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161.
Loss-of-function mutations in TYROBP (DAP12) result in a presenile dementia with bone cysts 总被引:20,自引:0,他引:20
Paloneva J Kestilä M Wu J Salminen A Böhling T Ruotsalainen V Hakola P Bakker AB Phillips JH Pekkarinen P Lanier LL Timonen T Peltonen L 《Nature genetics》2000,25(3):357-361
Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (PLOSL; MIM 221770), also known as Nasu-Hakola disease, is a recessively inherited disease characterized by a combination of psychotic symptoms rapidly progressing to presenile dementia and bone cysts restricted to wrists and ankles. PLOSL has a global distribution, although most of the patients have been diagnosed in Finland and Japan, with an estimated population prevalence of 2x10-6 (ref. 2) in the Finns. We have previously identified a shared 153-kb ancestor haplotype in all Finnish disease alleles between markers D19S1175 and D19S608 on chromosome 19q13.1 (refs 5,6). Here we characterize the molecular defect in PLOSL by identifying one large deletion in all Finnish PLOSL alleles and another mutation in a Japanese patient, both representing loss-of-function mutations, in the gene encoding TYRO protein tyrosine kinase binding protein (TYROBP; formerly DAP12). TYROBP is a transmembrane protein that has been recognized as a key activating signal transduction element in natural killer (NK) cells. On the plasma membrane of NK cells, TYROBP associates with activating receptors recognizing major histocompatibility complex (MHC) class I molecules. No abnormalities in NK cell function were detected in PLOSL patients homozygous for a null allele of TYROBP. 相似文献
162.
N Ito S E Phillips C Stevens Z B Ogel M J McPherson J N Keen K D Yadav P F Knowles 《Nature》1991,350(6313):87-90
Galactose oxidase is an extracellular enzyme secreted by the fungus Dactylium dendroides. It is monomeric, with a relative molecular mass of 68,000, catalyses the stereospecific oxidation of a broad range of primary alcohol substrates and possesses a unique mononuclear copper site essential for catalysing a two-electron transfer reaction during the oxidation of primary alcohols to corresponding aldehydes. Recent evidence arguing against a Cu(III)-Cu(I) couple implies the existence of a second redox-active site proposed to involve pyrroloquinoline quinone or a tyrosine radical. We now report the crystal structure of galactose oxidase at 1.7 A resolution. This reveals a unique structural feature at the copper site with a novel thioether bond linking Cys 228 and Tyr 272 in a stacking interaction with Trp 290. We propose that these molecular components stabilize the protein free-radical species essential for catalysis and thus provide a 'built-in' secondary cofactor. This feature may represent a new mechanism for mediating electron transfer in metalloenzymes in the absence of exogenous cofactors. 相似文献
163.
Extinction risk from climate change 总被引:20,自引:0,他引:20
Thomas CD Cameron A Green RE Bakkenes M Beaumont LJ Collingham YC Erasmus BF De Siqueira MF Grainger A Hannah L Hughes L Huntley B Van Jaarsveld AS Midgley GF Miles L Ortega-Huerta MA Peterson AT Phillips OL Williams SE 《Nature》2004,427(6970):145-148
Climate change over the past approximately 30 years has produced numerous shifts in the distributions and abundances of species and has been implicated in one species-level extinction. Using projections of species' distributions for future climate scenarios, we assess extinction risks for sample regions that cover some 20% of the Earth's terrestrial surface. Exploring three approaches in which the estimated probability of extinction shows a power-law relationship with geographical range size, we predict, on the basis of mid-range climate-warming scenarios for 2050, that 15-37% of species in our sample of regions and taxa will be 'committed to extinction'. When the average of the three methods and two dispersal scenarios is taken, minimal climate-warming scenarios produce lower projections of species committed to extinction ( approximately 18%) than mid-range ( approximately 24%) and maximum-change ( approximately 35%) scenarios. These estimates show the importance of rapid implementation of technologies to decrease greenhouse gas emissions and strategies for carbon sequestration. 相似文献
164.
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166.
