全文获取类型
收费全文 | 16797篇 |
免费 | 105篇 |
国内免费 | 89篇 |
专业分类
系统科学 | 69篇 |
丛书文集 | 137篇 |
教育与普及 | 41篇 |
理论与方法论 | 41篇 |
现状及发展 | 6992篇 |
研究方法 | 803篇 |
综合类 | 8663篇 |
自然研究 | 245篇 |
出版年
2012年 | 234篇 |
2011年 | 495篇 |
2010年 | 107篇 |
2009年 | 102篇 |
2008年 | 291篇 |
2007年 | 354篇 |
2006年 | 301篇 |
2005年 | 320篇 |
2004年 | 418篇 |
2003年 | 291篇 |
2002年 | 306篇 |
2001年 | 637篇 |
2000年 | 647篇 |
1999年 | 460篇 |
1994年 | 300篇 |
1992年 | 345篇 |
1991年 | 303篇 |
1990年 | 317篇 |
1989年 | 276篇 |
1988年 | 268篇 |
1987年 | 291篇 |
1986年 | 300篇 |
1985年 | 390篇 |
1984年 | 297篇 |
1983年 | 246篇 |
1982年 | 212篇 |
1981年 | 238篇 |
1980年 | 239篇 |
1979年 | 544篇 |
1978年 | 439篇 |
1977年 | 379篇 |
1976年 | 321篇 |
1975年 | 335篇 |
1974年 | 402篇 |
1973年 | 332篇 |
1972年 | 374篇 |
1971年 | 436篇 |
1970年 | 547篇 |
1969年 | 429篇 |
1968年 | 400篇 |
1967年 | 396篇 |
1966年 | 397篇 |
1965年 | 286篇 |
1959年 | 121篇 |
1958年 | 224篇 |
1957年 | 155篇 |
1956年 | 129篇 |
1955年 | 101篇 |
1954年 | 130篇 |
1948年 | 103篇 |
排序方式: 共有10000条查询结果,搜索用时 62 毫秒
61.
McCarroll SA Hadnott TN Perry GH Sabeti PC Zody MC Barrett JC Dallaire S Gabriel SB Lee C Daly MJ Altshuler DM;International HapMap Consortium 《Nature genetics》2006,38(1):86-92
The locations and properties of common deletion variants in the human genome are largely unknown. We describe a systematic method for using dense SNP genotype data to discover deletions and its application to data from the International HapMap Consortium to characterize and catalogue segregating deletion variants across the human genome. We identified 541 deletion variants (94% novel) ranging from 1 kb to 745 kb in size; 278 of these variants were observed in multiple, unrelated individuals, 120 in the homozygous state. The coding exons of ten expressed genes were found to be commonly deleted, including multiple genes with roles in sex steroid metabolism, olfaction and drug response. These common deletion polymorphisms typically represent ancestral mutations that are in linkage disequilibrium with nearby SNPs, meaning that their association to disease can often be evaluated in the course of SNP-based whole-genome association studies. 相似文献
62.
Scorpio A Blank TE Day WA Chabot DJ 《Cellular and molecular life sciences : CMLS》2006,63(19-20):2237-2248
Anthrax has been a major cause of death in grazing animals and an occasional cause of death in humans for thousands of years. Since the late 1800s there has been an exceptional international history of anthrax vaccine development. Due to animal vaccinations, the rate of infection has dropped dramatically. Anthrax vaccines have progressed from uncharacterized whole-cell vaccines in 1881, to pXO2-negative spores in the 1930s, to culture filtrates absorbed to aluminum hydroxide in 1970, and likely to recombinant protective antigen in the near future. Each of these refinements has increased safety without significant loss of efficacy. The threat of genetically engineered, antibiotic and vaccine resistant strains of Bacillus anthracis is fueling hypothesis-driven research and global techniques--including genomics, proteomics and transposon site hybridization--to facilitate the discovery of novel vaccine targets. This review highlights historical achievements and new developments in anthrax vaccine research. 相似文献
63.
Structure of the detoxification catalyst mercuric ion reductase from Bacillus sp. strain RC607 总被引:10,自引:0,他引:10
Several hundred million tons of toxic mercurials are dispersed in the biosphere. Microbes can detoxify organo-mercurials and mercury salts through sequential action of two enzymes, organomercury lyase and mercuric ion reductase (MerA). The latter, a homodimer with homology to the FAD-dependent disulphide oxidoreductases, catalyses the reaction NADPH + Hg(II)----NADP+ + H+ + Hg(0), one of the very rare enzymic reactions with metal substrates. Human glutathione reductase serves as a reference molecule for FAD-dependent disulphide reductases and between its primary structure and that of MerA from Tn501 (Pseudomonas), Tn21 (Shigella), p1258 (Staphylococcus) and Bacillus, 25-30% of the residues have been conserved. All MerAs have a C-terminal extension about 15 residues long but have very varied N termini. Although the enzyme from Streptomyces lividans has no addition, from Pseudomonas aeruginosa Tn501 and Bacillus sp. strain RC607 it has one and two copies respectively of a domain of 80-85 residues, highly homologous to MerP, the periplasmic component of proteins encoded by the mer operon. These domains can be proteolytically cleaved off without changing the catalytic efficiency. We report here the crystal structure of MerA from the Gram-positive bacterium Bacillus sp. strain RC607. Analysis of its complexes with nicotinamide dinucleotide substrates and the inhibitor Cd(II) reveals how limited structural changes enable an enzyme to accept as substrate what used to be a dangerous inhibitor. Knowledge of the mode of mercury ligation is a prerequisite for understanding this unique detoxification mechanism. 相似文献
64.
