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Elise E. Bruning Janet K. Coller Hannah R. Wardill Joanne M. Bowen 《Journal of cellular physiology》2021,236(2):877-888
Toll‐like receptor 4 (TLR4) is a highly conserved protein of innate immunity, responsible for the regulation and maintenance of homeostasis, as well as immune recognition of external and internal ligands. TLR4 is expressed on a variety of cell types throughout the gastrointestinal tract, including on epithelial and immune cell populations. In a healthy state, epithelial cell expression of TLR4 greatly assists in homeostasis by shaping the host microbiome, promoting immunoglobulin A production, and regulating follicle‐associated epithelium permeability. In contrast, immune cell expression of TLR4 in healthy states is primarily centred on the maturation of dendritic cells in response to stimuli, as well as adequately priming the adaptive immune system to fight infection and promote immune memory. Hence, in a healthy state, there is a clear distinction in the site‐specific roles of TLR4 expression. Similarly, recent research has indicated the importance of site‐specific TLR4 expression in inflammation and disease, particularly the impact of epithelial‐specific TLR4 on disease progression. However, the majority of evidence still remains ambiguous for cell‐specific observations, with many studies failing to provide the distinction of epithelial versus immune cell expression of TLR4, preventing specific mechanistic insight and greatly impacting the translation of results. The following review provides a critical overview of the current understanding of site‐specific TLR4 activity and its contribution to intestinal/immune homeostasis and inflammatory diseases. 相似文献
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Scott S. Hannah Sonyia McFadden Andrea McNeilly Conor McClean 《Journal of cellular physiology》2021,236(2):721-740
To maintain normal cellular and physiological function, sufficient oxygen is required. Recently, evidence has suggested that hypoxia, either pathological or environmental, may influence bone health. It appears that bone cells are distinctly responsive to hypoxic stimuli; for better or worse, this is still yet to be elucidated. Hypoxia has been shown to offer potentially therapeutic effects for bone by inducing an osteogenic–angiogenic response, although, others have noted excessive osteoclastic bone resorption instead. Much evidence suggests that the hypoxic‐inducible pathway is integral in mediating the changes in bone metabolism. Furthermore, many factors associated with hypoxia including changes in energy metabolism, acid–base balance and the increased generation of reactive oxygen species, are known to influence bone metabolism. This review aims to examine some of the putative mechanisms responsible for hypoxic‐induced alterations of bone metabolism, with regard to osteoclasts and osteoblasts, both positive and negative. 相似文献
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Valentina Ferrari Alison Tarke Hannah Fields Luca Ferrari Trevor Conley Franco Ferrari Zeynep Koşaloğlu-Yalçın Alessandro Sette Bjoern Peters Colin L. McCarthy Asad Bashey Dimitrios Tzachanis Edward D. Ball Tiffany N. Tanaka Rafael Bejar Thomas A. Lane Antonella Vitiello 《Cytotherapy》2021,23(4):320-328
Therapies that utilize immune checkpoint inhibition work by leveraging mutation-derived neoantigens and have shown greater clinical efficacy in tumors with higher mutational burden. Whether tumors with a low mutational burden are susceptible to neoantigen-targeted therapy has not been fully addressed. To examine the feasibility of neoantigen-specific adoptive T-cell therapy, the authors studied the T-cell response against somatic variants in five patients with myelodysplastic syndrome (MDS), a malignancy with a very low tumor mutational burden. DNA and RNA from tumor (CD34+) and normal (CD3+) cells isolated from the patients’ blood were sequenced to predict patient-specific MDS neopeptides. Neopeptides representing the somatic variants were used to induce and expand autologous T cells ex vivo, and these were systematically tested in killing assays to determine the proportion of neopeptides yielding neoantigen-specific T cells. The authors identified a total of 32 somatic variants (four to eight per patient) and found that 21 (66%) induced a peptide-specific T-cell response and 19 (59%) induced a T-cell response capable of killing autologous tumor cells. Of the 32 somatic variants, 11 (34%) induced a CD4+ response and 11 (34%) induced a CD8+ response that killed the tumor. These results indicate that in vitro induction of neoantigen-specific T cells is feasible for tumors with very low mutational burden and that this approach warrants investigation as a therapeutic option for such patients. 相似文献
