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Sharon H. Chou Aditya V. Shetty Yajun Geng Lipeng Xu Gnanasekar Munirathinam Anne Pipathsouk Isaiah Tan Timothy Morris Bin Wang Aoshuang Chen Guoxing Zheng 《Cancer immunology, immunotherapy : CII》2013,62(3):597-603
Purpose and experimental design
Recombinant human IL-2 (rhIL-2) is a potent cytokine and FDA-approved anticancer drug. However, its clinical use has been limited by severe toxicity, associated primarily with systemic administration with excess protein distributing freely throughout the body. We hypothesized that rhIL-2 in alternate forms permitting more restricted localization may exert stronger antitumor efficacy and less toxicity. Here, we have tested the utility of palmitate-derivatized rhIL-2. rhIL-2 was reacted with N-hydroxysuccinimide palmitate ester. The resultant lipidated rhIL-2 (pIL-2), when mixed with cells, could spontaneously transfer from solution to cell surfaces. Next, anticancer efficacy of pIL-2 was assessed in two modalities. For adoptive T cell therapy, antitumor cytotoxic T cells (CTLs) were protein transferred (“painted”) with pIL-2 and injected into mice bearing lymphoma. For in situ therapy, pIL-2 was injected intratumorally into mice bearing melanoma. Tumor growth and IL-2-associated toxicity were determined.Results
In the lymphoma model, painting of the antitumor CTLs with pIL-2 markedly increased their viability and titer. In the melanoma model, intratumoral injection of pIL-2, but not rhIL-2, increased the number of activated CD8+ T cells (IFN-γ+) in the spleen, reduced lung metastasis and prolonged the survival of treated mice. Moreover, while repeated intratumoral injection of rhIL-2 at an excessively high dose (10 injections of 10,000 IU/mouse) caused marked vascular leakage syndrome, the same regimen using pIL-2 caused no detectable toxicity.Conclusions
Transferring spontaneously from solution to cell surfaces, pIL-2 may bypass the current limitations of rhIL-2 and, thus, serve as a more effective and tolerable anticancer drug. 相似文献83.
Zhaojing Zheng Juan Geng Ru-en Yao Caihua Li Daming Ying Yongnian Shen Lei Ying Yongguo Yu Qihua Fu 《Gene》2013
Fanconi anemia is a rare genetic disease characterized by bone marrow failure, multiple congenital malformations, and an increased susceptibility to malignancy. At least 15 genes have been identified that are involved in the pathogenesis of Fanconi anemia. However, it is still a challenge to assign the complementation group and to characterize the molecular defects in patients with Fanconi anemia. In the current study, whole exome sequencing was used to identify the affected gene(s) in a boy with Fanconi anemia. A recurring, non-synonymous mutation was found (c.3971C>T, p.P1324L) as well as a novel frameshift mutation (c.989_995del, p.H330LfsX2) in FANCA gene. Our results indicate that whole exome sequencing may be useful in clinical settings for rapid identification of disease-causing mutations in rare genetic disorders such as Fanconi anemia. 相似文献
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Molecular dynamics simulation is used to study the decomposition and stability of SII hydrogen and hydrogen/tetrahydrofuran (THF) hydrates at 150 K, 220 K and 100 bar. The modelling of the microscopic decomposition process of hydrogen hydrate indicates that the decomposition of hydrogen hydrate is led by the diffusive behaviour of H2 molecules. The hydrogen/THF hydrate presents higher stability, by comparing the distributions of the tetrahedral angle of H2O molecules, radial distribution functions of H2O molecules and mean square displacements or diffusion coefficients of H2O and H2 molecules in hydrogen hydrate with those in hydrogen/THF hydrate. It is also found that the resistance of the diffusion behaviour of H2O and H2 molecules can be enhanced by encaging THF molecules in the (51264) cavities. Additionally, the motion of THF molecules is restricted due to its high interaction energy barrier. Accordingly, THF, as a stabiliser, is helpful in increasing the stability of hydrogen hydrate. 相似文献
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Xun Huang Qiuming Pan Danni Sun Wei Chen Aijun Shen Min Huang Jian Ding Meiyu Geng 《The Journal of biological chemistry》2013,288(51):36418-36425
O-GlcNAcylation is a post-translational modification that regulates a broad range of nuclear and cytoplasmic proteins and is emerging as a key regulator of various biological processes. Previous studies have shown that increased levels of global O-GlcNAcylation and O-GlcNAc transferase (OGT) are linked to the incidence of metastasis in breast cancer patients, but the molecular basis behind this is not fully known. In this study, we have determined that the actin-binding protein cofilin is O-GlcNAcylated by OGT and mainly, if not completely, mediates OGT modulation of cell mobility. O-GlcNAcylation at Ser-108 of cofilin is required for its proper localization in invadopodia at the leading edge of breast cancer cells during three-dimensional cell invasion. Loss of O-GlcNAcylation of cofilin leads to destabilization of invadopodia and impairs cell invasion, although the actin-severing activity or lamellipodial localization is not affected. Our study provides insights into the mechanism of post-translational modification in fine-tuning the regulation of cofilin activity and suggests its important implications in cancer metastasis. 相似文献
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Jing Yang Chao Wang Chang Shu Li Liu Jianing Geng Songnian Hu Jie Feng 《Microbial ecology》2013,65(4):975-981
The ocean is a natural habitat for antibiotic-producing bacteria, and marine aquaculture introduces antibiotics into the ocean to treat infections and improve aquaculture production. Studies have shown that the ocean is an important reservoir of antibiotic resistance genes. However, there is a lack of understanding and knowledge about the clinical importance of the ocean resistome. We investigated the relationship between the ocean bacterial resistome and pathogenic resistome. We applied high-throughput sequencing and metagenomic analyses to explore the resistance genes in bacterial plasmids from marine sediments. Numerous putative resistance determinants were detected among the resistance genes in the sediment bacteria. We also found that several contigs shared high identity with transposons or plasmids from human pathogens, indicating that the sediment bacteria recently contributed or acquired resistance genes from pathogens. Marine sediment bacteria could play an important role in the global exchange of antibiotic resistance. 相似文献
89.
Yan Geng Zhe He Zhen-Ming Lu Hong-Yu Xu Guo-Hua Xu Jin-Song Shi Zheng-Hong Xu 《Applied microbiology and biotechnology》2013,97(7):2851-2858
Antrodia camphorata is a well-known Chinese medicinal mushroom that protects against diverse health-related conditions. Submerged fermentation of A. camphorata is an alternative choice for the effective production of bioactive metabolites, but the effects of nutrition and environment on mycelial morphology are largely unknown. In this study, we show that A. camphorata American Type Culture Collection 200183 can form arthrospores in the end of liquid fermentation. Different morphologies of A. camphorata in submerged culture were analyzed using scanning electron microscopy. The optimal carbon and nitrogen sources for sporulation were soluble starch and yeast extract. We found that a carbon-to-nitrogen ratio (C/N) of 40:1, MgSO4 (0.5 g/l), KH2PO4 (3.0 g/l), an initial pH?5.0, and an inoculum size of 1.5?×?105 spores/ml led to maximum production of arthroconidia. Our results will be useful in the regulation and optimization of A. camphorata cultures for efficient production of arthroconidia in submerged culture, which can be used as inocula in subsequent fermentation processes. 相似文献
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