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排序方式: 共有143条查询结果,搜索用时 15 毫秒
51.
Chapman MA Lawrence MS Keats JJ Cibulskis K Sougnez C Schinzel AC Harview CL Brunet JP Ahmann GJ Adli M Anderson KC Ardlie KG Auclair D Baker A Bergsagel PL Bernstein BE Drier Y Fonseca R Gabriel SB Hofmeister CC Jagannath S Jakubowiak AJ Krishnan A Levy J Liefeld T Lonial S Mahan S Mfuko B Monti S Perkins LM Onofrio R Pugh TJ Rajkumar SV Ramos AH Siegel DS Sivachenko A Stewart AK Trudel S Vij R Voet D Winckler W Zimmerman T Carpten J Trent J Hahn WC Garraway LA Meyerson M Lander ES Getz G 《Nature》2011,471(7339):467-472
Multiple myeloma is an incurable malignancy of plasma cells, and its pathogenesis is poorly understood. Here we report the massively parallel sequencing of 38 tumour genomes and their comparison to matched normal DNAs. Several new and unexpected oncogenic mechanisms were suggested by the pattern of somatic mutation across the data set. These include the mutation of genes involved in protein translation (seen in nearly half of the patients), genes involved in histone methylation, and genes involved in blood coagulation. In addition, a broader than anticipated role of NF-κB signalling was indicated by mutations in 11 members of the NF-κB pathway. Of potential immediate clinical relevance, activating mutations of the kinase BRAF were observed in 4% of patients, suggesting the evaluation of BRAF inhibitors in multiple myeloma clinical trials. These results indicate that cancer genome sequencing of large collections of samples will yield new insights into cancer not anticipated by existing knowledge. 相似文献
52.
Capak PL Riechers D Scoville NZ Carilli C Cox P Neri R Robertson B Salvato M Schinnerer E Yan L Wilson GW Yun M Civano F Elvis M Karim A Mobasher B Staguhn JG 《Nature》2011,470(7333):233-235
Massive clusters of galaxies have been found that date from as early as 3.9 billion years (3.9 Gyr; z = 1.62) after the Big Bang, containing stars that formed at even earlier epochs. Cosmological simulations using the current cold dark matter model predict that these systems should descend from 'protoclusters'-early overdensities of massive galaxies that merge hierarchically to form a cluster. These protocluster regions themselves are built up hierarchically and so are expected to contain extremely massive galaxies that can be observed as luminous quasars and starbursts. Observational evidence for this picture, however, is sparse because high-redshift protoclusters are rare and difficult to observe. Here we report a protocluster region that dates from 1 Gyr (z = 5.3) after the Big Bang. This cluster of massive galaxies extends over more than 13 megaparsecs and contains a luminous quasar as well as a system rich in molecular gas. These massive galaxies place a lower limit of more than 4 × 10(11) solar masses of dark and luminous matter in this region, consistent with that expected from cosmological simulations for the earliest galaxy clusters. 相似文献
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Zhou A Carrell RW Murphy MP Wei Z Yan Y Stanley PL Stein PE Broughton Pipkin F Read RJ 《Nature》2010,468(7320):108-111
Blood pressure is critically controlled by angiotensins, which are vasopressor peptides specifically released by the enzyme renin from the tail of angiotensinogen-a non-inhibitory member of the serpin family of protease inhibitors. Although angiotensinogen has long been regarded as a passive substrate, the crystal structures solved here to 2.1?? resolution show that the angiotensin cleavage site is inaccessibly buried in its amino-terminal tail. The conformational rearrangement that makes this site accessible for proteolysis is revealed in our 4.4?? structure of the complex of human angiotensinogen with renin. The co-ordinated changes involved are seen to be critically linked by a conserved but labile disulphide bridge. Here we show that the reduced unbridged form of angiotensinogen is present in the circulation in a near 40:60 ratio with the oxidized sulphydryl-bridged form, which preferentially interacts with receptor-bound renin. We propose that this redox-responsive transition of angiotensinogen to a form that will more effectively release angiotensin at a cellular level contributes to the modulation of blood pressure. Specifically, we demonstrate the oxidative switch of angiotensinogen to its more active sulphydryl-bridged form in the maternal circulation in pre-eclampsia-the hypertensive crisis of pregnancy that threatens the health and survival of both mother and child. 相似文献
56.
