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981.
982.
Lundholt BK Linde V Loechel F Pedersen HC Møller S Praestegaard M Mikkelsen I Scudder K Bjørn SP Heide M Arkhammar PO Terry R Nielsen SJ 《Journal of biomolecular screening》2005,10(1):20-29
The PI3-kinase/Akt pathway is an important cell survival pathway that is deregulated in the majority of human cancers. Despite the apparent druggability of several kinases in the pathway, no specific catalytic inhibitors have been reported in the literature. The authors describe the development of a fluorometric imaging plate reader (FLIPR)-based Akt1 translocation assay to discover inhibitors of Akt1 activation. Screening of a diverse chemical library of 45,000 compounds resulted in identification of several classes of Akt1 translocation inhibitors. Using a combination of classical in vitro assays and translocation assays directed at different steps of the Akt pathway, the mechanisms of action of 2 selected chemical classes were further defined. Protein translocation assays emerge as powerful tools for hit identification and characterization. 相似文献
983.
Evidence for an RNA chaperone function of polypyrimidine tract-binding protein in picornavirus translation 总被引:4,自引:0,他引:4 下载免费PDF全文
Song Y Tzima E Ochs K Bassili G Trusheim H Linder M Preissner KT Niepmann M 《RNA (New York, N.Y.)》2005,11(12):1809-1824
The cellular polypyrimidine tract-binding protein (PTB) is recruited by the genomic RNAs of picornaviruses to stimulate translation initiation at their internal ribosome entry site (IRES) elements. We investigated the contribution of the individual RNA recognition motif (RRM) domains of PTB to its interaction with the IRES of foot-and-mouth disease virus (FMDV). Using a native gel system, we found that PTB is a monomer, confirming recent reports that challenged the previous view that PTB is a dimer. Mapping the spatial orientation of PTB relative to the bound IRES RNA, we found that the two C-terminal RRM domains III and IV of PTB bind in an oriented way to the IRES. Domain III contacts the IRES stem-loop 2, while domain IV contacts the separate IRES 3' region. PTB domain I appears not to be involved directly in RNA binding, but domain II stabilizes the RNA binding conferred by domains III and IV. A PTB protein containing only these two C-terminal PTB domains is sufficient to enhance the entry of initiation factor eIF4G to the IRES and stimulate IRES activity, and the long-lived PTB-IRES interaction stabilized by domain II is not a prerequisite for this function. Thus, PTB most likely acts as an RNA chaperone to stabilize IRES structure and, in that way, augment IRES activity. 相似文献
984.
Kempe DS Lang PA Eisele K Klarl BA Wieder T Huber SM Duranton C Lang F 《American journal of physiology. Cell physiology》2005,288(2):C396-C402
Pb+ intoxication causes anemia that is partially due to a decreased life span of circulating erythrocytes. As shown recently, a Ca2+-sensitive erythrocyte scramblase is activated by osmotic shock, oxidative stress, and/or energy depletion, leading to exposure of phosphatidylserine at the erythrocyte surface. Because macrophages are equipped with phosphatidylserine receptors, they bind, engulf, and degrade phosphatidylserine-exposing cells. The present experiments were performed to explore whether Pb+ ions trigger phosphatidylserine exposure of erythrocytes. The phosphatidylserine exposure was estimated on the basis of annexin binding as determined using fluorescence-activated cell sorting (FACS) analysis. Exposure to Pb+ ions [0.1 µM Pb(NO3)2] significantly increased annexin binding. This effect was paralleled by erythrocyte shrinkage, which was apparent on the basis of the decrease in forward scatter in FACS analysis. The effect of Pb+ ions on cell volume was virtually abolished, and the effect of Pb+ ions on annexin binding was blunted after increase of extracellular K+ concentration. Moreover, both effects of Pb+ ions were partially prevented in the presence of clotrimazole (10 µM), an inhibitor of the Ca2+-sensitive K+ channels in the erythrocyte cell membrane. Whole cell patch-clamp experiments disclosed a significant activation of a K+-selective conductance after Pb+ ion exposure, an effect requiring higher (10 µM) concentrations, however. In conclusion, Pb+ ions activate erythrocyte K+ channels, leading to erythrocyte shrinkage, and also activate the erythrocyte scramblase, leading to phosphatidylserine exposure. The effect could well contribute to the reported decreased life span of circulating erythrocytes during Pb+ intoxication. cell volume; annexin; apoptosis; Gardos channel; calcium 相似文献
985.
We carried out a two-part investigation that revealed habitat differences in marine invertebrate invasions. First, we compared
invasion levels of hard vs soft substrata in Elkhorn Slough, an estuary in Central California, by comparing abundance and
richness of native vs exotic species in quantitative samples from each habitat type. Our results revealed that the hard substrata
were much more heavily invaded than the soft substrata. Nearly all the hard substrata in Elkhorn Slough, as in most estuaries
along the Pacific coast of North America, are artificial (jetties, rip-rap, docks). Some exotic species may by chance be better
adapted to this novel habitat type than are natives. Two major vectors responsible for marine introductions, oyster culturing
and ship-hull fouling, are also more likely to transport species associated with hard vs soft substrata. Secondly, we compared
estuarine and open coast invasion rates. We examined species richness in Elkhorn Slough and adjacent rocky intertidal habitats
along the Central California coast. The absolute number of exotic species in the estuary was an order of magnitude higher
than along the open coast (58 vs 8 species), as was the percentage of the invertebrate fauna that was exotic (11% vs 1%).
