全文获取类型
收费全文 | 871篇 |
免费 | 60篇 |
出版年
2021年 | 11篇 |
2018年 | 6篇 |
2017年 | 10篇 |
2016年 | 8篇 |
2015年 | 18篇 |
2014年 | 30篇 |
2013年 | 25篇 |
2012年 | 37篇 |
2011年 | 36篇 |
2010年 | 39篇 |
2009年 | 24篇 |
2008年 | 32篇 |
2007年 | 29篇 |
2006年 | 39篇 |
2005年 | 26篇 |
2004年 | 39篇 |
2003年 | 24篇 |
2002年 | 31篇 |
2001年 | 24篇 |
2000年 | 29篇 |
1999年 | 21篇 |
1998年 | 11篇 |
1997年 | 11篇 |
1996年 | 8篇 |
1995年 | 11篇 |
1994年 | 9篇 |
1993年 | 10篇 |
1992年 | 23篇 |
1991年 | 22篇 |
1990年 | 13篇 |
1989年 | 13篇 |
1988年 | 12篇 |
1987年 | 10篇 |
1986年 | 15篇 |
1985年 | 10篇 |
1984年 | 11篇 |
1982年 | 10篇 |
1980年 | 7篇 |
1979年 | 13篇 |
1978年 | 10篇 |
1977年 | 14篇 |
1975年 | 11篇 |
1974年 | 10篇 |
1973年 | 11篇 |
1972年 | 6篇 |
1971年 | 8篇 |
1970年 | 9篇 |
1969年 | 8篇 |
1968年 | 6篇 |
1967年 | 6篇 |
排序方式: 共有931条查询结果,搜索用时 750 毫秒
61.
Okamoto O Bachy S Odenthal U Bernaud J Rigal D Lortat-Jacob H Smyth N Rousselle P 《The Journal of biological chemistry》2003,278(45):44168-44177
Basal keratinocytes of the epidermis adhere to their underlying basement membrane through a specific interaction with laminin-5, which is composed by the association of alpha3, beta3, and gamma2 chains. Laminin-5 has the ability to induce either stable cell adhesion or migration depending on specific processing of different parts of the molecule. One event results in the cleavage of the carboxyl-terminal globular domains 4 and 5 (LG4/5) of the alpha3 chain. In this study, we recombinantly expressed the human alpha3LG4/5 fragment in mammalian cells, and we show that this fragment induces adhesion of normal human keratinocytes and fibrosarcoma-derived HT1080 cells in a heparan- and chondroitin sulfate-dependent manner. Immunoprecipitation experiments with Na2 35SO4-labeled keratinocyte and HT1080 cell lysates as well as immunoblotting experiments revealed that the major proteoglycan receptor for the alpha3LG4/5 fragment is syndecan-1. Syndecan-4 from keratinocytes also bound to alpha3LG4/5. Furthermore we could show for the first time that unprocessed laminin-5 specifically binds syndecan-1, while processed laminin-5 does not. These results demonstrate that the LG4/5 modules within unprocessed laminin-5 permit its cell binding activity through heparan and chondroitin sulfate chains of syndecan-1 and reinforce previous data suggesting specific properties for the precursor molecule. 相似文献
62.
Involvement of tumor necrosis factor-related apoptosis-inducing ligand in surveillance of tumor metastasis by liver natural killer cells 总被引:21,自引:0,他引:21
Takeda K Hayakawa Y Smyth MJ Kayagaki N Yamaguchi N Kakuta S Iwakura Y Yagita H Okumura K 《Nature medicine》2001,7(1):94-100
Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in various tumor cells in vitro, but its physiological role in tumor surveillance remains unknown. Here, we report that TRAIL is constitutively expressed on murine natural killer (NK) cells in the liver and plays a substantial role in suppressing tumor metastasis. Freshly isolated NK cells, but not natural killer T cells or ordinary T cells, from the liver expressed cell surface TRAIL, which was responsible for spontaneous cytotoxicity against TRAIL-sensitive tumor cells in vitro along with perforin and Fas ligand (FasL). Administration of neutralizing monoclonal antibody against TRAIL significantly increased experimental liver metastases of several TRAIL-sensitive tumor cell lines. Such an anti-metastatic effect of TRAIL was not observed in NK cell-depleted mice or interferon-gamma-deficient mice, the latter of which lacked TRAIL on liver NK cells. These findings provide the first evidence for the physiological function of TRAIL as a tumor suppressor. 相似文献
63.
