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81.
82.
Aitman TJ Dong R Vyse TJ Norsworthy PJ Johnson MD Smith J Mangion J Roberton-Lowe C Marshall AJ Petretto E Hodges MD Bhangal G Patel SG Sheehan-Rooney K Duda M Cook PR Evans DJ Domin J Flint J Boyle JJ Pusey CD Cook HT 《Nature》2006,439(7078):851-855
Identification of the genes underlying complex phenotypes and the definition of the evolutionary forces that have shaped eukaryotic genomes are among the current challenges in molecular genetics. Variation in gene copy number is increasingly recognized as a source of inter-individual differences in genome sequence and has been proposed as a driving force for genome evolution and phenotypic variation. Here we show that copy number variation of the orthologous rat and human Fcgr3 genes is a determinant of susceptibility to immunologically mediated glomerulonephritis. Positional cloning identified loss of the newly described, rat-specific Fcgr3 paralogue, Fcgr3-related sequence (Fcgr3-rs), as a determinant of macrophage overactivity and glomerulonephritis in Wistar Kyoto rats. In humans, low copy number of FCGR3B, an orthologue of rat Fcgr3, was associated with glomerulonephritis in the autoimmune disease systemic lupus erythematosus. The finding that gene copy number polymorphism predisposes to immunologically mediated renal disease in two mammalian species provides direct evidence for the importance of genome plasticity in the evolution of genetically complex phenotypes, including susceptibility to common human disease. 相似文献
83.
The Golgi apparatus is composed of biochemically distinct early (cis, medial) and late (trans, TGN) cisternae. There is debate about the nature of these cisternae. The stable compartments model predicts that each cisterna is a long-lived structure that retains a characteristic set of Golgi-resident proteins. In this view, secretory cargo proteins are transported by vesicles from one cisterna to the next. The cisternal maturation model predicts that each cisterna is a transient structure that matures from early to late by acquiring and then losing specific Golgi-resident proteins. In this view, secretory cargo proteins traverse the Golgi by remaining within the maturing cisternae. Various observations have been interpreted as supporting one or the other mechanism. Here we provide a direct test of the two models using three-dimensional time-lapse fluorescence microscopy of the yeast Saccharomyces cerevisiae. This approach reveals that individual cisternae mature, and do so at a consistent rate. In parallel, we used pulse-chase analysis to measure the transport of two secretory cargo proteins. The rate of cisternal maturation matches the rate of protein transport through the secretory pathway, suggesting that cisternal maturation can account for the kinetics of secretory traffic. 相似文献
84.
Resistance reflexes from a crab muscle receptor without impulses 总被引:2,自引:0,他引:2
85.
86.
Petrographic and geochemical characterization of seep carbonate from Alaminos Canyon,Gulf of Mexico 总被引:3,自引:1,他引:2
Seep carbonates were collected from the Alaminos Canyon lease area, Gulf of Mexico. The carbonates are present as slabs and blocks. Bivalve shell and foraminifer are the dominant bioclasts in carbonate. Pores are common and usually filled with acicular aragonite crystals. XRD investigation shows that aragonite is the dominate mineral (98%). Peloids, clotted microfabirc and botryoidal aragonite are developed in carbonate and suggest a genesis linked with bacterial degradation of the hydrocarbons. The δ^13C value of bioclasts in carbonate is from -4.9‰ to -0.6‰, indicating that the carbon source is mainly from sea water as well as the small portion incorporation of the seep hydrocarbon. The microcrystalline and sparite aragonite shows the δ^13C value from -31.3‰ to -23.4‰, suggesting that their carbon is derived mainly from microbial degradation of crude oil. ^14C analyses give the radiocarbon age of about 10 ka. Rare earth elements (REE) analyses of the 5% HNO3-treated solution of the carbonates show that the total REE content of the carbonates is low, that is from 0.752 to 12.725 μg·g^-1. The shale-normalized REE patterns show significantly negative Ce anomalies. This suggests that cold seep carbonate is most likely formed in a relatively aerobic environment. 相似文献
87.
