全文获取类型
收费全文 | 1831篇 |
免费 | 149篇 |
国内免费 | 2篇 |
出版年
2023年 | 3篇 |
2022年 | 12篇 |
2021年 | 34篇 |
2020年 | 9篇 |
2019年 | 29篇 |
2018年 | 46篇 |
2017年 | 32篇 |
2016年 | 51篇 |
2015年 | 87篇 |
2014年 | 79篇 |
2013年 | 120篇 |
2012年 | 143篇 |
2011年 | 121篇 |
2010年 | 84篇 |
2009年 | 75篇 |
2008年 | 96篇 |
2007年 | 137篇 |
2006年 | 114篇 |
2005年 | 106篇 |
2004年 | 113篇 |
2003年 | 112篇 |
2002年 | 93篇 |
2001年 | 9篇 |
2000年 | 10篇 |
1999年 | 24篇 |
1998年 | 34篇 |
1997年 | 29篇 |
1996年 | 13篇 |
1995年 | 18篇 |
1994年 | 19篇 |
1993年 | 15篇 |
1992年 | 7篇 |
1991年 | 13篇 |
1990年 | 13篇 |
1989年 | 7篇 |
1988年 | 7篇 |
1987年 | 5篇 |
1986年 | 2篇 |
1985年 | 5篇 |
1984年 | 9篇 |
1983年 | 8篇 |
1982年 | 4篇 |
1981年 | 6篇 |
1980年 | 4篇 |
1979年 | 10篇 |
1978年 | 2篇 |
1976年 | 6篇 |
1975年 | 3篇 |
1974年 | 2篇 |
1964年 | 1篇 |
排序方式: 共有1982条查询结果,搜索用时 46 毫秒
981.
982.
Boulanger P Jacquot P Plançon L Chami M Engel A Parquet C Herbeuval C Letellier L 《The Journal of biological chemistry》2008,283(20):13556-13564
We report a bioinformatic and functional characterization of Pb2, a 121-kDa multimeric protein that forms phage T5 straight fiber and is implicated in DNA transfer into the host. Pb2 was predicted to consist of three domains. Region I (residues 1-1030) was mainly organized in coiled coil and shared features of tape measure proteins. Region II (residues 1030-1076) contained two alpha-helical transmembrane segments. Region III (residues 1135-1148) included a metallopeptidase motif. A truncated version of Pb2 (Pb2-Cterm, residues 964-1148) was expressed and purified. Pb2-Cterm shared common features with fusogenic membrane polypeptides. It formed oligomeric structures and inserted into liposomes triggering their fusion. Pb2-Cterm caused beta-galactosidase release from Escherichia coli cells and in vitro peptidoglycan hydrolysis. Based on these multifunctional properties, we propose that binding of phage T5 to its receptor triggers large conformational changes in Pb2. The coiled coil region would serve as a sensor for triggering the opening of the head-tail connector. The C-terminal region would gain access to the host envelope, permitting the local degradation of the peptidoglycan and the formation of the DNA pore by fusion of the two membranes. 相似文献
983.
Human primary endothelial cells stimulate human osteoprogenitor cell differentiation. 总被引:2,自引:0,他引:2
Bertrand Guillotin Chantal Bourget Murielle Remy-Zolgadri Reine Bareille Philippe Fernandez Véronique Conrad Jo?lle Amédée-Vilamitjana 《Cellular physiology and biochemistry》2004,14(4-6):325-332
Bone development and remodeling depend on complex interactions between bone-forming osteoblasts and other cells present within the bone microenvironment, particularly endothelial cells that may be pivotal members of a complex interactive communication network in bone. While cell cooperation was previously established between Human OsteoProgenitor cells (HOP) and Human Umbilical Vein Endothelial Cells (HUVEC) the aim of our study was to investigate if this interaction is specific to Human Endothelial cell types (ECs) from different sources. Osteoblastic cell differentiation analysis performed using different co-culture models with direct contact revealed that Alkaline Phosphatase (Al-P) activity was only increased by the direct contact of HOP with human primary vascular endothelial cell types including endothelial precursor cells (EPCs) isolated from blood cord, endothelial cells from Human Saphen Vein (HSV) while a transformed cell line, the Human Bone Marrow Endothelial Cell Line (HBMEC) did not modify osteoblastic differentiation of HOP. Because connexin 43, a specific gap junction protein, seemed to be involved in HUVEC/HOP cell cooperation, expression by RT-PCR and immunocytochemistry of this gap junctional protein was investigated in EPCs, HSV and HBMEC. Both endothelial cells are positive to this protein and the disruption of gap junction communication using 18alpha-glycyrrhetinic acid treatment decreased the positive effect of these endothelial co-cultures on HOP differentiation as was previously demonstrated for HUVEC and HOP co-cultures. These data seem to indicate that this cross talk between HOP and ECs, through gap junction communication constitutes an additional concept in cell differentiation control. 相似文献
984.
