全文获取类型
收费全文 | 905篇 |
免费 | 19篇 |
国内免费 | 16篇 |
专业分类
耳鼻咽喉 | 1篇 |
儿科学 | 19篇 |
妇产科学 | 1篇 |
基础医学 | 318篇 |
口腔科学 | 5篇 |
临床医学 | 54篇 |
内科学 | 154篇 |
皮肤病学 | 51篇 |
神经病学 | 31篇 |
特种医学 | 6篇 |
外科学 | 13篇 |
综合类 | 58篇 |
预防医学 | 75篇 |
眼科学 | 2篇 |
药学 | 91篇 |
中国医学 | 31篇 |
肿瘤学 | 30篇 |
出版年
2023年 | 1篇 |
2022年 | 4篇 |
2021年 | 9篇 |
2020年 | 6篇 |
2019年 | 32篇 |
2018年 | 40篇 |
2017年 | 33篇 |
2016年 | 17篇 |
2015年 | 17篇 |
2014年 | 59篇 |
2013年 | 64篇 |
2012年 | 46篇 |
2011年 | 71篇 |
2010年 | 66篇 |
2009年 | 48篇 |
2008年 | 49篇 |
2007年 | 57篇 |
2006年 | 39篇 |
2005年 | 50篇 |
2004年 | 33篇 |
2003年 | 51篇 |
2002年 | 18篇 |
2001年 | 19篇 |
2000年 | 13篇 |
1999年 | 14篇 |
1998年 | 12篇 |
1997年 | 11篇 |
1996年 | 9篇 |
1995年 | 3篇 |
1994年 | 10篇 |
1993年 | 4篇 |
1991年 | 3篇 |
1990年 | 2篇 |
1989年 | 2篇 |
1988年 | 3篇 |
1987年 | 2篇 |
1985年 | 5篇 |
1984年 | 9篇 |
1983年 | 1篇 |
1982年 | 3篇 |
1981年 | 3篇 |
1980年 | 2篇 |
排序方式: 共有940条查询结果,搜索用时 31 毫秒
31.
32.
KIR3DL1 is one of the best-characterised inhibitory NK cell receptors. Unusually, one common allele at the 3DL1 locus encodes an activating receptor known as 3DS1. There is genetic evidence for a protective role of 3DS1 in certain viral diseases, but there has been uncertainty about expression of the 3DS1 protein. Using transfection, we show that surface expression of 3DS1 is reliant on the adaptor protein DNAX-activating protein 12 (DAP12). KIR3DS1 was recognised by the antibody Z27, a reagent that also detects KIR3DL1 but no other killer immunoglobulin-like receptor (KIR) molecule. Z27 stained 3DS1 on the surface of fresh circulating NK cells from 3DS1/3DS1 homozygotes. By double-staining with Z27 and DX9, an antibody specific for 3DL1, we obtained evidence that in 3DS1/3DL1 heterozygous donors significant numbers of NK cells express 3DS1 without co-expressing 3DL1 and that NK cells expressing both alleles are difficult to detect. 相似文献
33.
《Vaccine》2018,36(15):1949-1957
Fasciolosis continues to be a major cause of economic losses in the livestock industry and a growing threat to humans. The limited spectrum of effective anthelmintics and the appearance of resistances urge the need for developing an effective vaccine. Most studies have been focused on the use of TH1-polarizing adjuvants and the use of recombinant Fasciola critical molecules and, despite the efforts, no reproducible protections have been achieved. The F. hepatica MF6p/FhHDM-1 protein is a heme-binding protein also reported to have immunomodulatory properties, constituting a promising target for vaccination and/or as target for the development of new flukicides. Thus, in this study, we investigated the effects of the TH1-polarizing adjuvant Quil A® on sheep immune response to MF6p/FhHDM-1, and the vaccine potential of both native and synthetic forms of this protein against ovine fasciolosis. Subcutaneous injection of Quil A® alone, i.e., without co-injecting any antigen, expands the antibody repertoire to MF6p/FhHDM-1 triggered by a subsequent primoinfection with metacercariae. This effect was not observed with aluminum hydroxide, the most frequently adjuvant used in commercial vaccines. On the other hand, vaccination with synthetic MF6p/FhHDM-1 in Quil A® prompted a 2–4-week delay in the antibody response induced in sheep by a challenge experimental infection. Moreover, fluke populations stablished showed stunted growth and low antigen release probably due to reduced metabolic activity. These observations suggest that primary circulating antibodies induced by the immunization had harmful effects on fluke development. Such effects could not be demonstrated to be associated to TH1 immune response linked events (production of IgG2 isotype antibodies and IFN-γ). 相似文献
34.
