排序方式: 共有16条查询结果,搜索用时 31 毫秒
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Vitart V Rudan I Hayward C Gray NK Floyd J Palmer CN Knott SA Kolcic I Polasek O Graessler J Wilson JF Marinaki A Riches PL Shu X Janicijevic B Smolej-Narancic N Gorgoni B Morgan J Campbell S Biloglav Z Barac-Lauc L Pericic M Klaric IM Zgaga L Skaric-Juric T Wild SH Richardson WA Hohenstein P Kimber CH Tenesa A Donnelly LA Fairbanks LD Aringer M McKeigue PM Ralston SH Morris AD Rudan P Hastie ND Campbell H Wright AF 《Nature genetics》2008,40(4):437-442
Uric acid is the end product of purine metabolism in humans and great apes, which have lost hepatic uricase activity, leading to uniquely high serum uric acid concentrations (200-500 microM) compared with other mammals (3-120 microM). About 70% of daily urate disposal occurs via the kidneys, and in 5-25% of the human population, impaired renal excretion leads to hyperuricemia. About 10% of people with hyperuricemia develop gout, an inflammatory arthritis that results from deposition of monosodium urate crystals in the joint. We have identified genetic variants within a transporter gene, SLC2A9, that explain 1.7-5.3% of the variance in serum uric acid concentrations, following a genome-wide association scan in a Croatian population sample. SLC2A9 variants were also associated with low fractional excretion of uric acid and/or gout in UK, Croatian and German population samples. SLC2A9 is a known fructose transporter, and we now show that it has strong uric acid transport activity in Xenopus laevis oocytes. 相似文献
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The Par complex directs asymmetric cell division by phosphorylating the cytoskeletal protein Lgl 总被引:18,自引:0,他引:18
To generate different cell types, some cells can segregate protein determinants into one of their two daughter cells during mitosis. In Drosophila neuroblasts, the Par protein complex localizes apically and directs localization of the cell fate determinants Prospero and Numb and the adaptor proteins Miranda and Pon to the basal cell cortex, to ensure their segregation into the basal daughter cell. The Par protein complex has a conserved function in establishing cell polarity but how it directs proteins to the opposite side is unknown. We show here that a principal function of this complex is to phosphorylate the cytoskeletal protein Lethal (2) giant larvae (Lgl; also known as L(2)gl). Phosphorylation by Drosophila atypical protein kinase C (aPKC), a member of the Par protein complex, releases Lgl from its association with membranes and the actin cytoskeleton. Genetic and biochemical experiments show that Lgl phosphorylation prevents the localization of cell fate determinants to the apical cell cortex. Lgl promotes cortical localization of Miranda, and we propose that phosphorylation of Lgl by aPKC at the apical neuroblast cortex restricts Lgl activity and Miranda localization to the opposite, basal side of the cell. 相似文献
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Schmeisser MJ Ey E Wegener S Bockmann J Stempel AV Kuebler A Janssen AL Udvardi PT Shiban E Spilker C Balschun D Skryabin BV Dieck St Smalla KH Montag D Leblond CS Faure P Torquet N Le Sourd AM Toro R Grabrucker AM Shoichet SA Schmitz D Kreutz MR Bourgeron T Gundelfinger ED Boeckers TM 《Nature》2012,486(7402):256-260
Autism spectrum disorders comprise a range of neurodevelopmental disorders characterized by deficits in social interaction and communication, and by repetitive behaviour. Mutations in synaptic proteins such as neuroligins, neurexins, GKAPs/SAPAPs and ProSAPs/Shanks were identified in patients with autism spectrum disorder, but the causative mechanisms remain largely unknown. ProSAPs/Shanks build large homo- and heteromeric protein complexes at excitatory synapses and organize the complex protein machinery of the postsynaptic density in a laminar fashion. Here we demonstrate that genetic deletion of ProSAP1/Shank2 results in an early, brain-region-specific upregulation of ionotropic glutamate receptors at the synapse and increased levels of ProSAP2/Shank3. Moreover, ProSAP1/Shank2(-/-) mutants exhibit fewer dendritic spines and show reduced basal synaptic transmission, a reduced frequency of miniature excitatory postsynaptic currents and enhanced N-methyl-d-aspartate receptor-mediated excitatory currents at the physiological level. Mutants are extremely hyperactive and display profound autistic-like behavioural alterations including repetitive grooming as well as abnormalities in vocal and social behaviours. By comparing the data on ProSAP1/Shank2(-/-) mutants with ProSAP2/Shank3αβ(-/-) mice, we show that different abnormalities in synaptic glutamate receptor expression can cause alterations in social interactions and communication. Accordingly, we propose that appropriate therapies for autism spectrum disorders are to be carefully matched to the underlying synaptopathic phenotype. 相似文献
