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961.
We have characterized the human gene SLC39A4, which encodes a protein with features characteristic of a ZIP zinc transporter. The chromosomal location and expression of SLC39A4, together with mutational analysis of eight families affected with acrodermatitis enteropathica, suggest that SLC39A4 is centrally involved in the pathogenesis of this condition. 相似文献
962.
Inherited variants of MYH associated with somatic G:C-->T:A mutations in colorectal tumors 总被引:5,自引:0,他引:5
Al-Tassan N Chmiel NH Maynard J Fleming N Livingston AL Williams GT Hodges AK Davies DR David SS Sampson JR Cheadle JP 《Nature genetics》2002,30(2):227-232
Inherited defects of base excision repair have not been associated with any human genetic disorder, although mutations of the genes mutM and mutY, which function in Escherichia coli base excision repair, lead to increased transversions of G:C to T:A. We have studied family N, which is affected with multiple colorectal adenomas and carcinoma but lacks an inherited mutation of the adenomatous polyposis coli gene (APC) that is associated with familial adenomatous polyposis. Here we show that 11 tumors from 3 affected siblings contain 18 somatic inactivating mutations of APC and that 15 of these mutations are G:C-->A transversions--a significantly greater proportion than is found in sporadic tumors or in tumors associated with familial adenomatous polyposis. Analysis of the human homolog of mutY, MYH, showed that the siblings were compound heterozygotes for the nonconservative missense variants Tyr165Cys and Gly382Asp. These mutations affect residues that are conserved in mutY of E. coli (Tyr82 and Gly253). Tyrosine 82 is located in the pseudo-helix-hairpin-helix (HhH) motif and is predicted to function in mismatch specificity. Assays of adenine glycosylase activity of the Tyr82Cys and Gly253Asp mutant proteins with 8-oxoG:A and G:A substrates show that their activity is reduced significantly. Our findings link the inherited variants in MYH to the pattern of somatic APC mutation in family N and implicate defective base excision repair in predisposition to tumors in humans. 相似文献
963.
Chatterton JE Awobuluyi M Premkumar LS Takahashi H Talantova M Shin Y Cui J Tu S Sevarino KA Nakanishi N Tong G Lipton SA Zhang D 《Nature》2002,415(6873):793-798
The N-methyl-D-aspartate subtype of glutamate receptor (NMDAR) serves critical functions in physiological and pathological processes in the central nervous system, including neuronal development, plasticity and neurodegeneration. Conventional heteromeric NMDARs composed of NR1 and NR2A-D subunits require dual agonists, glutamate and glycine, for activation. They are also highly permeable to Ca2+, and exhibit voltage-dependent inhibition by Mg2+. Coexpression of NR3A with NR1 and NR2 subunits modulates NMDAR activity. Here we report the cloning and characterization of the final member of the NMDAR family, NR3B, which shares high sequence homology with NR3A. From in situ and immunocytochemical analyses, NR3B is expressed predominantly in motor neurons, whereas NR3A is more widely distributed. Remarkably, when co-expressed in Xenopus oocytes, NR3A or NR3B co-assembles with NR1 to form excitatory glycine receptors that are unaffected by glutamate or NMDA, and inhibited by D-serine, a co-activator of conventional NMDARs. Moreover, NR1/NR3A or -3B receptors form relatively Ca2+-impermeable cation channels that are resistant to Mg2+, MK-801, memantine and competitive antagonists. In cerebrocortical neurons containing NR3 family members, glycine triggers a burst of firing, and membrane patches manifest glycine-responsive single channels that are suppressible by D-serine. By itself, glycine is normally thought of as an inhibitory neurotransmitter. In contrast, these NR1/NR3A or -3B 'NMDARs' constitute a type of excitatory glycine receptor. 相似文献
964.
The central biological clock of the mammalian brain is located in the suprachiasmatic nucleus. This hypothalamic region contains neurons that generate a circadian rhythm on a single-cell basis. Clock cells transmit their circadian timing signals to other brain areas by diurnal modulation of their spontaneous firing rate. The intracellular mechanism underlying rhythm generation is thought to consist of one or more self-regulating molecular loops, but it is unknown how these loops interact with the plasma membrane to modulate the ionic conductances that regulate firing behaviour. Here we demonstrate a diurnal modulation of Ca2+ current in suprachiasmatic neurons. This current strongly contributes to the generation of spontaneous oscillations in membrane potential, which occur selectively during daytime and are tightly coupled to spike generation. Thus, day-night modulation of Ca2+ current is a central step in transducing the intracellular cycling of molecular clocks to the rhythm in spontaneous firing rate. 相似文献
965.
