全文获取类型
收费全文 | 13034篇 |
免费 | 1063篇 |
国内免费 | 9篇 |
出版年
2023年 | 40篇 |
2022年 | 100篇 |
2021年 | 237篇 |
2020年 | 136篇 |
2019年 | 211篇 |
2018年 | 242篇 |
2017年 | 227篇 |
2016年 | 336篇 |
2015年 | 628篇 |
2014年 | 649篇 |
2013年 | 789篇 |
2012年 | 1068篇 |
2011年 | 1049篇 |
2010年 | 660篇 |
2009年 | 606篇 |
2008年 | 838篇 |
2007年 | 857篇 |
2006年 | 747篇 |
2005年 | 728篇 |
2004年 | 702篇 |
2003年 | 644篇 |
2002年 | 661篇 |
2001年 | 124篇 |
2000年 | 89篇 |
1999年 | 134篇 |
1998年 | 161篇 |
1997年 | 130篇 |
1996年 | 121篇 |
1995年 | 119篇 |
1994年 | 99篇 |
1993年 | 80篇 |
1992年 | 90篇 |
1991年 | 57篇 |
1990年 | 74篇 |
1989年 | 63篇 |
1988年 | 37篇 |
1987年 | 41篇 |
1986年 | 42篇 |
1985年 | 39篇 |
1984年 | 53篇 |
1983年 | 35篇 |
1982年 | 60篇 |
1981年 | 39篇 |
1980年 | 47篇 |
1979年 | 29篇 |
1978年 | 33篇 |
1977年 | 35篇 |
1976年 | 19篇 |
1975年 | 18篇 |
1973年 | 15篇 |
排序方式: 共有10000条查询结果,搜索用时 281 毫秒
991.
992.
Jacobsen M Detjen AK Mueller H Gutschmidt A Leitner S Wahn U Magdorf K Kaufmann SH 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(2):1331-1339
The role of CD8(+) T cells in human tuberculosis (TB) remains elusive. We analyzed the T cell repertoire and phenotype in 1) children with active TB (< or =4 years), 2) healthy latently Mycobacterium tuberculosis-infected children, and 3) noninfected age-matched (tuberculin skin test-negative) controls. Ex vivo phenotyping of T cell subpopulations by flow cytometry revealed a significant increase in the proportion of CD8(+)CD45RO(-)CD62L(-)CD28(-)CD27(-) effector T cells (T(EF)) in the peripheral blood of children with active TB (22.1 vs 9.5% in latently M. tuberculosis-infected children, vs 8.5% in tuberculin skin test-negative controls). Analyses of TCR variable beta-chains revealed markedly skewed repertoires in CD8(+) T(EF) and effector memory T cells. Expansions were restricted to single TCR variable beta-chains in individual donors indicating clonal growth. CDR3 spectratyping and DNA sequencing verified clonal expansion as the cause for CD8(+) effector T cell enrichment in individual TB patients. The most prominent enrichment of highly similar T(EF) clones (>70% of CD8(+) T(EF)) was found in two children with active severe TB. Therefore, clonal expansion of CD8(+) T(EF) occurs in childhood TB with potential impact on course and severity of disease. 相似文献
993.