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Nikolai Axmacher Andreas Draguhn Christian E. Elger Juergen Fell 《Cellular and molecular life sciences : CMLS》2009,66(14):2285-2297
Two-step theories of memory formation suggest that an initial encoding stage, during which transient neural assemblies are
formed in the hippocampus, is followed by a second step called consolidation, which involves re-processing of activity patterns
and is associated with an increasing involvement of the neocortex. Several studies in human subjects as well as in animals
suggest that memory consolidation occurs predominantly during sleep (standard consolidation model). Alternatively, it has
been suggested that consolidation may occur during waking state as well and that the role of sleep is rather to restore encoding
capabilities of synaptic connections (synaptic downscaling theory). Here, we review the experimental evidence favoring and
challenging these two views and suggest an integrative model of memory consolidation. 相似文献
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J.博科维斯基 《国外科技新书评介》2007,(2):17-17
让我们来考虑一个示例。拿一条具有1,2两个端点的线段和一个具有顶点3,4.5的三角形。这条线段是否与这个三角形相交?这个问题在计算机图形学、自动机工程学和许多几何问题中是基本的和决定性的问题。为了回答这个问题,许多人计算由这条线段给出的直线和由这个三角形给出的平面之间的交点,然后决定这个交点是否位于这个三角形和这条线段之内。在实际应用中具有许多这种类型的判定,这是很典型的。根据有向拟阵理论,我们了解到答案只是取决于5个符号,即由4个点的有序子集合构成的四面体的方向。 相似文献
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Complex traits such as human disease, growth rate, or crop yield are polygenic, or determined by the contributions from numerous genes in a quantitative manner. Although progress has been made in identifying major quantitative trait loci (QTL), experimental constraints have limited our knowledge of small-effect QTL, which may be responsible for a large proportion of trait variation. Here, we identified and dissected a one-centimorgan chromosome interval in Arabidopsis thaliana without regard to its effect on growth rate, and examined the signature of historical sequence polymorphism among Arabidopsis accessions. We found that the interval contained two growth rate QTL within 210 kilobases. Both QTL showed epistasis; that is, their phenotypic effects depended on the genetic background. This amount of complexity in such a small area suggests a highly polygenic architecture of quantitative variation, much more than previously documented. One QTL was limited to a single gene. The gene in question displayed a nucleotide signature indicative of balancing selection, and its phenotypic effects are reversed depending on genetic background. If this region typifies many complex trait loci, then non-neutral epistatic polymorphism may be an important contributor to genetic variation in complex traits. 相似文献
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Evolution of metal hyperaccumulation required cis-regulatory changes and triplication of HMA4 总被引:5,自引:0,他引:5
Hanikenne M Talke IN Haydon MJ Lanz C Nolte A Motte P Kroymann J Weigel D Krämer U 《Nature》2008,453(7193):391-395
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The overflow and descent of cold, dense water from the sills of the Denmark Strait and the Faroe Shetland channel into the North Atlantic Ocean is the principal means of ventilating the deep oceans, and is therefore a key element of the global thermohaline circulation. Most computer simulations of the ocean system in a climate with increasing atmospheric greenhouse-gas concentrations predict a weakening thermohaline circulation in the North Atlantic as the subpolar seas become fresher and warmer, and it is assumed that this signal will be transferred to the deep ocean by the two overflows. From observations it has not been possible to detect whether the ocean's overturning circulation is changing, but recent evidence suggests that the transport over the sills may be slackening. Here we show, through the analysis of long hydrographic records, that the system of overflow and entrainment that ventilates the deep Atlantic has steadily changed over the past four decades. We find that these changes have already led to sustained and widespread freshening of the deep ocean. 相似文献