全文获取类型
收费全文 | 1137篇 |
免费 | 75篇 |
国内免费 | 1篇 |
出版年
2024年 | 1篇 |
2023年 | 1篇 |
2022年 | 3篇 |
2021年 | 22篇 |
2020年 | 7篇 |
2019年 | 15篇 |
2018年 | 13篇 |
2017年 | 14篇 |
2016年 | 24篇 |
2015年 | 46篇 |
2014年 | 58篇 |
2013年 | 67篇 |
2012年 | 85篇 |
2011年 | 94篇 |
2010年 | 62篇 |
2009年 | 42篇 |
2008年 | 80篇 |
2007年 | 88篇 |
2006年 | 84篇 |
2005年 | 81篇 |
2004年 | 76篇 |
2003年 | 54篇 |
2002年 | 52篇 |
2001年 | 16篇 |
2000年 | 17篇 |
1999年 | 11篇 |
1998年 | 15篇 |
1997年 | 13篇 |
1996年 | 8篇 |
1995年 | 6篇 |
1994年 | 5篇 |
1993年 | 11篇 |
1992年 | 6篇 |
1991年 | 6篇 |
1990年 | 9篇 |
1989年 | 5篇 |
1988年 | 1篇 |
1987年 | 4篇 |
1986年 | 1篇 |
1985年 | 1篇 |
1981年 | 1篇 |
1980年 | 3篇 |
1978年 | 1篇 |
1977年 | 2篇 |
1974年 | 1篇 |
1970年 | 1篇 |
排序方式: 共有1213条查询结果,搜索用时 390 毫秒
991.
Mycoplasma arthritidis, an inflammatory murine pathogen, secretes a potent superantigen, Mycoplasma arthritidis mitogen (MAM) that contributes to toxic shock, arthritis and skin necrosis. Previously we showed that MAM induced type 2 T-cell cytokines in mice that express functional TLR2 and TLR4, but type 1 cytokines in mice that lack TLR4 function. We show here that IL-17, pSTAT3 and retinoid-related orphan nuclear receptorγt are rapidly expressed in wild-type C3H/HeSnJ (TLR2+/4+) mice but are significantly delayed in mutant C3H/HeJ (TLR2+/4-) mice. This marked kinetic difference was associated with a high level of IL-6 in TLR2+/4+ mice versus high levels of IL-1β and TNFα in TLR2+/4- mice. Also antibodies to IL-6 and IL-23, suppressed IL-17 responses to MAM in TLR2+/4+ mice whereas anti-IL-1β, but not anti-TNFα, enhanced IL-17 in TLR2+/4- mice. Antibody blocking of TLR4 in TLR2+/4+ mice decreased IL-17 and IL-6 but not IL-23. In addition both IL-17 and IL-6 but not IL-23 were elevated in TLR2 KO mice versus wild-type TLR2+/4+ mice given MAM. We conclude that the MAM interaction with TLR2 versus TLR4 leads to distinct cytokine pathways mediated primarily by IL-1β or IL-6/IL-17 signalling respectively. Our findings suggest that the differential interaction of MAM with different TLRs might play an important role in disease outcomes by M. arthritidis. 相似文献
992.
993.
Sun Young Kim Che C. Colpitts Gertrud Wiedemann Christina Jepson Mehrieh Rahimi Jordan R. Rothwell Adam D. McInnes Mitsuyasu Hasebe Ralf Reski Brian T. Sterenberg Dae-Yeon Suh 《The Journal of biological chemistry》2013,288(4):2767-2777
The plant type III polyketide synthases (PKSs), which produce diverse secondary metabolites with different biological activities, have successfully co-evolved with land plants. To gain insight into the roles that ancestral type III PKSs played during the early evolution of land plants, we cloned and characterized PpORS from the moss Physcomitrella. PpORS has been proposed to closely resemble the most recent common ancestor of the plant type III PKSs. PpORS condenses a very long chain fatty acyl-CoA with four molecules of malonyl-CoA and catalyzes decarboxylative aldol cyclization to yield the pentaketide 2′-oxoalkylresorcinol. Therefore, PpORS is a 2′-oxoalkylresorcinol synthase. Structure modeling and sequence alignments identified a unique set of amino acid residues (Gln218, Val277, and Ala286) at the putative PpORS active site. Substitution of the Ala286 to Phe apparently constricted the active site cavity, and the A286F mutant instead produced triketide alkylpyrones from fatty acyl-CoA substrates with shorter chain lengths. Phylogenetic analysis and comparison of the active sites of PpORS and alkylresorcinol synthases from sorghum and rice suggested that the gramineous enzymes evolved independently from PpORS to have similar functions but with distinct active site architecture. Microarray analysis revealed that PpORS is exclusively expressed in nonprotonemal moss cells. The in planta function of PpORS, therefore, is probably related to a nonprotonemal structure, such as the cuticle. 相似文献
994.