Perforin/granzyme-induced apoptosis is the main pathway used by cytotoxic lymphocytes to eliminate virus-infected or transformed cells. Studies in gene-disrupted mice indicate that perforin is vital for cytotoxic effector function; it has an indispensable, but undefined, role in granzyme-mediated apoptosis. Despite its vital importance, the molecular and cellular functions of perforin and the basis of perforin and granzyme synergy remain poorly understood. The purpose of this review is to evaluate critically recent findings on cytotoxic granule-mediated cell death and to assess the functional significance of postulated cell-death pathways in appropriate pathophysiological contexts, including virus infection and susceptibility to experimental or spontaneous tumorigenesis. 相似文献
64.
65.
Perforin (pfp)/Fas ligand (FasL) double-deficient mice have previously been shown to be infertile, lose weight and die prematurely due to tissue destruction caused by a significant inflammatory infiltrate of monocytes/macrophages and T cells. Herein we have compared disease progression in mice additionally deficient in the inflammatory mediator TNF. Unlike pfp/FasL double-deficient mice (TNF+/+ pfp-/- gld), mice lacking functional TNF, FasL and pfp (TNF-/- pfp-/- gld) were comparatively fertile, with the majority of mice not suffering severe pancreatitis or hysterosalphingitis in the first 5 months of life. The mean lifespan of TNF-/- pfp-/- gld mice was 217 +/- 79 days compared with 69 +/- 10 days for TNF+/+ pfp-/- gld mice and the majority of moribund TNF-/- pfp-/- gld mice appeared to die as a result of severe pancreatitis, suggesting that loss of TNF was not completely protective. At 8 weeks of age, characteristics associated with the gld phenotype, such as expansion of B220+ CD4- CD8- T cells, lymphadenopathy and hypergammaglobulinemia were comparable between TNF+/+ pfp-/- gld and TNF-/- pfp-/- gld mice, although the lymphoid organs of TNF+/+ pfp-/- gld mice contained greater numbers of B220+ CD4- CD8- T cells, macrophages and T cells. We conclude that TNF is necessary for the full manifestation of immune dysregulation caused by pfp/FasL-deficiency, in particular in the early and overwhelming tissue infiltration and destruction caused by inflammatory cells. 相似文献
66.
Pereverzev A Mikhna M Vajna R Gissel C Henry M Weiergräber M Hescheler J Smyth N Schneider T 《Molecular endocrinology (Baltimore, Md.)》2002,16(4):884-895
Multiple types of voltage-activated Ca(2+) channels (T, L, N, P, Q, R type) coordinate Ca(2+)-dependent processes in neurons and neuroendocrine cells. Expressional and functional data have suggested a role for Ca(v)2.3 Ca(2+) channels in endocrine processes. To verify its role in vivo, Ca(v)2.3(-/-) mutant mice were generated, thus deficient in alpha 1E/R-type Ca(2+) channel. Intraperitoneal injection of D-glucose showed that glucose tolerance was markedly reduced, and insulin release into plasma was impaired in Ca(v)2.3-deficient mice. In isolated islets of Langerhans from these animals, no glucose-induced insulin release was detected. Further, in stressed Ca(v)2.3-deficient mice, the rate of glucose release into the blood was only 29% of that observed for wild-type animals. Thus, the deletion of Ca(v)2.3 causes deficits not only in insulin release but also in stress-induced hyperglycemia. The complex phenotype of Ca(v)2.3-deficient mice has dual components related to endocrine and neurological defects. The present findings provide direct evidence of a functional role for the Ca(v)2.3 subunit in hormone secretion and glucose homeostasis. 相似文献
67.