Mitchison HM Schmidts M Loges NT Freshour J Dritsoula A Hirst RA O'Callaghan C Blau H Al Dabbagh M Olbrich H Beales PL Yagi T Mussaffi H Chung EM Omran H Mitchell DR 《Nature genetics》2012,44(4):381-9, S1-2
Primary ciliary dyskinesia most often arises from loss of the dynein motors that power ciliary beating. Here we show that DNAAF3 (also known as PF22), a previously uncharacterized protein, is essential for the preassembly of dyneins into complexes before their transport into cilia. We identified loss-of-function mutations in the human DNAAF3 gene in individuals from families with situs inversus and defects in the assembly of inner and outer dynein arms. Knockdown of dnaaf3 in zebrafish likewise disrupts dynein arm assembly and ciliary motility, causing primary ciliary dyskinesia phenotypes that include hydrocephalus and laterality malformations. Chlamydomonas reinhardtii PF22 is exclusively cytoplasmic, and a PF22-null mutant cannot assemble any outer and some inner dynein arms. Altered abundance of dynein subunits in mutant cytoplasm suggests that DNAAF3 (PF22) acts at a similar stage as other preassembly proteins, for example, DNAAF2 (also known as PF13 or KTU) and DNAAF1 (also known as ODA7 or LRRC50), in the dynein preassembly pathway. These results support the existence of a conserved, multistep pathway for the cytoplasmic formation of assembly competent ciliary dynein complexes. 相似文献
57.
DE Neafsey K Galinsky RH Jiang L Young SM Sykes S Saif S Gujja JM Goldberg S Young Q Zeng SB Chapman AP Dash AR Anvikar PL Sutton BW Birren AA Escalante JW Barnwell JM Carlton 《Nature genetics》2012,44(9):1046-1050
We sequenced and annotated the genomes of four P. vivax strains collected from disparate geographic locations, tripling the number of genome sequences available for this understudied parasite and providing the first genome-wide perspective of global variability in this species. We observe approximately twice as much SNP diversity among these isolates as we do among a comparable collection of isolates of P. falciparum, a malaria-causing parasite that results in higher mortality. This indicates a distinct history of global colonization and/or a more stable demographic history for P. vivax relative to P. falciparum, which is thought to have undergone a recent population bottleneck. The SNP diversity, as well as additional microsatellite and gene family variability, suggests a capacity for greater functional variation in the global population of P. vivax. These findings warrant a deeper survey of variation in P. vivax to equip disease interventions targeting the distinctive biology of this neglected but major pathogen. 相似文献
58.
Ford CB Lin PL Chase MR Shah RR Iartchouk O Galagan J Mohaideen N Ioerger TR Sacchettini JC Lipsitch M Flynn JL Fortune SM 《Nature genetics》2011,43(5):482-486
Tuberculosis poses a global health emergency, which has been compounded by the emergence of drug-resistant Mycobacterium tuberculosis (Mtb) strains. We used whole-genome sequencing to compare the accumulation of mutations in Mtb isolated from cynomolgus macaques with active, latent or reactivated disease. We sequenced 33 Mtb isolates from nine macaques with an average genome coverage of 93% and an average read depth of 117×. Based on the distribution of SNPs observed, we calculated the mutation rates for these disease states. We found a similar mutation rate during latency as during active disease or in a logarithmically growing culture over the same period of time. The pattern of polymorphisms suggests that the mutational burden in vivo is because of oxidative DNA damage. We show that Mtb continues to acquire mutations during disease latency, which may explain why isoniazid monotherapy for latent tuberculosis is a risk factor for the emergence of isoniazid resistance. 相似文献
59.
Kopp JB Smith MW Nelson GW Johnson RC Freedman BI Bowden DW Oleksyk T McKenzie LM Kajiyama H Ahuja TS Berns JS Briggs W Cho ME Dart RA Kimmel PL Korbet SM Michel DM Mokrzycki MH Schelling JR Simon E Trachtman H Vlahov D Winkler CA 《Nature genetics》2008,40(10):1175-1184
The increased burden of chronic kidney and end-stage kidney diseases (ESKD) in populations of African ancestry has been largely unexplained. To identify genetic variants predisposing to idiopathic and HIV-1-associated focal segmental glomerulosclerosis (FSGS), we carried out an admixture-mapping linkage-disequilibrium genome scan on 190 African American individuals with FSGS and 222 controls. We identified a chromosome 22 region with a genome-wide logarithm of the odds (lod) score of 9.2 and a peak lod of 12.4 centered on MYH9, a functional candidate gene expressed in kidney podocytes. Multiple MYH9 SNPs and haplotypes were recessively associated with FSGS, most strongly a haplotype spanning exons 14 through 23 (OR = 5.0, 95% CI = 3.5-7.1; P = 4 x 10(-23), n = 852). This association extended to hypertensive ESKD (OR = 2.2, 95% CI = 1.5-3.4; n = 433), but not type 2 diabetic ESKD (n = 476). Genetic variation at the MYH9 locus substantially explains the increased burden of FSGS and hypertensive ESKD among African Americans. 相似文献