Natsuo Ohsawa Chang‐Hyun Song Akio Suzuki Hidefumi Furuoka Rie Hasebe Motohiro Horiuchi 《Microbiology and immunology》2013,57(4):288-297
It is generally thought that effective treatments for prion diseases need to inhibit prion propagation, protect neuronal tissues and promote functional recovery of degenerated nerve tissues. In addition, such treatments should be effective even when given after clinical onset of the disease and administered via a peripheral route. In this study, the effect of peripheral administration of an anti‐PrP antibody on disease progression in prion‐infected mice was examined. mAb 31C6 was administered via the tail veins of prion‐infected mice at the time of clinical onset (120 days post‐inoculation with the Chandler prion strain) and the distribution of this mAb in the brain and its effect on mouse survival assessed. The antibody was distributed to the cerebellums and thalami of the infected mice and more than half these mice survived longer than mice that had been given a negative control mAb. The level of PrPSc in the mAb 31C6‐treated mice was lower than that in mice treated with the negative control mAb and progression of neuropathological lesions in the cerebellum, where the mAb 31C6 was well distributed, appeared to be mitigated. These results suggest that administration of an anti‐PrP mAb through a peripheral route is a candidate for the treatment of prion diseases. 相似文献
995.
996.
High throughput quantitative glycomics and glycoform-focused proteomics of murine dermis and epidermis 总被引:2,自引:0,他引:2
Uematsu R Furukawa J Nakagawa H Shinohara Y Deguchi K Monde K Nishimura S 《Molecular & cellular proteomics : MCP》2005,4(12):1977-1989
Despite recent advances in our understanding of the significance of the protein glycosylation, the throughput of protein glycosylation analysis is still too low to be applied to the exhaustive glycoproteomic analysis. Aiming to elucidate the N-glycosylation of murine epidermis and dermis glycoproteins, here we used a novel approach for focused proteomics. A gross N-glycan profiling (glycomics) of epidermis and dermis was first elucidated both qualitatively and quantitatively upon N-glycan derivatization with novel, stable isotope-coded derivatization reagents followed by MALDI-TOF(/TOF) analysis. This analysis revealed distinct features of the N-glycosylation profile of epidermis and dermis for the first time. A high abundance of high mannose type oligosaccharides was found to be characteristic of murine epidermis glycoproteins. Based on this observation, we performed high mannose type glycoform-focused proteomics by direct tryptic digestion of protein mixtures and affinity enrichment. We identified 15 glycoproteins with 19 N-glycosylation sites that carry high mannose type glycans by off-line LC-MALDI-TOF/TOF mass spectrometry. Moreover the relative quantity of microheterogeneity of different glycoforms present at each N-glycan binding site was determined. Glycoproteins identified were often contained in lysosomes (e.g. cathepsin L and gamma-glutamyl hydrolase), lamellar granules (e.g. glucosylceramidase and cathepsin D), and desmosomes (e.g. desmocollin 1, desmocollin 3, and desmoglein). Lamellar granules are organelles found in the terminally differentiating cells of keratinizing epithelia, and desmosomes are intercellular junctions in vertebrate epithelial cells, thus indicating that N-glycosylation of tissue-specific glycoproteins may contribute to increase the relative proportion of high mannose glycans. The striking roles of lysosomal enzymes in epidermis during lipid remodeling and desquamation may also reflect the observed high abundance of high mannose glycans. 相似文献
997.
Shunji Nagaoka Yukiko Bito Rie Sakuma Hiroko Nomura Tadayoshi Hata Junpei Nishiyama Yutaka Hirata 《Biological Sciences in Space》2003,17(3):265-266
We analyzed and compared the frequency components of the heart rate variability in human neonate, rat, white chicken, turtle, and frog during the developments. Frequency analysis with autocorrelation-FFT method was applied to the heart rate and respiration waves to calculate the respiration induced frequency component in the power spectra. The comparative analysis of the cardiopulmonary reflex in human and rat neonates resulted in a similar developmental progress. In case of human immature neonate, respiration induced frequency component in the heart rate variability was negligible at day-old 0, and significantly increased at postnatal 1 month. The rat neonates also showed no or negligible respiration induced components until days 8 and it became significant approximately postnatal 1 month. The white chicken also indicated negligible respiration induced component before and a few days after hatching, and became significant after 38 days-old (17 days post hatching). However the frog and the turtle indicated no clear response in entire periods of the development even in adult. The results strongly suggested that gravity may be a possible essential factor of the appearance of the post natal development of the cardiopulmonary reflex. 相似文献
998.
