全文获取类型
收费全文 | 2715篇 |
免费 | 261篇 |
国内免费 | 1篇 |
出版年
2023年 | 14篇 |
2022年 | 28篇 |
2021年 | 52篇 |
2020年 | 25篇 |
2019年 | 41篇 |
2018年 | 55篇 |
2017年 | 51篇 |
2016年 | 77篇 |
2015年 | 128篇 |
2014年 | 140篇 |
2013年 | 173篇 |
2012年 | 199篇 |
2011年 | 155篇 |
2010年 | 129篇 |
2009年 | 108篇 |
2008年 | 149篇 |
2007年 | 159篇 |
2006年 | 133篇 |
2005年 | 153篇 |
2004年 | 137篇 |
2003年 | 133篇 |
2002年 | 117篇 |
2001年 | 26篇 |
2000年 | 17篇 |
1999年 | 28篇 |
1998年 | 41篇 |
1997年 | 34篇 |
1996年 | 25篇 |
1995年 | 34篇 |
1994年 | 25篇 |
1993年 | 27篇 |
1992年 | 22篇 |
1991年 | 15篇 |
1990年 | 13篇 |
1989年 | 11篇 |
1988年 | 21篇 |
1986年 | 16篇 |
1985年 | 13篇 |
1984年 | 16篇 |
1983年 | 16篇 |
1982年 | 20篇 |
1981年 | 10篇 |
1980年 | 15篇 |
1979年 | 10篇 |
1978年 | 16篇 |
1976年 | 17篇 |
1975年 | 9篇 |
1974年 | 9篇 |
1973年 | 14篇 |
1967年 | 8篇 |
排序方式: 共有2977条查询结果,搜索用时 31 毫秒
141.
Font-Montgomery E Weaver DD Walsh L Christensen C Thurston VC 《Birth defects research. Part A, Clinical and molecular teratology》2004,70(6):408-415
BACKGROUND: Fluorescent subtelomeric probes for the 41 different subtelomeric regions (the p arms of the acrocentric chromosomes were excluded) have been developed over the last 10 years. These probes can detect deletions, duplications, and translocations in the gene-rich subtelomeric regions of human chromosomes, regions where crossing over frequently occurs and where a high number of abnormalities have been found. Recently, commercially produced probes have become available, which has led to the detection of subtelomeric abnormalities in 7.4% of patients with moderate to severe mental retardation (Knight et al., 1999). CASES: We evaluated 43 dysmorphic children with developmental delay and/or mental retardation of unknown etiology and/or autism who were previously assessed for chromosome abnormalities, metabolic disorders, or recognizable dysmorphic syndromes, all of which were ruled out. Of the 43 children tested, 6 (14%) were found to have subtelomeric aberrations. CONCLUSIONS: We recommend that patients with dysmorphic features and mental retardation of unknown etiology who also have a normal standard chromosome analysis should have subtelomeric FISH testing performed earlier in their clinical workup. 相似文献
142.
143.
144.
Kent ML Whipps CM Matthews JL Florio D Watral V Bishop-Stewart JK Poort M Bermudez L 《Comparative biochemistry and physiology. Toxicology & pharmacology : CBP》2004,138(3):383-390
The Zebrafish International Resource Center was established to support the zebrafish research community, and includes a diagnostic service. One of the most common diseases that we have diagnosed is mycobacteriosis, which represented 18% of the diagnostic cases submitted from November 1999 to June 2003. We describe here the severity of the disease and associated pathological changes of 24 diagnostic cases from 14 laboratories. Identifications of the bacteria are provided for seven of these cases. For two cases in which culture of the organism was not successful, these identifications were based on ribosomal DNA (rDNA) sequence analysis obtained directly from infected tissues. Biochemical characteristics and rDNA sequence analysis from cultures are reported for the other isolates. Two severe outbreaks from different facilities on different continents were associated with an organism identified as Mycobacterium haemophilum based on rDNA sequence from tissues. Another severe outbreak was associated with an organism most closely related to Mycobacterium peregrinum. These species are recognized pathogens of humans, but this is the first report of them from fish. Bacteria identified as Mycobacterium chelonae or M. abscessus were recovered from fish in cases categorized as moderate disease or as an incidental finding. These findings indicate that species of Mycobacterium previously undescribed from fish (i.e., M. haemophilum and M. peregrinum) may pose significant health problems in zebrafish research facilities, whereas species and strains that are already recognized as common in fish usually cause limited disease on a population basis in zebrafish. 相似文献
145.
