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排序方式: 共有129条查询结果,搜索用时 343 毫秒
81.
Graham RR Kozyrev SV Baechler EC Reddy MV Plenge RM Bauer JW Ortmann WA Koeuth T González Escribano MF;Argentine Spanish Collaborative Groups Pons-Estel B Petri M Daly M Gregersen PK Martín J Altshuler D Behrens TW Alarcón-Riquelme ME 《Nature genetics》2006,38(5):550-555
Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by activation of the type I interferon (IFN) pathway. Here we convincingly replicate association of the IFN regulatory factor 5 (IRF5) rs2004640 T allele with SLE in four independent case-control cohorts (P = 4.4 x 10(-16)) and by family-based transmission disequilibrium test analysis (P = 0.0006). The rs2004640 T allele creates a 5' donor splice site in an alternate exon 1 of IRF5, allowing expression of several unique IRF5 isoforms. We also identify an independent cis-acting variant associated with elevated expression of IRF5 and linked to the exon 1B splice site. Haplotypes carrying the variant associated with elevated expression and lacking the exon 1B donor site do not confer risk of SLE. Thus, a common IRF5 haplotype driving elevated expression of multiple unique isoforms of IRF5 is an important genetic risk factor for SLE, establishing a causal role for type I IFN pathway genes in human autoimmunity. 相似文献
82.
Genetic variation in Mon1a affects protein trafficking and modifies macrophage iron loading in mice 总被引:2,自引:0,他引:2
Wang F Paradkar PN Custodio AO McVey Ward D Fleming MD Campagna D Roberts KA Boyartchuk V Dietrich WF Kaplan J Andrews NC 《Nature genetics》2007,39(8):1025-1032
We undertook a quantitative trait locus (QTL) analysis in mice to identify modifier genes that might influence the severity of human iron disorders. We identified a strong QTL on mouse chromosome 9 that differentially affected macrophage iron burden in C57BL/10J and SWR/J mice. A C57BL/10J missense allele of an evolutionarily conserved gene, Mon1a, cosegregated with the QTL in congenic mouse lines. We present evidence that Mon1a is involved in trafficking of ferroportin, the major mammalian iron exporter, to the surface of iron-recycling macrophages. Differences in amounts of surface ferroportin correlate with differences in cellular iron content. Mon1a is also important for trafficking of cell-surface and secreted molecules unrelated to iron metabolism, suggesting that it has a fundamental role in the mammalian secretory apparatus. 相似文献
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Lindblad-Toh K Garber M Zuk O Lin MF Parker BJ Washietl S Kheradpour P Ernst J Jordan G Mauceli E Ward LD Lowe CB Holloway AK Clamp M Gnerre S Alföldi J Beal K Chang J Clawson H Cuff J Di Palma F Fitzgerald S Flicek P Guttman M Hubisz MJ Jaffe DB Jungreis I Kent WJ Kostka D Lara M Martins AL Massingham T Moltke I Raney BJ Rasmussen MD Robinson J Stark A Vilella AJ Wen J Xie X Zody MC;Broad Institute Sequencing Platform Whole Genome Assembly Team Baldwin J Bloom T Chin CW Heiman D Nicol R 《Nature》2011,478(7370):476-482
The comparison of related genomes has emerged as a powerful lens for genome interpretation. Here we report the sequencing and comparative analysis of 29 eutherian genomes. We confirm that at least 5.5% of the human genome has undergone purifying selection, and locate constrained elements covering ~4.2% of the genome. We use evolutionary signatures and comparisons with experimental data sets to suggest candidate functions for ~60% of constrained bases. These elements reveal a small number of new coding exons, candidate stop codon readthrough events and over 10,000 regions of overlapping synonymous constraint within protein-coding exons. We find 220 candidate RNA structural families, and nearly a million elements overlapping potential promoter, enhancer and insulator regions. We report specific amino acid residues that have undergone positive selection, 280,000 non-coding elements exapted from mobile elements and more than 1,000 primate- and human-accelerated elements. Overlap with disease-associated variants indicates that our findings will be relevant for studies of human biology, health and disease. 相似文献
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Amino acid sequence changes in the haemagglutinin of A/Hong Kong (H3N2) influenza virus during the period 1968--77 总被引:12,自引:0,他引:12
Haemagglutinin molecules from nine strains of A/Hong Kong/68 (H3N2) influenza virus, isolated between 1968 and 1977, were examined for changes in amino acid sequences. At least 18 changes, 9 of which were located precisely, occurred in the soluble tryptic peptides of the large haemagglutinin polypeptide (HA1) during this period. These peptides contained 262 residues (82% of HA1). In HA2, only two changes in 129 residues (58% of HA2) were detected. Sequential changes at a particular locus were not found; and as far as we can tell, once an amino acid changed, it did not change again in any subsequent variant examined. 相似文献
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