Simson L Ellyard JI Dent LA Matthaei KI Rothenberg ME Foster PS Smyth MJ Parish CR 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(7):4222-4229
The role of the immune system in the surveillance of transformed cells has seen a resurgence of interest in the last 10 years, with a substantial body of data in mice and humans supporting a role for the immune system in host protection from tumor development and in shaping tumor immunogenicity. A number of earlier studies have demonstrated that eosinophils, when recruited into tumors, can very effectively eradicate transplantable tumors. In this study, we investigated whether eosinophils also play a role in tumor immune surveillance by determining the incidence of methylcholanthrene (MCA)-induced fibrosarcomas in IL-5 transgenic mice that have greatly enhanced levels of circulating eosinophils, CCL11 (eotaxin-1)-deficient mice that lack a key chemokine that recruits eosinophils into tissues, and the eosinophil-deficient mouse strains, IL-5/CCL11(-/-) and DeltadblGATA. It was found that MCA-induced tumor incidence and growth were significantly attenuated in IL-5 transgenic mice of both the BALB/c and C57BL/6 backgrounds. Histological examination revealed that the protective effect of IL-5 was associated with massively enhanced numbers of eosinophils within and surrounding tumors. Conversely, there was a higher tumor incidence in CCL11(-/-) BALB/c mice, which was associated with a reduced eosinophil influx into tumors. This correlation was confirmed in the eosinophil-deficient IL-5/CCL11(-/-) and DeltadblGATA mouse strains, where tumor incidence was greatly increased in the total absence of eosinophils. In addition, subsequent in vitro studies found that eosinophils could directly kill MCA-induced fibrosarcoma cells. Collectively, our data support a potential role for the eosinophil as an effector cell in tumor immune surveillance. 相似文献
994.
Müller V Viemann D Schmidt M Endres N Ludwig S Leverkus M Roth J Goebeler M 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(12):8435-8445
995.
Aronoff DM Peres CM Serezani CH Ballinger MN Carstens JK Coleman N Moore BB Peebles RS Faccioli LH Peters-Golden M 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(3):1628-1634
PGI(2) (prostacyclin) is a lipid mediator with vasodilatory and antithrombotic effects used in the treatment of vasoconstrictive/ischemic diseases including pulmonary artery hypertension. However, emerging research supports a role for PGs, including PGI(2), in the regulation of both innate and acquired immunity. As PGI(2) is unstable, we sought to define the effects of various PGI(2) analogs on resident alveolar macrophage (AM) and peritoneal macrophage (PM) innate immune functions. The effects of iloprost, carbaprostacyclin, and treprostinil on the regulation of phagocytosis, bacterial killing, and inflammatory mediator production were determined in both macrophage populations from rats. Iloprost failed to suppress AM functions to the same degree that it did in PMs, a characteristic shared by carbaprostacyclin. This difference reflected greater expression of the G(alphas) protein-coupled I prostanoid receptor and greater cAMP generation in PMs than AMs. Treprostinil inhibited phagocytosis, bacterial killing, and cytokine generation in AMs to a much greater degree than the other PGI(2) analogs and more closely resembled the effects of PGE(2). Studies with the E prostanoid (EP) 2 receptor antagonist AH-6809 and EP2-null macrophages indicated that this was due in part to the previously unknown ability of treprostinil to stimulate the EP2 receptor. The present investigation for the first time identifies differences in immunoregulatory properties of clinically administered PGI(2) analogs. These studies are the first to explore the capacity of PGI(2) to regulate bacterial killing and phagocytosis in macrophages, and our findings may hold important consequences regarding the risk of infection for patients receiving such agents. 相似文献
996.
997.
998.
The BCL-2 homologue MCL-1 plays an important role in the regulation of cell fate by blocking apoptosis as well as regulating cell cycle. MCL-1 has an unusual N-terminal extension, which contains a PEST domain and several phosphorylation sites that have been suggested to regulate its turnover. Here we report that the first 79 amino acids of MCL-1 regulate its subcellular localization. Deletion of this domain impairs both its mitochondrial localization and its anti-apoptotic activity. Conversely, expression of the N terminus of MCL-1 promotes both the association of MCL-1 with mitochondria and cell survival in a fashion that is dependent on the presence of endogenous MCL-1. In addition, the N terminus of MCL-1 has an antagonistic effect on proliferation. Although MCL-1 decreases proliferation through binding to proliferating cell nuclear antigen and cyclin-dependent kinase 1 in the nucleus, the N terminus of MCL-1 accelerates cell division. On the other hand, deletion of this region further increases the anti-proliferative activity of MCL-1. These results suggest that the N terminus of MCL-1 plays a major regulatory role, regulating coordinately the mitochondrial (anti-apoptotic) and nuclear (anti-proliferative) functions of MCL-1. 相似文献
999.