65.
MacArthur DG Seto JT Raftery JM Quinlan KG Huttley GA Hook JW Lemckert FA Kee AJ Edwards MR Berman Y Hardeman EC Gunning PW Easteal S Yang N North KN 《Nature genetics》2007,39(10):1261-1265
More than a billion humans worldwide are predicted to be completely deficient in the fast skeletal muscle fiber protein alpha-actinin-3 owing to homozygosity for a premature stop codon polymorphism, R577X, in the ACTN3 gene. The R577X polymorphism is associated with elite athlete status and human muscle performance, suggesting that alpha-actinin-3 deficiency influences the function of fast muscle fibers. Here we show that loss of alpha-actinin-3 expression in a knockout mouse model results in a shift in muscle metabolism toward the more efficient aerobic pathway and an increase in intrinsic endurance performance. In addition, we demonstrate that the genomic region surrounding the 577X null allele shows low levels of genetic variation and recombination in individuals of European and East Asian descent, consistent with strong, recent positive selection. We propose that the 577X allele has been positively selected in some human populations owing to its effect on skeletal muscle metabolism. 相似文献
66.
Larrucea S Butta N Rodriguez RB Alonso-Martin S Arias-Salgado EG Ayuso MS Parrilla R 《Cellular and molecular life sciences : CMLS》2007,64(22):2965-2974
Podocalyxin (PODXL) is a mucin protein of the CD34 family expressed in kidney glomerular podocytes, vascular endothelium,
progenitor bone marrow and tumor cells. It is assumed that PODXL plays an anti-adherent role in kidney podocytes. CHO cells
stably expressing human PODXL (CHO-PODXL) or human tumor cells (Tera-1) inherently expressing PODXL showed increased adherence
to platelets. The adherence of cells was inhibited (70%) by blockers of platelet P-selectin, prevented by the soluble ectodomain
of human PODXL (PODXL-Δ) or by the arginine-glycine-aspartate (RGDS) peptide and partially impeded by inhibition of integrin
αVβ3/αVβ5, suggesting a coordinated action of P-selectin and integrins. Colocalization of platelet P-selectin and PODXL expressed
on CHO cells was demonstrated by confocal immunofluorescence. No adherence to platelets was observed when PODXL was expressed
in glycomutant CHO cells deficient in sialic acid.
Received 14 August 2007; received after revision 12 September 2007; accepted 13 September 2007 相似文献
67.
Liu F Thirumangalathu S Gallant NM Yang SH Stoick-Cooper CL Reddy ST Andl T Taketo MM Dlugosz AA Moon RT Barlow LA Millar SE 《Nature genetics》2007,39(1):106-112
Fungiform taste papillae form a regular array on the dorsal tongue. Taste buds arise from papilla epithelium and, unusually for epithelial derivatives, synapse with neurons, release neurotransmitters and generate receptor and action potentials. Despite the importance of taste as one of our five senses, genetic analyses of taste papilla and bud development are lacking. We demonstrate that Wnt-beta-catenin signaling is activated in developing fungiform placodes and taste bud cells. A dominant stabilizing mutation of epithelial beta-catenin causes massive overproduction of enlarged fungiform papillae and taste buds. Likewise, genetic deletion of epithelial beta-catenin or inhibition of Wnt-beta-catenin signaling by ectopic dickkopf1 (Dkk1) blocks initiation of fungiform papilla morphogenesis. Ectopic papillae are innervated in the stabilizing beta-catenin mutant, whereas ectopic Dkk1 causes absence of lingual epithelial innervation. Thus, Wnt-beta-catenin signaling is critical for fungiform papilla and taste bud development. Altered regulation of this pathway may underlie evolutionary changes in taste papilla patterning. 相似文献
68.
69.
70.
Pyruvate dehydrogenase kinase regulatory mechanisms and inhibition in treating diabetes, heart ischemia, and cancer 总被引:2,自引:2,他引:0
The fraction of pyruvate dehydrogenase complex (PDC) in the active form is reduced by the activities of dedicated PD kinase
isozymes (PDK1, PDK2, PDK3 and PDK4). Via binding to the inner lipoyl domain (L2) of the dihydrolipoyl acetyltransferase (E2
60mer), PDK rapidly access their E2-bound PD substrate. The E2-enhanced activity of the widely distributed PDK2 is limited
by dissociation of ADP from its C-terminal catalytic domain, and this is further slowed by pyruvate binding to the N-terminal
regulatory (R) domain. Via the reverse of the PDC reaction, NADH and acetyl-CoA reductively acetylate lipoyl group of L2,
which binds to the R domain and stimulates PDK2 activity by speeding up ADP dissociation. Activation of PDC by synthetic PDK
inhibitors binding at the pyruvate or lipoyl binding sites decreased damage during heart ischemia and lowered blood glucose
in insulin-resistant animals. PDC activation also triggers apoptosis in cancer cells that selectively convert glucose to lactate.
Received 25 August 2006; received after revision 20 November 2006; accepted 20 December 2006 相似文献