Rie Masho 《Development, growth & differentiation》1990,32(1):57-64
To examine whether the first cleavage plane demarcates the dorsal-ventral axis (Klein, 1987) or it is random in relation to the plane of bilateral symmetry (Danilchik and Black, 1988), one blastomere of two-cell-stage Xenopus laevis embryos was labeled with injected fluorescein dextran amine. In resulting embryos, the first cleavage plane was represented by the boundary between the labeled and non-labeled cells. In more than 90% of the embryos whose first cleavage plane had coincided with or inclined by 45 degrees to the plane of bilateral symmetry of surface pigmentation, the boundary fell within 30 degrees of the midline at the early gastrula stage. By contrast, in most embryos (10 out of 11) whose first cleavage plane was perpendicular to the plane of bilateral symmetry (up to 0.4% of a batch), the boundary fell between the dorsal and ventral regions. When randomly taken out from batches, more than 90% of the embryos had the first cleavage plane lying within 30 degrees of the dorsal midline at the initial gastrula stage. Thus the present results support neither Klein's nor Danilchik and Black's results, but confirm the currently accepted view that the first cleavage plane marks the dorsal midline with some range of deviation. 相似文献
999.
Masanori Tsujimoto Gen Kuroyanagi Rie Matsushima-Nishiwaki Yuko Kito Yukiko Enomoto Hiroki Iida Shinji Ogura Takanobu Otsuka Haruhiko Tokuda Osamu Kozawa Toru Iwama 《PloS one》2016,11(2)
Selective inhibitors of factor Xa (FXa) are widely recognized as useful therapeutic tools for stroke prevention in non-valvular atrial fibrillation or venous thrombosis. Thrombin, which is rapidly generated from pro-thrombin through the activation of factor X to FXa, acts as a potent activator of human platelets. Thus, the reduction of thrombin generation by FXa inhibitor eventually causes a suppressive effect on platelet aggregation. However, little is known whether FXa inhibitors directly affect the function of human platelets. We have previously reported that collagen induces the phosphorylation of heat shock protein 27 (HSP27), a low-molecular weight heat shock protein via Rac-dependent activation of p44/p42 mitogen-activated protein (MAP) kinase in human platelets, eventually resulting in the release of HSP27. In the present study, we investigated the direct effect of FXa inhibitor on the collagen-induced human platelet activation. Rivaroxaban as well as edoxaban significantly reduced the collagen-induced phosphorylation of both HSP27 and p44/p42 MAP kinase without affecting the platelet aggregation. Rivaroxaban significantly inhibited the release of phosphorylated HSP27 from collagen-stimulated platelets but not the secretion of platelet derived growth factor-AB. In patients administrated with rivaroxaban, the collagen-induced levels of phosphorylated HSP27 were markedly diminished after 2 days of administration, which failed to affect the platelet aggregation. These results strongly suggest that FXa inhibitor reduces the collagen-stimulated release of phosphorylated HSP27 from human platelets due to the inhibition of HSP27 phosphorylation via p44/p42 MAP kinase. 相似文献
1000.
Prion-infected cells have been used for analyzing the effect of compounds on the formation of abnormal isoform of prion protein (PrPSc). PrPSc is usually detected using anti-prion protein (PrP) antibodies after the removal of the cellular isoform of prion protein (PrPC) by proteinase K (PK) treatment. However, it is expected that the PK-sensitive PrPSc (PrPSc-sen), which possesses higher infectivity and conversion activity than the PK-resistant PrPSc (PrPSc-res), is also digested through PK treatment. To overcome this problem, we established a novel cell-based ELISA in which PrPSc can be directly detected from cells persistently infected with prions using anti-PrP monoclonal antibody (mAb) 132 that recognizes epitope consisting of mouse PrP amino acids 119–127. The novel cell-based ELISA could distinguish prion-infected cells from prion-uninfected cells without cell lysis and PK treatment. MAb 132 could detect both PrPSc-sen and PrPSc-res even if all PrPSc molecules were not detected. The analytical dynamic range for PrPSc detection was approximately 1 log. The coefficient of variation and signal-to-background ratio were 7%–11% and 2.5–3.3, respectively, demonstrating the reproducibility of this assay. The addition of a cytotoxicity assay immediately before PrPSc detection did not affect the following PrPSc detection. Thus, all the procedures including cell culture, cytotoxicity assay, and PrPSc detection were completed in the same plate. The simplicity and non-requirement for cell lysis or PK treatment are advantages for the high throughput screening of anti-prion compounds. 相似文献