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991.
992.
Kopka IE Lin LS Mumford RA Lanza T Magriotis PA Young D DeLaszlo SE MacCoss M Mills SG Van Riper G McCauley E Lyons K Vincent S Egger LA Kidambi U Stearns R Colletti A Teffera Y Tong S Owens K Levorse D Schmidt JA Hagmann WK 《Bioorganic & medicinal chemistry letters》2002,12(17):2415-2418
A series of substituted N-(3,5-dichlorobenzenesulfonyl)-(L)-prolyl- and (L)-azetidyl-beta-biaryl beta-alanine derivatives was prepared as selective and potent VLA-4 antagonists. The 2,6-dioxygenated biaryl substitution pattern is important for optimizing potency. Oral bioavailability was variable and may be a result of binding to circulating plasma proteins. 相似文献
993.
Young JR Huang SX Walsh TF Wyvratt MJ Yang YT Yudkovitz JB Cui J Mount GR Ren RN Wu TJ Shen X Lyons KA Mao AH Carlin JR Karanam BV Vincent SH Cheng K Goulet MT 《Bioorganic & medicinal chemistry letters》2002,12(5):827-832
A series of 2-arylindoles containing novel heteroaromatic substituents on the tryptamine tether, based on compound 1, was prepared and evaluated for their ability to act as gonadotropin releasing hormone (GnRH) antagonists. Successful modifications of 1 included chain length variation (reduction) and replacement of the pyridine with heteroaromatic groups. These alterations culminated in the discovery of compound 27kk which had excellent in vitro potency and oral efficacy in rodents. 相似文献
994.
Kathryn J. Hooper Gerd Bobe William R. Vorachek Janell K. Bishop-Stewart Wayne D. Mosher Gene J. Pirelli Michael L. Kent Jean A. Hall 《Biological trace element research》2014,161(3):308-317
Gastrointestinal parasites cause substantial economic losses in pasture-based sheep production systems. Supranutritional organic selenium (Se) supplementation may be beneficial because it improves immune responses to pathogens. To evaluate the effect of Se-yeast supplementation on gastrointestinal parasite load, 30 ewes per treatment group were drenched weekly with no Se, 4.9 mg Se/week as Se yeast (maximum FDA-allowed concentration), or supranutritional concentrations of Se yeast (14.7 and 24.5 mg Se/week) starting early fall for 85 weeks. Fecal samples were collected at weeks 63, 66, 78, and 84 and counted for total trichostrongyle-type eggs and Haemonchus contortus eggs (in samples with ≥200 trichostrongyle eggs/g feces). During breeding season (fall), ewes were kept on pasture; ewes receiving 24.5 mg Se/week had lower fecal trichostrongyle egg counts (93?±?40 eggs/g feces) compared with ewes receiving no Se (537?±?257 eggs/g feces; P?=?0.007) or ewes receiving 4.9 mg Se/week as Se yeast (398?±?208 eggs/g feces; P?=?0.03). In winter, fecal trichostrongyle egg counts decreased, and group differences were not apparent. During lambing season (spring), ewes were kept in the barn and fecal trichostrongyle egg counts increased, although no group differences were observed. However, none of the ewes receiving supranutritional Se yeast, and with trichostrongyle egg counts ≥200 eggs/g of feces, but four of the ewes receiving lower Se dosages had H. contortus egg counts ≥1,000 eggs/g feces (P?=?0.04). Our results suggest that supranutritional Se-yeast supplementation may enhance resistance to naturally occurring H. contortus gastrointestinal parasitism in sheep. 相似文献
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996.
Paolo Franchini Carmelo Fruciano Maria L. Spreitzer Julia C. Jones Kathryn R. Elmer Frederico Henning Axel Meyer 《Molecular ecology》2014,23(7):1828-1845
Determining the genetic bases of adaptations and their roles in speciation is a prominent issue in evolutionary biology. Cichlid fish species flocks are a prime example of recent rapid radiations, often associated with adaptive phenotypic divergence from a common ancestor within a short period of time. In several radiations of freshwater fishes, divergence in ecomorphological traits — including body shape, colour, lips and jaws — is thought to underlie their ecological differentiation, specialization and, ultimately, speciation. The Midas cichlid species complex (Amphilophus spp.) of Nicaragua provides one of the few known examples of sympatric speciation where species have rapidly evolved different but parallel morphologies in young crater lakes. This study identified significant QTL for body shape using SNPs generated via ddRAD sequencing and geometric morphometric analyses of a cross between two ecologically and morphologically divergent, sympatric cichlid species endemic to crater Lake Apoyo: an elongated limnetic species (Amphilophus zaliosus) and a high‐bodied benthic species (Amphilophus astorquii). A total of 453 genome‐wide informative SNPs were identified in 240 F2 hybrids. These markers were used to construct a genetic map in which 25 linkage groups were resolved. Seventy‐two segregating SNPs were linked to 11 QTL. By annotating the two most highly supported QTL‐linked genomic regions, genes that might contribute to divergence in body shape along the benthic–limnetic axis in Midas cichlid sympatric adaptive radiations were identified. These results suggest that few genomic regions of large effect contribute to early stage divergence in Midas cichlids. 相似文献
997.
