells results in a large elevation in the level of these lipids.
Abstract: Ras (p21ras) interacts directly with the catalytic subunit of phosphatidylinositol-3-OH kinase in a GTP-dependent manner through the Ras effector site. In vivo, dominant negative Ras mutant N17 inhibits growth factor induced production of 3' phosphorylated phosphoinositides in PC12 cells, and transfection of Ras, but not Raf, into COS cells results in a large elevation in the level of these lipids. Therefore Ras can probably regulate phosphatidylinositol-3-OH kinase, providing a point of divergence in signalling pathways downstream of Ras.
TL;DR: In this article, a generalized approach to the synthesis of periodic mesophases of metal oxides and cationic or anionic surfactants under a range of pH conditions is presented.
Abstract: THE recent synthesis of silica-based mesoporous materials1,2 by the cooperative assembly of periodic inorganic and surfactant-based structures has attracted great interest because it extends the range of molecular-sieve materials into the very-large-pore regime. If the synthetic approach can be generalized to transition-metal oxide mesostructures, the resulting nanocomposite materials might find applications in electrochromic or solid-electrolyte devices3,4, as high-surface-area redox catalysts5 and as substrates for biochemical separations. We have proposed recently6 that the matching of charge density at the surfactant/inorganic interfaces governs the assembly process; such co-organization of organic and inorganic phases is thought to be a key aspect of biomineralization7. Here we report a generalized approach to the synthesis of periodic mesophases of metal oxides and cationic or anionic surfactants under a range of pH conditions. We suggest that the assembly process is controlled by electrostatic complementarity between the inorganic ions in solution, the charged surfactant head groups and—when these charges both have the same sign—inorganic counterions. We identify a number of different general strategies for obtaining a variety of ordered composite materials.
TL;DR: In this article, it was shown that the presence of copper is not a prerequisite for the existence of superconductivity in a layered perovskite, and that the low value of the superconducting transition temperature (Tc = 0.93 K) points towards a special role for copper in the high-temperature superconductors.
Abstract: FOLLOWING the discovery of superconductivity at ∼30 K in La2−xBaxCuO4 (ref. 1), a large number of related compounds have been found that are superconducting at relatively high temperatures. The feature common to all of these materials is a layered crystal structure based on a perovskite template and containing planar networks of copper and oxygen. This raises the question of whether superconductivity can occur in layered perovskites that do not contain copper. To the best of our knowledge, no such material has been found to date, despite nearly a decade of searching. We describe here the discovery of superconductivity in Sr2RuO4, a layered perovskite isostructural with La2−xBaxCuO4 (Fig. 1). Our results demonstrate that the presence of copper is not a prerequisite for the existence of superconductivity in a layered perovskite. But the low value of the superconducting transition temperature (Tc = 0.93 K) points towards a special role for copper in the high-temperature superconductors.
TL;DR: A mammalian FKBP–rapamycin-associated protein (FRAP) is isolate whose binding to structural variants of rapamycin complexed to FK BP12 correlates with the ability of these ligands to inhibit cell-cycle progression.
Abstract: THE structurally related natural products rapamycin and FK506 bind to the same intracellular receptor, FKBP12, yet the resulting complexes interfere with distinct signalling pathways1,2. FKBP12–rapamycin inhibits progression through the Gl phase of the cell cycle in osteosarcoma3, liver4, 5 and T cells6, 7 as well as in yeast8 and interferes with mitogenic signalling pathways that are involved in Gl progression9, 10 namely with activation of the protein p70S6k (refs 5,11–13) and cyclin-dependent kinases3, 14–16. Here we isolate a mammalian FKBP–rapamycin-associated protein (FRAP) whose binding to structural variants of rapamycin complexed to FKBP12 correlates with the ability of these ligands to inhibit cell-cycle progression. Peptide sequences from purified bovine FRAP were used to isolate a human cDNA clone that is highly related to the DRR1/TOR1 and DRR2/TOR2 gene products from Saccharomyces cerevisiae8, 17, 18. Although it has not been previously demonstrated that either of the DRR/TOR gene products can bind the FKBP–rapamycin complex directly17, 19 these yeast genes have been genetically linked to a rapamycin-sensitive pathway and are thought to encode lipid kinases17–20.
TL;DR: This article showed that primary productivity in more diverse plant communities is more resistant to, and recovers more fully from, a major drought and that each additional species lost from our grasslands had a progressively greater impact on drought resistance.
