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排序方式: 共有413条查询结果,搜索用时 15 毫秒
321.
M Krauthammer Y Kong BH Ha P Evans A Bacchiocchi JP McCusker E Cheng MJ Davis G Goh M Choi S Ariyan D Narayan K Dutton-Regester A Capatana EC Holman M Bosenberg M Sznol HM Kluger DE Brash DF Stern MA Materin RS Lo S Mane S Ma KK Kidd NK Hayward RP Lifton J Schlessinger TJ Boggon R Halaban 《Nature genetics》2012,44(9):1006-1014
We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1(P29S)) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1(P29S) showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit. 相似文献
322.
Mosaic overgrowth with fibroadipose hyperplasia is caused by somatic activating mutations in PIK3CA 总被引:1,自引:0,他引:1
Lindhurst MJ Parker VE Payne F Sapp JC Rudge S Harris J Witkowski AM Zhang Q Groeneveld MP Scott CE Daly A Huson SM Tosi LL Cunningham ML Darling TN Geer J Gucev Z Sutton VR Tziotzios C Dixon AK Helliwell T O'Rahilly S Savage DB Wakelam MJ Barroso I Biesecker LG Semple RK 《Nature genetics》2012,44(8):928-933
The phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway is critical for cellular growth and metabolism. Correspondingly, loss of function of PTEN, a negative regulator of PI3K, or activating mutations in AKT1, AKT2 or AKT3 have been found in distinct disorders featuring overgrowth or hypoglycemia. We performed exome sequencing of DNA from unaffected and affected cells from an individual with an unclassified syndrome of congenital progressive segmental overgrowth of fibrous and adipose tissue and bone and identified the cancer-associated mutation encoding p.His1047Leu in PIK3CA, the gene that encodes the p110α catalytic subunit of PI3K, only in affected cells. Sequencing of PIK3CA in ten additional individuals with overlapping syndromes identified either the p.His1047Leu alteration or a second cancer-associated alteration, p.His1047Arg, in nine cases. Affected dermal fibroblasts showed enhanced basal and epidermal growth factor (EGF)-stimulated phosphatidylinositol 3,4,5-trisphosphate (PIP(3)) generation and concomitant activation of downstream signaling relative to their unaffected counterparts. Our findings characterize a distinct overgrowth syndrome, biochemically demonstrate activation of PI3K signaling and thereby identify a rational therapeutic target. 相似文献
323.
Ouellette AJ 《Cellular and molecular life sciences : CMLS》2011,68(13):2215-2229
Paneth cells at the base of small intestinal crypts of Lieberkühn secrete high levels of α-defensins in response to cholinergic
and microbial stimuli. Paneth cell α-defensins are broad spectrum microbicides that function in the extracellular environment
of the intestinal lumen, and they are responsible for the majority of secreted bactericidal peptide activity. Paneth cell
α-defensins confer immunity to oral infection by Salmonella enterica serovar Typhimurium, and they are major determinants of the composition of the small intestinal microbiome. In addition to
host defense molecules such as α-defensins, lysozyme, and Pla2g2a, Paneth cells also produce and release proinflammatory mediators
as components of secretory granules. Disruption of Paneth cell homeostasis, with subsequent induction of endoplasmic reticulum
stress, autophagy, or apoptosis, contributes to inflammation in diverse genetic and experimental mouse models. 相似文献
324.
325.
The deserts of southern California house a diverse and unique insect fauna. Velvet ants (Hymenoptera: Mutillidae) are common in these deserts. Velvet ants are important to ecosystem health, particularly in desert environments, because they are parasitic on the bees and wasps that help maintain overall ecosystem function. The goal of this study was to measure velvet ant diversity across the deserts of southern California. We made preliminary collections from 10 sites in a variety of areas in the western Sonoran Desert (Colorado Desert), the Mojave Desert, and the Great Basin Desert. We measured β-diversity using Sørensen’s similarity index to compare velvet ant richness and relative abundance between different sites. To determine how accurate our similarity estimates were, and to gain an understanding of actual velvet ant diversity, we also compared velvet ant richness of 2 sites (Algodones Sand Dunes and Deep Canyon) using data obtained from the examination of museum specimens borrowed from over 12 museums across the West. Comparisons of velvet ant faunas between sites revealed low similarities (0.167–0.75 species richness only; 0.022–0.67 both abundance and richness). Low similarity values indicate that a rich velvet ant fauna exists in the deserts of southern California. 相似文献
326.