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Ricardo I. MartínezZamudio Hannah K. Dewald Themistoklis Vasilopoulos Lisa GittensWilliams Patricia FitzgeraldBocarsly Utz Herbig 《Aging cell》2021,20(5)
Aging leads to a progressive functional decline of the immune system, rendering the elderly increasingly susceptible to disease and infection. The degree to which immune cell senescence contributes to this decline remains unclear, however, since markers that label immune cells with classical features of cellular senescence accurately and comprehensively have not been identified. Using a second‐generation fluorogenic substrate for β‐galactosidase and multi‐parameter flow cytometry, we demonstrate here that peripheral blood mononuclear cells (PBMCs) isolated from healthy humans increasingly display cells with high senescence‐associated β‐galactosidase (SA‐βGal) activity with advancing donor age. The greatest age‐associated increases were observed in CD8+ T‐cell populations, in which the fraction of cells with high SA‐βGal activity reached average levels of 64% in donors in their 60s. CD8+ T cells with high SA‐βGal activity, but not those with low SA‐βGal activity, were found to exhibit features of telomere dysfunction‐induced senescence and p16‐mediated senescence, were impaired in their ability to proliferate, developed in various T‐cell differentiation states, and had a gene expression signature consistent with the senescence state previously observed in human fibroblasts. Based on these results, we propose that senescent CD8+ T cells with classical features of cellular senescence accumulate to levels that are significantly higher than previously reported and additionally provide a simple yet robust method for the isolation and characterization of senescent CD8+ T cells with predictive potential for biological age. 相似文献
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Emily B. Cohen Kyle G. Horton Peter P. Marra Hannah L. Clipp Andrew Farnsworth Jaclyn A. Smolinsky Daniel Sheldon Jeffrey J. Buler 《Ecology letters》2021,24(1):38-49
Migrating birds require en route habitats to rest and refuel. Yet, habitat use has never been integrated with passage to understand the factors that determine where and when birds stopover during spring and autumn migration. Here, we introduce the stopover‐to‐passage ratio (SPR), the percentage of passage migrants that stop in an area, and use 8 years of data from 12 weather surveillance radars to estimate over 50% SPR during spring and autumn through the Gulf of Mexico and Atlantic coasts of the south‐eastern US, the most prominent corridor for North America’s migratory birds. During stopovers, birds concentrated close to the coast during spring and inland in forested landscapes during autumn, suggesting seasonal differences in habitat function and highlighting the vital role of stopover habitats in sustaining migratory communities. Beyond advancing understanding of migration ecology, SPR will facilitate conservation through identification of sites that are disproportionally selected for stopover by migrating birds. 相似文献
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Chuang Li K. David Hambright Hannah G. Bowen Majoi A. Trammell Hans-Peter Grossart Michele A. Burford David P. Hamilton Helong Jiang Delphine Latour Elisabeth I. Meyer Judit Padisák Richard M. Zamor Lee R. Krumholz 《Environmental microbiology》2021,23(11):6503-6519
Global warming and eutrophication contribute to the worldwide increase in cyanobacterial blooms, and the level of cyanobacterial biomass is strongly associated with rises in methane emissions from surface lake waters. Hence, methane-metabolizing microorganisms may be important for modulating carbon flow in cyanobacterial blooms. Here, we surveyed methanogenic and methanotrophic communities associated with floating Microcystis aggregates in 10 lakes spanning four continents, through sequencing of 16S rRNA and functional marker genes. Methanogenic archaea (mainly Methanoregula and Methanosaeta) were detectable in 5 of the 10 lakes and constituted the majority (~50%–90%) of the archaeal community in these lakes. Three of the 10 lakes contained relatively more abundant methanotrophs than the other seven lakes, with the methanotrophic genera Methyloparacoccus, Crenothrix, and an uncultured species related to Methylobacter dominating and nearly exclusively found in each of those three lakes. These three are among the five lakes in which methanogens were observed. Operational taxonomic unit (OTU) richness and abundance of methanotrophs were strongly positively correlated with those of methanogens, suggesting that their activities may be coupled. These Microcystis-aggregate-associated methanotrophs may be responsible for a hitherto overlooked sink for methane in surface freshwaters, and their co-occurrence with methanogens sheds light on the methane cycle in cyanobacterial aggregates. 相似文献
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