Vizziano D Baron D Randuineau G Mahè S Cauty C Guiguen Y 《Biology of reproduction》2008,78(5):939-946
The present study was designed to obtain new insights into fish gonadal sex differentiation by comparing the effects of two different masculinizing treatments on some candidate gene expression profiles. Masculinization was induced in rainbow trout, Oncorhynchus mykiss, genetic all-female populations using either an active fish androgen (11betaAnd, 11beta-hydroxyandrostenedione) or an aromatase inhibitor (ATD, 1,4,6-androstatriene-3,17-dione). The expression profiles of 100 candidate genes were obtained by real-time RT-PCR, and 46 profiles displayed a significant differential expression between control populations (males and females) and ATD/11betaAnd-treated populations. These expression profiles were grouped in four temporally correlated expression clusters. Among the common responses shared by the two masculinizing treatments, the inhibition of some early female differentiating genes (cyp19a1, foxl2a, fst, and fshb) appears to be crucial for effective masculinization, suggesting that these genes act together via a short regulation loop to maintain high sex-specific ovarian expression of cyp19a1. This simultaneous down-regulation of female-specific genes could be triggered by some testicular genes, such as dmrt1, nr0b1 (also known as dax1), and pdgfra, which are quickly up-regulated by the two masculinizing treatments. In contrast to 11betaAnd, ATD quickly restored the expression levels of steroidogenesis related genes (cyp11b2.1, cyp11b2.2, hsd3b1, cyp17a, star, and nr5a1) and some Sertoli cell markers (sox9a2 and amh) to the expression levels observed during control testicular differentiation. This demonstrates that these genes are probably not needed for active masculinization and that the inhibition of endogenous estrogen synthesis produces a much more complete and specific testicular pattern of gene expression than that observed following androgen-induced masculinization. 相似文献
985.
Properdin binds to late apoptotic and necrotic cells independently of C3b and regulates alternative pathway complement activation 总被引:4,自引:0,他引:4
Xu W Berger SP Trouw LA de Boer HC Schlagwein N Mutsaers C Daha MR van Kooten C 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(11):7613-7621
Cells that undergo apoptosis or necrosis are promptly removed by phagocytes. Soluble opsonins such as complement can opsonize dying cells, thereby promoting their removal by phagocytes and modulating the immune response. The pivotal role of the complement system in the handling of dying cells has been demonstrated for the classical pathway (via C1q) and lectin pathway (via mannose-binding lectin and ficolin). Herein we report that the only known naturally occurring positive regulator of complement, properdin, binds predominantly to late apoptotic and necrotic cells, but not to early apoptotic cells. This binding occurs independently of C3b, which is additional to the standard model wherein properdin binds to preexisting clusters of C3b on targets and stabilizes the convertase C3bBb. By binding to late apoptotic or necrotic cells, properdin serves as a focal point for local amplification of alternative pathway complement activation. Furthermore, properdin exhibits a strong interaction with DNA that is exposed on the late stage of dying cells. Our data indicate that direct recognition of dying cells by properdin is essential to drive alternative pathway complement activation. 相似文献
986.
Kanamaru Y Pfirsch S Aloulou M Vrtovsnik F Essig M Loirat C Deschênes G Guérin-Marchand C Blank U Monteiro RC 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(4):2669-2678
Inhibitory signaling is an emerging function of ITAM-bearing immunoreceptors in the maintenance of homeostasis. Monovalent targeting of the IgA Fc receptor (FcalphaRI or CD89) by anti-FcalphaRI Fab triggers potent inhibitory ITAM (ITAM(i)) signaling through the associated FcRgamma chain (FcalphaRI-FcRgamma ITAM(i)) that prevents IgG phagocytosis and IgE-mediated asthma. It is not known whether FcalphaRI-FcRgamma ITAM(i) signaling controls receptors that do not function through an ITAM and whether this inhibition requires Src homology protein 1 phosphatase. We show in this study that FcalphaRI-Fcgamma ITAM(i) signals depend on Src homology protein 1 phosphatase to target multiple non-ITAM-bearing receptors such as chemotactic receptors, cytokine receptors, and TLRs. We found that anti-FcalphaRI Fab treatment in vivo reduced kidney inflammation in models of immune-mediated glomerulonephritis and nonimmune obstructive nephropathy by a mechanism that involved decreased inflammatory cell infiltration and fibrosis development. This treatment also prevented ex vivo LPS activation of monocytes from patients with lupus nephritis or vasculitis, as well as receptor activation through serum IgA complexes from IgA nephropathy patients. These findings point to a crucial role of FcalphaRI-FcRgamma ITAM(i) signaling in the control of multiple heterologous or autologous inflammatory responses. They also identify anti-FcalphaRI Fab as a new potential therapeutic tool for preventing progression of renal inflammatory diseases. 相似文献
987.