Shalak V Guigou L Kaminska M Wautier MP Wautier JL Mirande M 《The Journal of biological chemistry》2007,282(15):10935-10943
In human, nine aminoacyl tRNA synthetases are associated with the three auxiliary proteins, p18, p38, and p43, to form a stable multiprotein complex. The p43 component, which has a potent tRNA binding capacity, is associated to the complex via its N-terminal moiety. This protein is also the precursor of the endothelial monocyte-activating polypeptide II (p43(EMAPII), corresponding to the C-terminal moiety of p43), a cytokine generated during apoptosis. Here we examined the cellular pathway that, starting from the p43 subunit of the complex, leads to this extracellular cytokine. We identified a new intermediate in this pathway, named p43(ARF) for Apoptosis-released Factor. This intermediate is produced in cellulo by proteolytic cleavage of endogenous p43 and is rapidly recovered in the culture medium. This p43 derivative was purified from the medium of human U937 cells subjected to serum starvation. It contains 40 additional N-terminal amino acid residues as compared with the cytokine p43(EMAPII) and may be generated by a member of the matrix metalloproteinase family. Recombinant p43(ARF) is a monomer in solution and binds tRNA with a Kd of approximately 6 nM, 30-fold lower than that of p43. Highly purified p43(ARF) or p43(EMAPII) do not stimulate the expression of E-selectin by human umbilical vein endothelial cells. Our results suggest that the cleavage of p43 and its cellular delocalization, and thus the release of this tRNA binding subunit from the complex, is one of the molecular mechanisms leading to the shut down of protein synthesis in apoptosis. 相似文献
1000.
A role for ATP-citrate lyase, malic enzyme, and pyruvate/citrate cycling in glucose-induced insulin secretion 总被引:2,自引:0,他引:2
Guay C Madiraju SR Aumais A Joly E Prentki M 《The Journal of biological chemistry》2007,282(49):35657-35665
In pancreatic beta-cells, metabolic coupling factors generated during glucose metabolism and pyruvate cycling through anaplerosis/cataplerosis processes contribute to the regulation of insulin secretion. Pyruvate/citrate cycling across the mitochondrial membrane leads to the production of malonyl-CoA and NADPH, two candidate coupling factors. To examine the implication of pyruvate/citrate cycling in glucose-induced insulin secretion (GIIS), different steps of the cycle were inhibited in INS 832/13 cells by pharmacological inhibitors and/or RNA interference (RNAi) technology: mitochondrial citrate export, ATP-citrate lyase (ACL), and cytosolic malic enzyme (ME1). The inhibitors of the di- and tri-carboxylate carriers, n-butylmalonate and 1,2,3-benzenetricarboxylate, respectively, reduced GIIS, indicating the importance of transmitochondrial transport of tri- and dicarboxylates in the action of glucose. To directly test the role of ACL and ME1 in GIIS, small hairpin RNA (shRNA) were used to selectively decrease ACL or ME1 expression in transfected INS 832/13 cells. shRNA-ACL reduced ACL protein levels by 67%, and this was accompanied by a reduction in GIIS. The amplification/K(ATP)-independent pathway of GIIS was affected by RNAi knockdown of ACL. The ACL inhibitor radicicol also curtailed GIIS. shRNA-ME1 reduced ME1 activity by 62% and decreased GIIS. RNAi suppression of either ACL or ME1 did not affect glucose oxidation. However, because ACL is required for malonyl-CoA formation, inhibition of ACL expression by shRNA-ACL decreased glucose incorporation into palmitate and increased fatty acid oxidation in INS 832/13 cells. Taken together, the results underscore the importance of pyruvate/citrate cycling in pancreatic beta-cell metabolic signaling and the regulation of GIIS. 相似文献