327.
We surveyed bats throughout the White and Inyo Mountains of California and Nevada. From December 1990 to November 1996, we surveyed hibernating bats, and foraging bats from June 1992 to September 1996. The White-Inyo Range rests in a unique biogeographical junction between the Sierra Nevada, Mojave Desert, and Great Basin Regions. Elevational gradients of 305-4340 m, combined with limited human development, further enhance the interest of natural history and faunal distributions in this range. We found 13 bat species in the course of 2668 observations. Three of these species, the spotted bat ( Euderma maculatum ), silver-haired bat ( Lasionycteris noctivagans ), and hoary bat ( Lasturus cinereus ), have no previous records from the White-Inyo Range. We found bats in all vegetation zones except alpine, 3500-4342 m. Despite an abundance of mines in this range, only Townsend's big-eared bat ( Corynorhinus townsendii ) and western small-footed myotis ( Myotis ciliolabrum ) used them routinely. Our data also indicated the importance of surface water to bat populations in arid regions. 相似文献
328.
Xu B Roos JL Dexheimer P Boone B Plummer B Levy S Gogos JA Karayiorgou M 《Nature genetics》2011,43(9):864-868
Despite its high heritability, a large fraction of individuals with schizophrenia do not have a family history of the disease (sporadic cases). Here we examined the possibility that rare de novo protein-altering mutations contribute to the genetic component of schizophrenia by sequencing the exomes of 53 sporadic cases, 22 unaffected controls and their parents. We identified 40 de novo mutations in 27 cases affecting 40 genes, including a potentially disruptive mutation in DGCR2, a gene located in the schizophrenia-predisposing 22q11.2 microdeletion region. A comparison to rare inherited variants indicated that the identified de novo mutations show a large excess of non-synonymous changes in schizophrenia cases, as well as a greater potential to affect protein structure and function. Our analyses suggest a major role for de novo mutations in schizophrenia as well as a large mutational target, which together provide a plausible explanation for the high global incidence and persistence of the disease. 相似文献
329.
Valente EM Silhavy JL Brancati F Barrano G Krishnaswami SR Castori M Lancaster MA Boltshauser E Boccone L Al-Gazali L Fazzi E Signorini S Louie CM Bellacchio E;International Joubert Syndrome Related Disorders Study Group Bertini E Dallapiccola B Gleeson JG 《Nature genetics》2006,38(6):623-625
Joubert syndrome-related disorders (JSRD) are a group of syndromes sharing the neuroradiological features of cerebellar vermis hypoplasia and a peculiar brainstem malformation known as the 'molar tooth sign'. We identified mutations in the CEP290 gene in five families with variable neurological, retinal and renal manifestations. CEP290 expression was detected mostly in proliferating cerebellar granule neuron populations and showed centrosome and ciliary localization, linking JSRDs to other human ciliopathies. 相似文献
330.
Service S DeYoung J Karayiorgou M Roos JL Pretorious H Bedoya G Ospina J Ruiz-Linares A Macedo A Palha JA Heutink P Aulchenko Y Oostra B van Duijn C Jarvelin MR Varilo T Peddle L Rahman P Piras G Monne M Murray S Galver L Peltonen L Sabatti C Collins A Freimer N 《Nature genetics》2006,38(5):556-560
The genome-wide distribution of linkage disequilibrium (LD) determines the strategy for selecting markers for association studies, but it varies between populations. We assayed LD in large samples (200 individuals) from each of 11 well-described population isolates and an outbred European-derived sample, using SNP markers spaced across chromosome 22. Most isolates show substantially higher levels of LD than the outbred sample and many fewer regions of very low LD (termed 'holes'). Young isolates known to have had relatively few founders show particularly extensive LD with very few holes; these populations offer substantial advantages for genome-wide association mapping. 相似文献