Abstract: One of the ecological tenets justifying conservation of biodiversity is that diversity begets stability. Impacts of biodiversity on population dynamics and ecosystem functioning have long been debated1–7, however, with many theoretical explorations2–6,8–11 but few field studies12–15. Here we describe a long-term study of grasslands16,17 which shows that primary productivity in more diverse plant communities is more resistant to, and recovers more fully from, a major drought. The curvilinear relationship we observe suggests that each additional species lost from our grasslands had a progressively greater impact on drought resistance. Our results support the diversity—stability hypothesis5,6,18,19, but not the alternative hypothesis that most species are functionally redundant19–21. This study implies that the preservation of biodiversity is essential for the maintenance of stable productivity in ecosystems.
TL;DR: The ion-selective permeability, the gating properties and the pharmacological profile of the channel formed by coexpressing the three subunits in oocytes are similar to that of the native channel.
Abstract: The amiloride-sensitive epithelial sodium channel constitutes the rate-limiting step for sodium reabsorption in epithelial cells that line the distal part of the renal tubule, the distal colon, the duct of several exocrine glands, and the lung. The activity of this channel is upregulated by vasopressin and aldosterone, hormones involved in the maintenance of sodium balance, blood volume and blood pressure. We have identified the primary structure of the alpha-subunit of the rat epithelial sodium channel by expression cloning in Xenopus laevis oocytes. An identical subunit has recently been reported. Here we identify two other subunits (beta and gamma) by functional complementation of the alpha-subunit of the rat epithelial Na+ channel. The ion-selective permeability, the gating properties and the pharmacological profile of the channel formed by coexpressing the three subunits in oocytes are similar to that of the native channel.
TL;DR: Abnormalities of these regulatory mechanisms and isoform variations may contribute to diseases of smooth muscle, and the G-protein-coupled inhibition of protein phosphatase is also likely to be impor-tant in regulating non-muscle cell functions mediated by cytoplasmic myosin II.
Abstract: Smooth muscle cells in the walls of many organs are vital for most bodily functions, and their abnormalities contribute to a range of diseases. Although based on a sliding-filament mechanism similar to that of striated muscles, contraction of smooth muscle is regulated by pharmacomechanical as well as by electromechanical coupling mechanisms. Recent studies have revealed previously unrecognized contractile regulatory processes, such as G-protein-coupled inhibition of myosin light-chain phosphatase, regulation of myosin light-chain kinase by other kinases, and the functional effects of smooth muscle myosin isoforms. Abnormalities of these regulatory mechanisms and isoform variations may contribute to diseases of smooth muscle, and the G-protein-coupled inhibition of protein phosphatase is also likely to be impor-tant in regulating non-muscle cell functions mediated by cytoplasmic myosin II.
TL;DR: It is shown that common allelic variants in the gene encoding the vitamin D receptor can be used to predict differences in bone density, accounting for up to 75% of the total genetic effect on bone density in healthy individuals.
Abstract: Bone density achieved in early adulthood is the major determinant of risk of osteoporotic fracture. Up to 60% of women suffer osteoporotic fractures as a result of low bone density, which is under strong genetic control acting through effects on bone turnover. Here we show that common allelic variants in the gene encoding the vitamin D receptor can be used to predict differences in bone density, accounting for up to 75% of the total genetic effect on bone density in healthy individuals. The genotype associated with lower bone density was overrepresented in postmenopausal women with bone densities more than 2 standard deviations below values in young normal women. The molecular mechanisms by which bone density is regulated by the vitamin D receptor gene are not certain, although allelic differences in the 3' untranslated region may alter messenger RNA levels. These findings could open new avenues to the development and targeting of prophylactic interventions. It follows that other pathophysiological processes considered to be subject to complex multifactorial genetic regulation may also be modulated by a single gene with pleiotropic transcriptional actions.
TL;DR: A global assessment of the potential impact of climate change on world food supply suggests that doubling of the atmospheric carbon dioxide concentration will lead to only a small decrease in global crop production.
Abstract: A global assessment of the potential impact of climate change on world food supply suggests that doubling of the atmospheric carbon dioxide concentration will lead to only a small decrease in global crop production. But developing countries are likely to bear the brunt of the problem, and simulations of the effect of adaptive measures by farmers imply that these will do little to reduce the disparity between developed and developing countries.
