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Bone Cell-autonomous Contribution of Type 2 Cannabinoid Receptor to Breast Cancer-induced Osteolysis
Antonia Sophocleous Silvia Marino John G. Logan Patrick Mollat Stuart H. Ralston Aymen I. Idris 《The Journal of biological chemistry》2015,290(36):22049-22060
The cannabinoid type 2 receptor (CB2) has previously been implicated as a regulator of tumor growth, bone remodeling, and bone pain. However, very little is known about the role of the skeletal CB2 receptor in the regulation of osteoblasts and osteoclasts changes associated with breast cancer. Here we found that the CB2-selective agonists HU308 and JWH133 reduced the viability of a variety of parental and bone-tropic human and mouse breast cancer cells at high micromolar concentrations. Under conditions in which these ligands are used at the nanomolar range, HU308 and JWH133 enhanced human and mouse breast cancer cell-induced osteoclastogenesis and exacerbated osteolysis, and these effects were attenuated in cultures obtained from CB2-deficient mice or in the presence of a CB2 receptor blocker. HU308 and JWH133 had no effects on osteoblast growth or differentiation in the presence of conditioned medium from breast cancer cells, but under these circumstances both agents enhanced parathyroid hormone-induced osteoblast differentiation and the ability to support osteoclast formation. Mechanistic studies in osteoclast precursors and osteoblasts showed that JWH133 and HU308 induced PI3K/AKT activity in a CB2-dependent manner, and these effects were enhanced in the presence of osteolytic and osteoblastic factors such as RANKL (receptor activator of NFκB ligand) and parathyroid hormone. When combined with published work, these findings suggest that breast cancer and bone cells exhibit differential responses to treatment with CB2 ligands depending upon cell type and concentration used. We, therefore, conclude that both CB2-selective activation and antagonism have potential efficacy in cancer-associated bone disease, but further studies are warranted and ongoing. 相似文献
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The compound p-mercuribenzenefulfonate was found to affect the self-association behavior of both spectrin and actin. The reagent brings about the depolymerization of F-actin, as judged from the decrease in the fluorescence of an attached pyrene label, with a second-order rate constant an order of magnitude less than that for the disruption of isolated erythrocyte cytoskeletons. Therefore, it is unlikely that the depolymerization of actin is the rate-determining step in the mercurial-dependent disruption of the erythrocyte cytoskeleton. Low reagent concentrations caused an initial rapid dissociation of spectrin tetramers at a rate comparable with that of cytoskeleton disruption. Prolonged incubation, or higher reagent concentrations, resulted in subsequent aggregation of spectrin. The reagent also prevented the interaction between spectrin and actin, presumably through its depolymerization of actin and its effects on spectrin. The early event in the disruption of isolated erythrocyte cytoskeletons by p-mercuribenzenesulfonate thus appears to be the dissociation of spectrin oligomers. Subsequent depolymerization of actin brought about by the reagent then results in total disruption of the cytoskeleton. 相似文献
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Summary The carbon cycle of a loblolly pine plantation in North Carolina was examined during its 12th through 16th years from planting. Net primary production during the study period averaged 2056 g C m-2 year-1. With autotrophic respiration equal to 2068 g C, the calculated gross production was 4124 g C m-2 year-1. Heterotrophic respiration of 694 g C m-2 year-1 resulted in net ecosystem production of 1362 g C m-2 year-1. In carbon cycle comparisons between forest ecosystems, autotrophic respiration rates were found to be closely coupled to regional temperature. 相似文献
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Food subsidies have the potential to modify ecosystems and affect the provision of goods and services. Predictable Anthropogenic Food Subsidies (PAFS) modify ecosystems by altering ecological processes and food webs. The global concern over the effects of PAFS in ecosystems has led to development of environmental policies aimed at curbing the production or ultimately banning of PAFS. However, the effects of reducing or banning PAFS are not known. We explore the consequences of PAFS removal in a marine ecosystem under two scenarios: 1) gradual reduction, or 2) an abrupt ban, using a mass balance model to test these hypotheses–The reduction or loss of PAFS will: i) modify trophic levels and food webs through effects on foraging by opportunistic species, ii) increase the resilience of opportunistic species to food shortages, and iii) modify predator–prey interactions through shifts in prey consumption. We found that PAFS lower the trophic levels of opportunistic scavengers and increase their food pathways. Scavengers are able to switch prey when PAFS are reduced gradually but they decline when PAFS are abruptly banned. PAFS reduction to a certain minimal level causes a drop in the ecosystem’s stability. We recommend gradual reduction of PAFS to a minimal level that would maintain the ecosystem’s stability and allow species exploiting PAFS to habituate to the food subsidy reduction. 相似文献
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Nikolas K. Haass D. Ripperger E. Wladykowski P. Dawson P. A. Gimotty C. Blome F. Fischer P. Schmage I. Moll Johanna M. Brandner 《Histochemistry and cell biology》2010,133(1):113-124
Melanoma depends on, interacts with and reacts to the stroma in which it is embedded, including fibroblasts, extracellular
matrix, endothelial cells and immune cells. However, the impact of melanoma on the epidermal tumor microenvironment—the multilayered
epithelium of the skin—is poorly understood. Gap junctions are essential for intercellular communication and involved in proliferation,
differentiation and homeostasis of keratinocytes. We have shown previously that the gap junction proteins connexin 26 and
30 (Cx26 and Cx30) are induced in the epidermal tumor microenvironment of skin cancers including melanoma. This study compares
the extent of Cx26, Cx30 and Cx43 expression in the epidermal microenvironment of melanocytic nevi and melanomas and its association
with melanoma thickness, proliferative index of the tumor and its microenvironment, and with 5-year metastasis and survival.
We found that induction of Cx26 and Cx30 cell–cell border expression in the epidermal tumor microenvironment correlates to
malignancy. Importantly, there was a significant correlation of tumor thickness with the vertical epidermal Cx26 and Cx30
expression pattern and the horizontal Cx26 dissemination. Furthermore, horizontal Cx26 expression correlated with metastasis.
Vertical epidermal expression patterns of Cx26 and Cx30 significantly correlated with the proliferative index in the epidermal
tumor microenvironment but not with the proliferative index in the tumor. In contrast, Cx43 did not correlate with malignancy,
thickness or proliferative index. In summary, here we show for the first time a significant association between the progression
of melanoma and alterations in its epithelial tumor microenvironment. 相似文献
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Synthetic peptides corresponding to 57% of the sequence of alpha subunits of acetylcholine receptors from Torpedo californica electric organ and extending from the NH2 to the COOCH terminus have been synthesized. The alpha-bungarotoxin binding site on denatured alpha subunits was mapped within the sequence alpha 185-199 by assaying binding of 125I-alpha-bungarotoxin to slot blots of synthetic peptides. Further studies showed that residues in the sequence alpha 190-194, especially cysteines-alpha 192, 193, were critical for binding alpha-bungarotoxin. Reduction and alkylation studies suggested that these cysteines must be disulfide linked for alpha-bungarotoxin to bind. Binding sites for serum antibodies to native receptors or alpha subunits were mapped by indirect immunoprecipitation of 125I-peptides. Several antigenic sequences were identified, but a synthetic peptide corresponding to the main immunogenic region (which is highly conformation dependent) was not identified. 相似文献