全文获取类型
收费全文 | 1567篇 |
免费 | 115篇 |
国内免费 | 1篇 |
专业分类
1683篇 |
出版年
2023年 | 4篇 |
2022年 | 19篇 |
2021年 | 34篇 |
2020年 | 23篇 |
2019年 | 26篇 |
2018年 | 39篇 |
2017年 | 33篇 |
2016年 | 47篇 |
2015年 | 81篇 |
2014年 | 87篇 |
2013年 | 131篇 |
2012年 | 130篇 |
2011年 | 115篇 |
2010年 | 91篇 |
2009年 | 70篇 |
2008年 | 121篇 |
2007年 | 85篇 |
2006年 | 90篇 |
2005年 | 84篇 |
2004年 | 62篇 |
2003年 | 67篇 |
2002年 | 54篇 |
2001年 | 12篇 |
2000年 | 10篇 |
1999年 | 13篇 |
1998年 | 12篇 |
1997年 | 11篇 |
1996年 | 10篇 |
1995年 | 9篇 |
1994年 | 3篇 |
1993年 | 6篇 |
1992年 | 8篇 |
1991年 | 8篇 |
1990年 | 7篇 |
1989年 | 8篇 |
1988年 | 10篇 |
1987年 | 4篇 |
1986年 | 4篇 |
1985年 | 9篇 |
1984年 | 9篇 |
1983年 | 6篇 |
1982年 | 4篇 |
1981年 | 7篇 |
1980年 | 3篇 |
1979年 | 2篇 |
1975年 | 2篇 |
1974年 | 4篇 |
1973年 | 4篇 |
1970年 | 1篇 |
1965年 | 1篇 |
排序方式: 共有1683条查询结果,搜索用时 15 毫秒
91.
Martino A Casetti R Sacchi A Poccia F 《Journal of immunology (Baltimore, Md. : 1950)》2007,179(5):3057-3064
In humans, innate immune recognition of mycobacteria, including Mycobacterium tuberculosis and bacillus Calmette-Guérin (BCG), is a feature of cells as dendritic cells (DC) and gammadelta T cells. In this study, we show that BCG infection of human monocyte-derived DC induces a rapid activation of Vgamma9Vdelta2 T cells (the major subset of gammadelta T cell pool in human peripheral blood). Indeed, in the presence of BCG-infected DC, Vgamma9Vdelta2 T cells increase both their expression of CD69 and CD25 and the production of TNF-alpha and IFN-gamma, in contrast to DC treated with Vgamma9Vdelta2 T cell-specific Ags. Without further exogenous stimuli, BCG-infected DC expand a functionally cytotoxic central memory Vgamma9Vdelta2 T cell population. This subset does not display lymph node homing receptors, but express a high amount of perforin. They are highly efficient in the killing of mycobacterial-infected primary monocytes or human monocytic THP-1 cells preserving the viability of cocultured, infected DC. This study provides further evidences about the complex relationship between important players of innate immunity and suggests an immunoregulatory role of Vgamma9Vdelta2 T cells in the control of mycobacterial infection. 相似文献
92.
Russano AM Bassotti G Agea E Bistoni O Mazzocchi A Morelli A Porcelli SA Spinozzi F 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(6):3620-3626
Gammadelta T cells are present in the mucosal intestinal epithelia and secrete factors necessary to maintain tissue integrity. Ags recognized by these cells are poorly defined, although in mice non-classical MHC class I molecules have been implicated. Since MHC class I-like CD1 receptors are widely expressed at the surface of epithelial and dendritic intestinal cells and have the capacity to present lipid Ags to T cells, we hypothesized that these molecules might present autologous and/or exogenous phospholipids to intestinal gammadelta T lymphocytes. Intraepithelial T lymphocytes from normal human duodenal mucosal biopsies were cloned and exposed to natural and synthetic phospholipids using CD1a-, CD1b-, CD1c- or CD1d-transfected C1R lymphoblastoid or HeLa cell lines as APCs. Their cytolytic properties and regulatory cytokine secretion were also examined. Most clones obtained from duodenal mucosa (up to 70%) were TCRalphabeta+, and either CD4+ or CD8+, whereas 20% were CD4-CD8- (6 clones) or TCRgammadelta+ (12 clones). A relevant percentage (up to 66%) of TCRgammadelta+ but few (<5%) TCRalphabeta+ T cell clones responded to synthetic and/or natural phospholipids presented by CD1 molecules, as measured by both [(3)H]thymidine incorporation and IL-4 release assays. A Th1-like cytolytic and functional activity along with the ability to secrete regulatory cytokines was observed in most phospholipid-specific gammadelta T cell clones. Thus, a substantial percentage of TCRgammadelta+ but few TCRalphabeta+ from human duodenal mucosa recognize exogenous phospholipids in a CD1-restricted fashion. This adaptive response could contribute to mucosal homeostasis, but could also favor the emergence of inflammatory or allergic intestinal diseases. 相似文献
93.