Smyth JT Abbott AL Lee B Sienaert I Kasri NN De Smedt H Ducibella T Missiaen L Parys JB Fissore RA 《The Journal of biological chemistry》2002,277(38):35061-35070
KN-93, a Ca(2+)/calmodulin-dependent protein kinase II (CaMKII) inhibitor, concentration-dependently and reversibly inhibited inositol 1,4,5-trisphosphate receptor (IP(3)R)-mediated [Ca(2+)](i) signaling in mouse eggs and permeabilized A7r5 smooth muscle cells, two cell types predominantly expressing type-1 IP(3)R (IP(3)R-1). KN-92, an inactive analog, was ineffective. The inhibitory action of KN-93 on Ca(2+) signaling depended neither on effects on IP(3) metabolism nor on the filling grade of Ca(2+) stores, suggesting a direct action on the IP(3)R. Inhibition was independent of CaMKII, since in identical conditions other CaMKII inhibitors (KN-62, peptide 281-309, and autocamtide-related inhibitory peptide) were ineffective and since CaMKII activation was precluded in permeabilized cells. Moreover, KN-93 was most effective in the absence of Ca(2+). Analysis of Ca(2+) release in A7r5 cells at varying [IP(3)], of IP(3)R-1 degradation in eggs, and of [(3)H]IP(3) binding in Sf9 microsomes all indicated that KN-93 did not affect IP(3) binding. Comparison of the inhibition of Ca(2+) release and of [(3)H]IP(3) binding by KN-93 and calmodulin (CaM), either separately or combined, was compatible with a specific interaction of KN-93 with a CaM-binding site on IP(3)R-1. This was also consistent with the much smaller effect of KN-93 in permeabilized 16HBE14o(-) cells that predominantly express type 3 IP(3)R, which lacks the high affinity CaM-binding site. These findings indicate that KN-93 inhibits IP(3)R-1 directly and may therefore be a useful tool in the study of IP(3)R functional regulation. 相似文献
68.
Microbial decolourisation and degradation of textile dyes 总被引:33,自引:0,他引:33
McMullan G Meehan C Conneely A Kirby N Robinson T Nigam P Banat IM Marchant R Smyth WF 《Applied microbiology and biotechnology》2001,56(1-2):81-87
Dyes and dyestuffs find use in a wide range of industries but are of primary importance to textile manufacturing. Wastewater from the textile industry can contain a variety of polluting substances including dyes. Increasingly, environmental legislation is being imposed to control the release of dyes, in particular azo-based compounds, into the environment. The ability of microorganisms to decolourise and metabolise dyes has long been known, and the use of bioremediation based technologies for treating textile wastewater has attracted interest. Within this review, we investigate the mechanisms by which diverse categories of microorganisms, such as the white-rot fungi and anaerobic bacterial consortia, bring about the degradation of dyestuffs. 相似文献
69.
The LIM-only protein DRAL/FHL2 binds to the cytoplasmic domain of several alpha and beta integrin chains and is recruited to adhesion complexes 总被引:5,自引:0,他引:5
Wixler V Geerts D Laplantine E Westhoff D Smyth N Aumailley M Sonnenberg A Paulsson M 《The Journal of biological chemistry》2000,275(43):33669-33678
LIM proteins contain one or more double zinc finger structures (LIM domains) mediating specific contacts between proteins that participate in the formation of multiprotein complexes. We report that the LIM-only protein DRAL/FHL2, with four and a half LIM domains, can associate with alpha(3A), alpha(3B), alpha(7A), and several beta integrin subunits as shown in yeast two-hybrid assays as well as after overexpression in human cells. The amino acid sequence immediately following the conserved membrane-proximal region in the integrin alpha subunits or the C-terminal region with the conserved NXXY motif of the integrin beta subunits are critical for binding DRAL/FHL2. Furthermore, the DRAL/FHL2 associates with itself and with other molecules that bind to the cytoplasmic domain of integrin alpha subunits. Deletion analysis of DRAL/FHL2 revealed that particular LIM domains or LIM domain combinations bind the different proteins. These results, together with the fact that full-length DRAL/FHL2 is found in cell adhesion complexes, suggest that it is an adaptor/docking protein involved in integrin signaling pathways. 相似文献
70.