TL;DR: In this article, the authors uncovered the general protein apparatus used by all eukaryotes for intracellular transport, including secretion and endocytosis, and for triggered exocytotic of hormones and neurotransmitters.
Abstract: Recent advances have uncovered the general protein apparatus used by all eukaryotes for intracellular transport, including secretion and endocytosis, and for triggered exocytosis of hormones and neurotransmitters. Membranes are shaped into vesicles by cytoplasmic coats which then dissociate upon GTP hydrolysis. Both vesicles and their acceptor membranes carry targeting proteins which interact specifically to initiate docking. A general apparatus then assembles at the docking site and fuses the vesicle with its target.
TL;DR: A new member of the p16INK4 family is isolated, p15INK4B, which is induced ∼30-fold in human keratinocytes by treatment with TGF-β, suggesting that pi5 may act as an effector of T GF-β-mediated cell cycle arrest.
Abstract: TRANSFORMING growth factor-beta (TGF-β) inhibits cell proliferation by inducing a Gl-phase cell cycle arrest1. Normal progression through Gl is promoted by the activity of the cyclin-dependent protein kinases CDK4 and CDK6 (ref. 2), which are inhibited by the protein p16INK4. We have isolated a new member of the p16INK4 family, p15INK4B. p15 expression is induced ∼30-fold in human keratinocytes by treatment with TGF-β, suggesting that pi5 may act as an effector of TGF-β-mediated cell cycle arrest. The gene encoding p15 is located on chromosome 9 adjacent to the p16 gene at a frequent site of chromosomal abnormality in human tumours (9p21).
TL;DR: Polymerase chain reaction and Southern blot analysis confirmed the frequent deletion or rearrangement of the CDK4-inhibitor gene in melanomas, gliomas, lung cancers and leukaemias, and the absence of detectable gene transcripts.
Abstract: CYTOGENETIC abnormalities of chromosome 9p21 are characteristic of malignant melanomas1,2, gliomas3, lung cancers4 and leukaemias5. From a panel of 46 human malignant cell lines, we localized by positional cloning the most frequently deleted region on 9p21. Sequence analysis of the isolated fragment reveals two open reading frames identical to the recently described complementary DNA for the inhibitor of cyclin-dependent kinase 4 (CDK4) 6. Polymerase chain reaction and Southern blot analysis confirmed the frequent deletion or rearrangement of the CDK4-inhibitor gene in melanomas, gliomas, lung cancers and leukaemias, and the absence of detectable gene transcripts. One carcinoma had a deletion entirely within the CDK4-inhibitor gene. The CDK4-inhibitor gene from a patient with dysplastic nevus syndrome had a germ-line nonsense mutation. The CDK4 inhibitor is thought to be a physiological suppressor of proliferation. Cells unable to produce the inhibitor may be prone to neoplastic transformation.
TL;DR: A new in vitro assay using a feedback enhanced laser trap system allows direct measurement of force and displacement that results from the interaction of a single myosin molecule with a single suspended actin filament.
Abstract: A new in vitro assay using a feedback enhanced laser trap system allows direct measurement of force and displacement that results from the interaction of a single myosin molecule with a single suspended actin filament. Discrete stepwise movements averaging 11 nm were seen under conditions of low load, and single force transients averaging 3-4 pN were measured under isometric conditions. The magnitudes of the single forces and displacements are consistent with predictions of the conventional swinging-crossbridge model of muscle contraction.
TL;DR: It is shown that polymorphic microsatellites (primarily CA repeats) allow trees of human individuals to be constructed that reflect their geographic origin with remarkable accuracy by the analysis of a large number of loci for each individual, in spite of the small variations in allele frequencies existing between populations.
Abstract: Genetic variation at hypervariable loci is being used extensively for linkage analysis and individual identification, and may be useful for inter-population studies. Here we show that polymorphic microsatellites (primarily CA repeats) allow trees of human individuals to be constructed that reflect their geographic origin with remarkable accuracy. This is achieved by the analysis of a large number of loci for each individual, in spite of the small variations in allele frequencies existing between populations. Reliable evolutionary relationships could also be established in comparisons among human populations but not among great ape species, probably because of constraints on allele length variation. Among human populations, diversity of microsatellites is highest in Africa, which is in contrast to other nuclear markers and supports the hypothesis of an African origin for humans.