Estuaries on this coast are geologically young, heavily altered by humans, and subject to numerous transport vectors bringing
invasive propagules: all these factors may explain why they are strikingly more invaded than the open coast. The finding that
the more species rich habitat – the open coast – is less invaded is in contrast to many terrestrial examples, where native
and exotic species richness appear to be positively correlated at a broad geographic scale. 相似文献
986.
Marie Ekberg-Aronsson Kerstin Pehrsson Jan-?ke Nilsson Peter M Nilsson Claes-G?ran L?fdahl 《Respiratory research》2005,6(1):98
Background
The GOLD classification of COPD severity introduces a stage 0 (at risk) comprising individuals with productive cough and normal lung function. The aims of this study were to investigate total mortality risks in GOLD stages 0–4 with special focus on stage 0, and furthermore to assess the influence of symptoms of chronic bronchitis on mortality risks in GOLD stages 1–4.Method
Between 1974 and 1992, a total of 22 044 middle-aged individuals participated in a health screening, which included a spirometry as well as recording of respiratory symptoms and smoking habits. Individuals with comorbidity at baseline (diabetes, stroke, cancer, angina pectoris, or heart infarction) were excluded from the analyses. Hazard ratios (HR 95% CI) of total mortality were analyzed in GOLD stages 0–4 with individuals with normal lung function and without symptoms of chronic bronchitis as a reference group. HR:s in smoking individuals with symptoms of chronic bronchitis within the stages 1–4 were calculated with individuals with the same GOLD stage but without symptoms of chronic bronchitis as reference.Results
The number of deaths was 3674 for men and 832 for women based on 352 324 and 150 050 person-years respectively. The proportion of smokers among men was 50% and among women 40%. Self reported comorbidity was present in 4.6% of the men and 6.6% of the women. Among smoking men, Stage 0 was associated with an increased mortality risk, HR; 1.65 (1.32–2.08), of similar magnitude as in stage 2, HR; 1.41 (1.31–1.70). The hazard ratio in stage 0 was significantly higher than in stage 1 HR; 1.13 (0.98–1.29). Among male smokers with stage 1; HR: 2.04 (1.34–3.11), and among female smokers with stage 2 disease; HR: 3.16 (1.38–7.23), increased HR:s were found in individuals with symptoms of chronic bronchitis as compared to those without symptoms of chronic bronchitis.Conclusion
Symptoms fulfilling the definition of chronic bronchitis were associated with an increased mortality risk among male smokers with normal pulmonary function (stage 0) and also with an increased risk of death among smoking individuals with mild to moderate COPD (stage 1 and 2). 相似文献987.
Hitte C Madeoy J Kirkness EF Priat C Lorentzen TD Senger F Thomas D Derrien T Ramirez C Scott C Evanno G Pullar B Cadieu E Oza V Lourgant K Jaffe DB Tacher S Dréano S Berkova N André C Deloukas P Fraser C Lindblad-Toh K Ostrander EA Galibert F 《Nature reviews. Genetics》2005,6(8):643-648
Accurate and comprehensive sequence coverage for large genomes has been restricted to only a few species of specific interest. Lower sequence coverage (survey sequencing) of related species can yield a wealth of information about gene content and putative regulatory elements. But survey sequences lack long-range continuity and provide only a fragmented view of a genome. Here we show the usefulness of combining survey sequencing with dense radiation-hybrid (RH) maps for extracting maximum comparative genome information from model organisms. Based on results from the canine system, we propose that from now on all low-pass sequencing projects should be accompanied by a dense, gene-based RH map-construction effort to extract maximum information from the genome with a marginal extra cost. 相似文献
988.
989.
990.
Tiedemann K Sasaki T Gustafsson E Göhring W Bätge B Notbohm H Timpl R Wedel T Schlötzer-Schrehardt U Reinhardt DP 《The Journal of biological chemistry》2005,280(12):11404-11412
Mutational defects in fibrillin-rich microfibrils give rise to a number of heritable connective tissue disorders, generally termed microfibrillopathies. To understand the pathogenesis of these microfibrillopathies, it is important to elucidate the supramolecular composition of microfibrils and their interaction properties with extracellular matrix components. Here we demonstrate that the proteoglycan perlecan is an associated component of microfibrils typically close to basement membrane zones. Double immunofluorescence studies demonstrate colocalization of fibrillin-1, the major backbone component of microfibrils, with perlecan in fibroblast cultures as well as in dermal and ocular tissues. Double immunogold labeling further confirms colocalization of perlecan to microfibrils in various tissues at the ultrastructural level. Extraction studies revealed that perlecan is not covalently associated with microfibrils. High affinity interactions between fibrillin-1 and perlecan were found by kinetic binding studies with dissociation constants in the low nanomolar range. A detailed mapping study of the interaction epitopes by solid phase binding assays primarily revealed interactions of perlecan domains I and II with a central region of fibrillin-1. Analysis of perlecan null embryos showed less microfibrils at the dermal-epidermal junction as compared with wild-type littermates. The data presented indicate a functional significance for perlecan in anchoring microfibrils to basement membranes and in the biogenesis of microfibrils. 相似文献