Kathryn L. Turner Harald Sontheimer 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2014,369(1638)
Profound cell volume changes occur in primary brain tumours as they proliferate, invade surrounding tissue or undergo apoptosis. These volume changes are regulated by the flux of Cl− and K+ ions and concomitant movement of water across the membrane, making ion channels pivotal to tumour biology. We discuss which specific Cl− and K+ channels are involved in defined aspects of glioma biology and how these channels are regulated. Cl− is accumulated to unusually high concentrations in gliomas by the activity of the NKCC1 transporter and serves as an osmolyte and energetic driving force for volume changes. Cell volume condensation is required as cells enter M phase of the cell cycle and this pre-mitotic condensation is caused by channel-mediated ion efflux. Similarly, Cl− and K+ channels dynamically regulate volume in invading glioma cells allowing them to adjust to small extracellular brain spaces. Finally, cell condensation is a hallmark of apoptosis and requires the concerted activation of Cl− and Ca2+-activated K+ channels. Given the frequency of mutation and high importance of ion channels in tumour biology, the opportunity exists to target them for treatment. 相似文献
998.
Hector J. I. Page Daniel M. Walters Rebecca Knight Caitlin E. Piette Kathryn J. Jeffery Simon M. Stringer 《Philosophical transactions of the Royal Society of London. Series B, Biological sciences》2014,369(1635)
Head direction (HD) cell responses are thought to be derived from a combination of internal (or idiothetic) and external (or allothetic) sources of information. Recent work from the Jeffery laboratory shows that the relative influence of visual versus vestibular inputs upon the HD cell response depends on the disparity between these sources. In this paper, we present simulation results from a model designed to explain these observations. The model accurately replicates the Knight et al. data. We suggest that cue conflict resolution is critically dependent on plastic remapping of visual information onto the HD cell layer. This remap results in a shift in preferred directions of a subset of HD cells, which is then inherited by the rest of the cells during path integration. Thus, we demonstrate how, over a period of several minutes, a visual landmark may gain cue control. Furthermore, simulation results show that weaker visual landmarks fail to gain cue control as readily. We therefore suggest a second longer term plasticity in visual projections onto HD cell areas, through which landmarks with an inconsistent relationship to idiothetic information are made less salient, significantly hindering their ability to gain cue control. Our results provide a mechanism for reliability-weighted cue averaging that may pertain to other neural systems in addition to the HD system. 相似文献
999.
Laurent Gatto Lisa M. Breckels Thomas Burger Daniel J. H. Nightingale Arnoud J. Groen Callum Campbell Nino Nikolovski Claire M. Mulvey Andy Christoforou Myriam Ferro Kathryn S. Lilley 《Molecular & cellular proteomics : MCP》2014,13(8):1937-1952
Quantitative mass-spectrometry-based spatial proteomics involves elaborate, expensive, and time-consuming experimental procedures, and considerable effort is invested in the generation of such data. Multiple research groups have described a variety of approaches for establishing high-quality proteome-wide datasets. However, data analysis is as critical as data production for reliable and insightful biological interpretation, and no consistent and robust solutions have been offered to the community so far. Here, we introduce the requirements for rigorous spatial proteomics data analysis, as well as the statistical machine learning methodologies needed to address them, including supervised and semi-supervised machine learning, clustering, and novelty detection. We present freely available software solutions that implement innovative state-of-the-art analysis pipelines and illustrate the use of these tools through several case studies involving multiple organisms, experimental designs, mass spectrometry platforms, and quantitation techniques. We also propose sound analysis strategies for identifying dynamic changes in subcellular localization by comparing and contrasting data describing different biological conditions. We conclude by discussing future needs and developments in spatial proteomics data analysis. 相似文献
1000.