Thrombopoietin (TPO) plays a pivotal role in megakaryopoiesis. TPO initiates its biological effects by binding to its receptor Mpl. A recombinant protein consisting of a carrier Fc domain linked to multiple Mpl-binding domains was constructed, and is called AMG531. To define the biological activity of AMG531, we examined the ability of AMG531 to support CFU-Meg growth and to promote megakaryocyte maturation in vitro. AMG531 stimulates CFU-Meg growth in a dose-dependent manner, and acts in concert with erythropoietin, stem cell factor, interleukin-3, and interleukin-6 to enhance CFU-Meg growth, similar to parallel experiments with TPO. AMG531-stimulated serum-free liquid cultures support the development of mature polyploid megakaryocytes with a predominant DNA content of 32 N and 64 N, identical to that of parallel TPO-stimulated cultures. Competitive binding experiments show that AMG531 effectively competes with 125I-TPO for binding to BaF3-Mpl cells or normal platelets. Treatment of BaF3-Mpl cells with AMG531 or with TPO resulted in rapid tyrosine phosphorylation of Mpl, JAK2, and STAT5. These results indicate that AMG531 is a potent stimulant of megakarypoiesis in vitro, and provide support for its further characterization in vivo. 相似文献
146.
Venema RC Venema VJ Ju H Harris MB Snead C Jilling T Dimitropoulou C Maragoudakis ME Catravas JD 《American journal of physiology. Heart and circulatory physiology》2003,285(2):H669-H678
Soluble guanylate cyclase (sGC) is an important downstream intracellular target of nitric oxide (NO) that is produced by endothelial NO synthase (eNOS) and inducible NO synthase (iNOS). In this study, we demonstrate that sGC exists in a complex with eNOS and heat shock protein 90 (HSP90) in aortic endothelial cells. In addition, we show that in aortic smooth muscle cells, sGC forms a complex with HSP90. Formation of the sGC/eNOS/HSP90 complex is increased in response to eNOS-activating agonists in a manner that depends on HSP90 activity. In vitro binding assays with glutathione S-transferase fusion proteins that contain the alpha- or beta-subunit of sGC show that the sGC beta-subunit interacts directly with HSP90 and indirectly with eNOS. Confocal immunofluorescent studies confirm the subcellular colocalization of sGC and HSP90 in both endothelial and smooth muscle cells. Complex formation of sGC with HSP90 facilitates responses to NO donors in cultured cells (cGMP accumulation) as well as in anesthetized rats (hypotension). These complexes likely function to stabilize sGC as well as to provide directed intracellular transfer of NO from NOS to sGC, thus preventing inactivation of NO by superoxide anion and formation of peroxynitrite, which is a toxic molecule that has been implicated in the pathology of several vascular diseases. 相似文献
147.
Segarra CI Casalongué CA Pinedo ML Ronchi VP Conde RD 《Journal of experimental botany》2003,54(386):1335-1341
A protein resistant to heat and proteolysis that inhibits serine proteases was isolated from wheat leaf apoplasts. Based on trypsin inhibition, its more active form was a 66-69 kDa oligomer. It was dissociated in an 18-21 kDa monomer having an amino terminal sequence identical to the Box A of germins and germin-like proteins. Like these proteins, it was glycosylated and showed manganese superoxide dismutase activity. The monomer displayed three forms when examined by 2D western blot: two of 19 kDa, pI 5.8 and 6.2; and one of 21 kDa, pI 5.8. It was found that the protein controls serine protease activity in the apoplast of plants challenged with the fungus Septoria tritici. 相似文献
148.