Olga Scherer Heinrich Steinmetz Christoph Kaether Christina Weinigel Dagmar Barz Hartmut Kleinert Dirk Menche Rolf Müller Carlo Pergola Oliver Werz 《Biochemical pharmacology》2014
The macrolide archazolid inhibits vacuolar-type H(+)-ATPase (V-ATPase), a proton-translocating enzyme involved in protein transport and pH regulation of cell organelles, and potently suppresses cancer cell growth at low nanomolar concentrations. In view of the growing link between inflammation and cancer, we investigated whether inhibition of V-ATPase by archazolid may affect primary human monocytes that can promote cancer by sustaining inflammation through the release of tumor-promoting cytokines. Human primary monocytes express V-ATPase, and archazolid (10–100 nM) increases the vesicular pH in these cells. Archazolid (10 nM) markedly reduced the release of pro-inflammatory (TNF-α, interleukin-6 and -8) but also of anti-inflammatory (interleukin-10) cytokines in monocytes stimulated with LPS, without affecting cell viability up to 1000 nM. Of interest, secretion of interleukin-1β was increased by archazolid. Comparable effects were obtained by the V-ATPase inhibitors bafilomycin and apicularen. The phosphorylation of p38 MAPK and ERK-1/2, Akt, SAPK/JNK or of the inhibitor of NFκB (IκBα) as well as mRNA expression of IL-8 were not altered by archazolid in LPS-stimulated monocytes. Instead, archazolid caused endoplasmic reticulum (ER) stress response visualized by increased BiP expression and accumulation of IL-8 (and TNF-α) at the ER, indicating a perturbation of protein secretion. In conclusion, by interference with V-ATPase, archazolid significantly affects the secretion of cytokines due to accumulation at the ER which might be of relevance when using these agents for cancer therapy. 相似文献
35.
36.
Katja Nitschke Alejandro Barriga Julia Schmidt Jörg Timm Sergei Viazov Thomas Kuntzen Arthur Y. Kim Georg M. Lauer Todd M. Allen Silvana Gaudieri Andri Rauch Christian M. Lange Christoph Sarrazin Thomas Eiermann John Sidney Alessandro Sette Robert Thimme Daniel López Christoph Neumann-Haefelin 《Journal of hepatology》2014
37.
38.
Background
Coxsackievirus B3 (CVB3) infection causes myocarditis, pancreatitis, and aseptic meningitis. Targeting antigen-specific T cell reactions might be a promising way to alleviate the inflammatory response induced by CVB3 infection. IL-2-inducible T-cell kinase (ITK), a member of Tec kinase family expressed mainly in T cells, plays an important role in the activation of T cells. The role of ITK in viral myocarditis induced by CVB3 has not been documented.Methodology
In this study, we inhibited the ITK expression in Jurkat cells, primary human peripheral blood mononuclear cells (PBMC), and mouse splenocytes by ITK-specific siRNA. The inhibition efficiently suppressed cell proliferation (P < 0.05) and T-cell related cytokine secretion (P < 0.05). In order to inhibit ITK in vivo, the pGCSIL plasmid containing short hairpin RNAs targeting ITK was constructed and transduced into mice infected with CVB3. ITK-inhibited mice showed reduced cell proliferation (3, 5, and 7 days post-challenge, P < 0.05) as well as CD4+ and CD8+ T cells (5 days post-challenge, P < 0.05). The altered production of inflammatory cytokines alleviated pathologic heart damage and improved mice survival rate (P < 0.05).Conclusion
ITK played an important role in the T cell development and represented a new target for the modulation of T-cell-mediated inflammatory response by CVB3 infection. 相似文献39.
Junya Ohtake Takayuki Ohkuri Yuji Togashi Hidemitsu Kitamura Kiyotaka Okuno Takashi Nishimura 《Immunology letters》2014
We identified novel helper epitope peptides of Survivin cancer antigen, which are presented to both HLA-DRB1*01:01 and DQB1*06:01. The helper epitope also contained three distinct Survivin-killer epitopes presented to HLA-A*02:01 and A*24:02. This 19 amino-acids epitope peptide (SU18) induced weak responses of Survivin-specific CD4+ and CD8+ T cells though it contained both helper and killer epitopes. To enhance the vaccine efficacy, we synthesized a long peptide by conjugating SU18 peptide and another DR53-restricted helper epitope peptide (SU22; 12 amino-acids) using glycine-linker. We designated this artificial 40 amino-acids long peptide containing two helper and three killer epitopes as Survivin-helper/killer-hybrid epitope long peptide (Survivin-H/K-HELP). Survivin-H/K-HELP allowed superior activation of IFN-γ-producing CD4+ Th1 cells and CD8+ Tc1 cells compared with the mixture of its component peptides (SU18 and SU22) in the presence of OK-432-treated monocyte-derived DC (Mo-DC). Survivin-H/K-HELP-pulsed Mo-DC pretreated with OK-432 also exhibited sustained antigen-presentation capability of stimulating Survivin-specific Th1 cells compared with Mo-DC pulsed with a mixture of SU18 and SU22 short peptides. Moreover, we demonstrated that Survivin-H/K-HELP induced a complete response in a breast cancer patient with the induction of cellular and humoral immune responses. Thus, we believe that an artificially synthesized Survivin-H/K-HELP will become an innovative cancer vaccine. 相似文献
40.