Giordanetto F Karlsson O Lindberg J Larsson LO Linusson A Evertsson E Morgan DG Inghardt T 《Bioorganic & medicinal chemistry letters》2007,17(15):4232-4241
We herein report the optimization of cyclopentane- and cyclohexane-1,3-diamine derivatives as novel and potent MCH-R1 antagonists. Structural modifications of the 2-amino-quinoline and thiophene moieties found in the initial lead compound served to improve its metabolic stability profile and MCH-R1 affinity, and revealed unprecedented SAR when compared to other 2-amino-quinoline-containing MCH-R1 antagonists. 相似文献
94.
95.
Human TH17 lymphocytes promote blood-brain barrier disruption and central nervous system inflammation 总被引:23,自引:0,他引:23
Kebir H Kreymborg K Ifergan I Dodelet-Devillers A Cayrol R Bernard M Giuliani F Arbour N Becher B Prat A 《Nature medicine》2007,13(10):1173-1175
T(H)17 lymphocytes appear to be essential in the pathogenesis of numerous inflammatory diseases. We demonstrate here the expression of IL-17 and IL-22 receptors on blood-brain barrier endothelial cells (BBB-ECs) in multiple sclerosis lesions, and show that IL-17 and IL-22 disrupt BBB tight junctions in vitro and in vivo. Furthermore, T(H)17 lymphocytes transmigrate efficiently across BBB-ECs, highly express granzyme B, kill human neurons and promote central nervous system inflammation through CD4+ lymphocyte recruitment. 相似文献
96.
Edito Fabrizio Nicola Vanacore Marcella Valente Alfonso Rubino Giuseppe Meco 《BMC neurology》2007,7(1):24
Background
Occupational and chronic exposure to solvents and metals is considered a possible risk factor for Parkinson's disease and essential tremor. While manufacturing dental prostheses, dental technicians are exposed to numerous chemicals that contain toxins known to affect the central nervous system, such as solvents (which contain n-hexane in particular) and metals (which contain mercury, iron, chromium, cobalt and nickel). 相似文献97.
Manuela Mellone Silvia Pelucchi Lorenzo Alberti Armando A. Genazzani Monica Di Luca Fabrizio Gardoni 《Journal of neurochemistry》2015,132(2):159-168
Zinc (Zn2+) is believed to play a relevant role in the physiology and pathophysiology of the brain. Hence, Zn2+ homeostasis is critical and involves different classes of molecules, including Zn2+ transporters. The ubiquitous Zn2+ transporter‐1 (ZNT‐1) is a transmembrane protein that pumps cytosolic Zn2+ to the extracellular space, but its function in the central nervous system is not fully understood. Here, we show that ZNT‐1 interacts with GluN2A‐containing NMDA receptors, suggesting a role for this transporter at the excitatory glutamatergic synapse. First, we found that ZNT‐1 is highly expressed at the hippocampal postsynaptic density (PSD) where NMDA receptors are enriched. Two‐hybrid screening, coimmunoprecipitation experiments and clustering assay in COS‐7 cells demonstrated that ZNT‐1 specifically binds the GluN2A subunit of the NMDA receptor. GluN2A deletion mutants and pull‐down assays indicated GluN2A(1390–1464) domain as necessary for the binding to ZNT‐1. Most importantly, ZNT‐1/GluN2A complex was proved to be dynamic, since it was regulated by induction of synaptic plasticity. Finally, modulation of ZNT‐1 expression in hippocampal neurons determined a significant change in dendritic spine morphology, PSD‐95 clusters and GluN2A surface levels, supporting the involvement of ZNT‐1 in the dynamics of excitatory PSD.
98.
99.
100.
Vacca F D'Ambrosi N Nestola V Amadio S Giustizieri M Cucchiaroni ML Tozzi A Velluz MC Mercuri NB Volonté C 《Glycobiology》2011,21(5):634-643
N-Glycosylation affects the function of ion channels at the level of multisubunit assembly, protein trafficking, ligand binding and channel opening. Like the majority of membrane proteins, ionotropic P2X receptors for extracellular ATP are glycosylated in their extracellular moiety. Here, we used site-directed mutagenesis to the four predicted N-glycosylation sites of P2X(3) receptor (Asn(139), Asn(170), Asn(194) and Asn(290)) and performed comparative analysis of the role of N-glycans on protein stability, plasma membrane delivery, trimer formation and inward currents. We have found that in transiently transfected HEK293 cells, Asn(170) is apparently the most important site for receptor stability, since its mutation causes a primary loss in protein content and indirect failure in membrane expression, oligomeric association and inward current responses. Even stronger effects are obtained when mutating Thr(172) in the same glycosylation consensus. Asn(194) and Asn(290) are the most dispensable, since even their simultaneous mutation does not affect any tested receptor feature. All double mutants containing Asn(170) mutation or the Asn(139)/Asn(290) double mutant are instead almost unable to assemble into a functional trimeric structure. The main emerging finding is that the inability to assemble into trimers might account for the impaired function in P2X(3) mutants where residue Asn(170) is replaced. These results improve our knowledge about the role of N-glycosylation in proper folding and oligomeric association of P2X(3) receptor. 相似文献