Large-scale association studies hold substantial promise for unraveling the genetic basis of common human diseases. A well-known problem with such studies is the presence of undetected population structure, which can lead to both false positive results and failures to detect genuine associations. Here we examine approximately 15,000 genome-wide single-nucleotide polymorphisms typed in three population groups to assess the consequences of population structure on the coming generation of association studies. The consequences of population structure on association outcomes increase markedly with sample size. For the size of study needed to detect typical genetic effects in common diseases, even the modest levels of population structure within population groups cannot safely be ignored. We also examine one method for correcting for population structure (Genomic Control). Although it often performs well, it may not correct for structure if too few loci are used and may overcorrect in other settings, leading to substantial loss of power. The results of our analysis can guide the design of large-scale association studies. 相似文献
167.
Chromosome-wide distribution of haplotype blocks and the role of recombination hot spots 总被引:19,自引:0,他引:19
Phillips MS Lawrence R Sachidanandam R Morris AP Balding DJ Donaldson MA Studebaker JF Ankener WM Alfisi SV Kuo FS Camisa AL Pazorov V Scott KE Carey BJ Faith J Katari G Bhatti HA Cyr JM Derohannessian V Elosua C Forman AM Grecco NM Hock CR Kuebler JM Lathrop JA Mockler MA Nachtman EP Restine SL Varde SA Hozza MJ Gelfand CA Broxholme J Abecasis GR Boyce-Jacino MT Cardon LR 《Nature genetics》2003,33(3):382-387
Recent studies of human populations suggest that the genome consists of chromosome segments that are ancestrally conserved ('haplotype blocks'; refs. 1-3) and have discrete boundaries defined by recombination hot spots. Using publicly available genetic markers, we have constructed a first-generation haplotype map of chromosome 19. As expected for this marker density, approximately one-third of the chromosome is encompassed within haplotype blocks. Evolutionary modeling of the data indicates that recombination hot spots are not required to explain most of the observed blocks, providing that marker ascertainment and the observed marker spacing are considered. In contrast, several long blocks are inconsistent with our evolutionary models, and different mechanisms could explain their origins. 相似文献
168.
Selective non-covalent interactions have been widely exploited in solution-based chemistry to direct the assembly of molecules into nanometre-sized functional structures such as capsules, switches and prototype machines. More recently, the concepts of supramolecular organization have also been applied to two-dimensional assemblies on surfaces stabilized by hydrogen bonding, dipolar coupling or metal co-ordination. Structures realized to date include isolated rows, clusters and extended networks, as well as more complex multi-component arrangements. Another approach to controlling surface structures uses adsorbed molecular monolayers to create preferential binding sites that accommodate individual target molecules. Here we combine these approaches, by using hydrogen bonding to guide the assembly of two types of molecules into a two-dimensional open honeycomb network that then controls and templates new surface phases formed by subsequently deposited fullerene molecules. We find that the open network acts as a two-dimensional array of large pores of sufficient capacity to accommodate several large guest molecules, with the network itself also serving as a template for the formation of a fullerene layer. 相似文献
169.
The crystal structure of the met repressor-operator complex shows two dimeric repressor molecules bound to adjacent sites 8 base pairs apart on an 18-base-pair DNA fragment. Sequence specificity is achieved by insertion of double-stranded antiparallel protein beta-ribbons into the major groove of B-form DNA, with direct hydrogen-bonding between amino-acid side chains and the base pairs. The repressor also recognizes sequence-dependent distortion or flexibility of the operator phosphate backbone, conferring specificity even for inaccessible base pairs. 相似文献
170.
Robert F. Phillips 《Journal of forecasting》1988,7(2):131-137
This paper extends the method of using linear composites of forecasts for testing the efficiency of one forecast compared to a finite collection of other forecasts. It also gives necessary and sufficient conditions for forecast optimality in the mean square error sense. Information sets are found to be unnecessary for forecast optimality. Finally, the paper shows that a consistent test of forecast optimality cannot in general be obtained using linear composites. A similar conclusion applies to tests of specification optimality based on linear composites. 相似文献