Homogeneous organometallic catalysts and many enzymes activate reactants through coordination to metal atoms; that is, the reactants are turned into ligands and their reactivity controlled through other ligands in the metal's coordination sphere. In the case of supported metal clusters, catalytic performance is influenced by the support and by adsorbed reactants, intermediates or products. The adsorbates are usually treated as ligands, whereas the influence of the supports is usually ascribed to electronic interactions, even though metal clusters supported on oxides and zeolites form chemical bonds to support oxygen atoms. Here we report direct observations of the structure of supported metal clusters consisting of four iridium atoms, and the identification of hydrocarbon ligands bound to them during propene hydrogenation. We find that propene and molecular hydrogen form propylidyne and hydride ligands, respectively, whereas simultaneous exposure of the reactants to the supported iridium cluster yields ligands that are reactive intermediates during the catalytic propane-formation reaction. These intermediates weaken the bonding within the tetrahedral iridium cluster and the interactions between the cluster and the support, while replacement of the MgO support with gamma-Al2O3 boosts the catalytic activity tenfold, by affecting the bonding between the reactant-derived ligands and the cluster and therefore also the abundance of individual ligands. This interplay between the support and the reactant-derived ligands, whereby each influences the interaction of the metal cluster with the other, shows that the catalytic properties of supported metal catalysts can be tuned by careful choice of their supports. 相似文献
966.
Kurth WS Gurnett DA Hospodarsky GB Farrell WM Roux A Dougherty MK Joy SP Kivelson MG Walker RJ Crary FJ Alexander CJ 《Nature》2002,415(6875):991-994
Limited single-spacecraft observations of Jupiter's magnetopause have been used to infer that the boundary moves inward or outward in response to variations in the dynamic pressure of the solar wind. At Earth, multiple-spacecraft observations have been implemented to understand the physics of how this motion occurs, because they can provide a snapshot of a transient event in progress. Here we present a set of nearly simultaneous two-point measurements of the jovian magnetopause at a time when the jovian magnetopause was in a state of transition from a relatively larger to a relatively smaller size in response to an increase in solar-wind pressure. The response of Jupiter's magnetopause is very similar to that of the Earth, confirming that the understanding built on studies of the Earth's magnetosphere is valid. The data also reveal evidence for a well-developed boundary layer just inside the magnetopause. 相似文献
967.
An amino-acid taste receptor 总被引:52,自引:0,他引:52
The sense of taste provides animals with valuable information about the nature and quality of food. Mammals can recognize and respond to a diverse repertoire of chemical entities, including sugars, salts, acids and a wide range of toxic substances. Several amino acids taste sweet or delicious (umami) to humans, and are attractive to rodents and other animals. This is noteworthy because L-amino acids function as the building blocks of proteins, as biosynthetic precursors of many biologically relevant small molecules, and as metabolic fuel. Thus, having a taste pathway dedicated to their detection probably had significant evolutionary implications. Here we identify and characterize a mammalian amino-acid taste receptor. This receptor, T1R1+3, is a heteromer of the taste-specific T1R1 and T1R3 G-protein-coupled receptors. We demonstrate that T1R1 and T1R3 combine to function as a broadly tuned L-amino-acid sensor responding to most of the 20 standard amino acids, but not to their D-enantiomers or other compounds. We also show that sequence differences in T1R receptors within and between species (human and mouse) can significantly influence the selectivity and specificity of taste responses. 相似文献
968.
Spontaneous breaking of time-reversal symmetry in the pseudogap state of a high-Tc superconductor 总被引:1,自引:0,他引:1
Kaminski A Rosenkranz S Fretwell HM Campuzano JC Li Z Raffy H Cullen WG You H Olson CG Varma CM Höchst H 《Nature》2002,416(6881):610-613
A change in 'symmetry' is often observed when matter undergoes a phase transition-the symmetry is said to be spontaneously broken. The transition made by underdoped high-transition-temperature (high-Tc) superconductors is unusual, in that it is not a mean-field transition as seen in other superconductors. Rather, there is a region in the phase diagram above the superconducting transition temperature Tc (where phase coherence and superconductivity begin) but below a characteristic temperature T* where a 'pseudogap' appears in the spectrum of electronic excitations. It is therefore important to establish if T* is just a cross-over temperature arising from fluctuations in the order parameter that will establish superconductivity at Tc (refs 3, 4), or if it marks a phase transition where symmetry is spontaneously broken. Here we report that, for a material in the pseudogap state, left-circularly polarized photons give a different photocurrent from right-circularly polarized photons. This shows that time-reversal symmetry is spontaneously broken below T*, which therefore corresponds to a phase transition. 相似文献
969.
Peterson AT Ortega-Huerta MA Bartley J Sánchez-Cordero V Soberón J Buddemeier RH Stockwell DR 《Nature》2002,416(6881):626-629
Global climates are changing rapidly, with unexpected consequences. Because elements of biodiversity respond intimately to climate as an important driving force of distributional limitation, distributional shifts and biodiversity losses are expected. Nevertheless, in spite of modelling efforts focused on single species or entire ecosystems, a few preliminary surveys of fauna-wide effects, and evidence of climate change-mediated shifts in several species, the likely effects of climate change on species' distributions remain little known, and fauna-wide or community-level effects are almost completely unexplored. Here, using a genetic algorithm and museum specimen occurrence data, we develop ecological niche models for 1,870 species occurring in Mexico and project them onto two climate surfaces modelled for 2055. Although extinctions and drastic range reductions are predicted to be relatively few, species turnover in some local communities is predicted to be high (>40% of species), suggesting that severe ecological perturbations may result. 相似文献
970.