The ground state of embryonic stem cell self-renewal 总被引:3,自引:0,他引:3
Ying QL Wray J Nichols J Batlle-Morera L Doble B Woodgett J Cohen P Smith A 《Nature》2008,453(7194):519-523
88.
The gap in our understanding of the evolutionary transition from fish to tetrapod is beginning to close thanks to the discovery of new intermediate forms such as Tiktaalik roseae. Here we narrow it further by presenting the skull, exceptionally preserved braincase, shoulder girdle and partial pelvis of Ventastega curonica from the Late Devonian of Latvia, a transitional intermediate form between the 'elpistostegids' Panderichthys and Tiktaalik and the Devonian tetrapods (limbed vertebrates) Acanthostega and Ichthyostega. Ventastega is the most primitive Devonian tetrapod represented by extensive remains, and casts light on a part of the phylogeny otherwise only represented by fragmentary taxa: it illuminates the origin of principal tetrapod structures and the extent of morphological diversity among the transitional forms. 相似文献
89.
Jakobsson M Scholz SW Scheet P Gibbs JR VanLiere JM Fung HC Szpiech ZA Degnan JH Wang K Guerreiro R Bras JM Schymick JC Hernandez DG Traynor BJ Simon-Sanchez J Matarin M Britton A van de Leemput J Rafferty I Bucan M Cann HM Hardy JA Rosenberg NA Singleton AB 《Nature》2008,451(7181):998-1003
Genome-wide patterns of variation across individuals provide a powerful source of data for uncovering the history of migration, range expansion, and adaptation of the human species. However, high-resolution surveys of variation in genotype, haplotype and copy number have generally focused on a small number of population groups. Here we report the analysis of high-quality genotypes at 525,910 single-nucleotide polymorphisms (SNPs) and 396 copy-number-variable loci in a worldwide sample of 29 populations. Analysis of SNP genotypes yields strongly supported fine-scale inferences about population structure. Increasing linkage disequilibrium is observed with increasing geographic distance from Africa, as expected under a serial founder effect for the out-of-Africa spread of human populations. New approaches for haplotype analysis produce inferences about population structure that complement results based on unphased SNPs. Despite a difference from SNPs in the frequency spectrum of the copy-number variants (CNVs) detected--including a comparatively large number of CNVs in previously unexamined populations from Oceania and the Americas--the global distribution of CNVs largely accords with population structure analyses for SNP data sets of similar size. Our results produce new inferences about inter-population variation, support the utility of CNVs in human population-genetic research, and serve as a genomic resource for human-genetic studies in diverse worldwide populations. 相似文献
90.
Guo W Lasky JL Chang CJ Mosessian S Lewis X Xiao Y Yeh JE Chen JY Iruela-Arispe ML Varella-Garcia M Wu H 《Nature》2008,453(7194):529-533
Cancer stem cells, which share many common properties and regulatory machineries with normal stem cells, have recently been proposed to be responsible for tumorigenesis and to contribute to cancer resistance. The main challenges in cancer biology are to identify cancer stem cells and to define the molecular events required for transforming normal cells to cancer stem cells. Here we show that Pten deletion in mouse haematopoietic stem cells leads to a myeloproliferative disorder, followed by acute T-lymphoblastic leukaemia (T-ALL). Self-renewable leukaemia stem cells (LSCs) are enriched in the c-Kit(mid)CD3(+)Lin(-) compartment, where unphosphorylated beta-catenin is significantly increased. Conditional ablation of one allele of the beta-catenin gene substantially decreases the incidence and delays the occurrence of T-ALL caused by Pten loss, indicating that activation of the beta-catenin pathway may contribute to the formation or expansion of the LSC population. Moreover, a recurring chromosomal translocation, T(14;15), results in aberrant overexpression of the c-myc oncogene in c-Kit(mid)CD3(+)Lin(-) LSCs and CD3(+) leukaemic blasts, recapitulating a subset of human T-ALL. No alterations in Notch1 signalling are detected in this model, suggesting that Pten inactivation and c-myc overexpression may substitute functionally for Notch1 abnormalities, leading to T-ALL development. Our study indicates that multiple genetic or molecular alterations contribute cooperatively to LSC transformation. 相似文献