Mishizen-Eberz AJ Guttmann RP Giasson BI Day GA Hodara R Ischiropoulos H Lee VM Trojanowski JQ Lynch DR 《Journal of neurochemistry》2003,86(4):836-847
Parkinson's disease (PD) is characterized by fibrillary neuronal inclusions called Lewy bodies (LBs) consisting largely of alpha-synuclein (alpha-syn), the protein mutated in some patients with familial PD. The mechanisms of alpha-syn fibrillization and LB formation are unknown, but may involve aberrant degradation or turnover. We examined the ability of calpain I to cleave alpha-syn in vitro. Calpain I cleaved wild-type alpha-syn predominantly after amino acid 57 and within the non-amyloid component (NAC) region. In contrast, calpain I cleaved fibrillized alpha-syn primarily in the region of amino acid 120 to generate fragments like those that increase susceptibility to dopamine toxicity and oxidative stress. Further, while calpain I cleaved wild-type alpha-syn after amino acid 57, this did not occur in mutant A53T alpha-syn. This paucity of proteolysis could increase the stability of A53T alpha-syn, suggesting that calpain I might protect cells from forming LBs by specific cleavages of soluble wild-type alpha-syn. However, once alpha-syn has polymerized into fibrils, calpain I may contribute to toxicity of these forms of alpha-syn by cleaving at aberrant sites within the C-terminal region. Elucidating the role of calpain I in the proteolytic processing of alpha-syn in normal and diseased brains may clarify mechanisms of neurodegenerative alpha-synucleinopathies. 相似文献
149.
Effects of oxidative and nitrative challenges on alpha-synuclein fibrillogenesis involve distinct mechanisms of protein modifications 总被引:7,自引:0,他引:7
Norris EH Giasson BI Ischiropoulos H Lee VM 《The Journal of biological chemistry》2003,278(29):27230-27240
Filamentous inclusions of alpha-synuclein protein are hallmarks of neurodegenerative diseases collectively known as synucleinopathies. Previous studies have shown that exposure to oxidative and nitrative species stabilizes alpha-synuclein filaments in vitro, and this stabilization may be due to dityrosine cross-linking. To test this hypothesis, we mutated tyrosine residues to phenylalanine and generated recombinant wild type and mutant alpha-synuclein proteins. alpha-Synuclein proteins lacking some or all tyrosine residues form fibrils to the same extent as the wild type protein. Tyrosine residues are not required for protein cross-linking or filament stabilization resulting from transition metal-mediated oxidation, because higher Mr SDS-resistant oligomers and filaments stable to chaotropic agents are detected using all Tyr --> Phe alpha-synuclein mutants. By contrast, cross-linking resulting from exposure to nitrating agents required the presence of one or more tyrosine residues. Furthermore, tyrosine cross-linking is involved in filament stabilization, because nitrating agent-exposed assembled wild type, but not mutant alpha-synuclein lacking all tyrosine residues, was stable to chaotropic treatment. In addition, the formation of stable alpha-synuclein inclusions in intact cells after exposure to oxidizing and nitrating species requires tyrosine residues. These findings demonstrate that nitrative and/or oxidative stress results in distinct mechanisms of alpha-synuclein protein modifications that can influence the formation of stable alpha-synuclein fibrils. 相似文献
150.
Kuiper MJ Lankin C Gauthier SY Walker VK Davies PL 《Biochemical and biophysical research communications》2003,300(3):645-648
Antifreeze proteins (AFPs) can protect organisms from freezing injury by adsorbing to ice and inhibiting its growth. We describe here a method where ice, grown on a cold finger, is used to selectively adsorb and purify these ice-binding proteins from a crude mixture. Type III recombinant AFP was enriched approximately 50-fold after one round of partitioning into ice and purified to homogeneity by a second round. This method can also be used to purify non-ice-binding proteins by linkage to AFP domains as demonstrated by the recovery of a 50 kDa maltose-binding protein-AFP fusion from a crude lysate of Escherichia coli. 相似文献