Hams E Colmont CS Dioszeghy V Hammond VJ Fielding CA Williams AS Tanaka M Miyajima A Taylor PR Topley N Jones SA 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(3):2174-2180
Although the IL-6-related cytokine oncostatin M (OSM) affects processes associated with disease progression, the specific function of OSM in the face of an inflammatory challenge remains unclear. In this report, a peritoneal model of acute inflammation was used to define the influence of OSM on chemokine-mediated leukocyte recruitment. When compared with wild-type and IL-6-deficient mice, peritoneal inflammation in oncostatin M receptor-beta-deficient (OSMR-KO) mice resulted in enhanced monocytic cell trafficking. In contrast to IL-6-deficient mice, OSMR-KO mice displayed no difference in neutrophil and lymphocyte migration. Subsequent in vitro studies using human peritoneal mesothelial cells and an in vivo appraisal of inflammatory chemokine expression after peritoneal inflammation identified OSM as a prominent regulator of CCL5 expression. Specifically, OSM inhibited IL-1beta-mediated NF-kappaB activity and CCL5 expression in human mesothelial cells. This was substantiated in vivo where peritoneal inflammation in OSMR-KO mice resulted in a temporal increase in both CCL5 secretion and NF-kappaB activation. These findings suggest that IL-6 and OSM individually affect the profile of leukocyte trafficking, and they point to a hitherto unidentified interplay between OSM signaling and the inflammatory activation of NF-kappaB. 相似文献
988.
Fielding CA McLoughlin RM McLeod L Colmont CS Najdovska M Grail D Ernst M Jones SA Topley N Jenkins BJ 《Journal of immunology (Baltimore, Md. : 1950)》2008,181(3):2189-2195
The successful resolution of inflammation is dependent upon the coordinated transition from the initial recruitment of neutrophils to a more sustained population of mononuclear cells. IL-6, which signals via the common receptor subunit gp130, represents a crucial checkpoint regulator of neutrophil trafficking during the inflammatory response by orchestrating chemokine production and leukocyte apoptosis. However, the relative contribution of specific IL-6-dependent signaling pathways to these processes remains unresolved. To define the receptor-mediated signaling events responsible for IL-6-driven neutrophil trafficking, we used a series of gp130 knockin mutant mice displaying altered IL-6-signaling capacities in an experimental model of acute peritoneal inflammation. Hyperactivation of STAT1 and STAT3 in gp130(Y757F/Y757F) mice led to a more rapid clearance of neutrophils, and this coincided with a pronounced down-modulation in production of the neutrophil-attracting chemokine CXCL1/KC. By contrast, the proportion of apoptotic neutrophils in the inflammatory infiltrate remained unaffected. In gp130(Y757F/Y757F) mice lacking IL-6, neutrophil trafficking and CXCL1/KC levels were normal, and this corresponded with a reduction in the level of STAT1/3 activity. Furthermore, monoallelic ablation of Stat3 in gp130(Y757F/Y757F) mice specifically reduced STAT3 activity and corrected both the rapid clearance of neutrophils and impaired CXCL1/KC production. Conversely, genetic deletion of Stat1 in gp130(Y757F/Y757F) mice failed to rescue the altered responses observed in gp130(Y757F/Y757F) mice. Collectively, these data genetically define that IL-6-driven signaling via STAT3, but not STAT1, limits the inflammatory recruitment of neutrophils, and therefore represents a critical event for the termination of the innate immune response. 相似文献
989.
Heterologous Production, Assembly, and Secretion of a Minicellulosome by Clostridium acetobutylicum ATCC 824 总被引:1,自引:0,他引:1 下载免费PDF全文
Florence Mingardon Stéphanie Perret Anne Béla?ch Chantal Tardif Jean-Pierre Béla?ch Henri-Pierre Fierobe 《Applied microbiology》2005,71(3):1215-1222
The gene man5K encoding the mannanase Man5K from Clostridium cellulolyticum was cloned alone or as an operon with the gene cipC1 encoding a truncated scaffoldin (miniCipC1) of the same origin in the solventogenic Clostridium acetobutylicum. The expression of the heterologous gene(s) was under the control of a weakened thiolase promoter Pthl. The recombinant strains of the solventogenic bacterium were both found to secrete active Man5K in the range of milligrams per liter. In the case of the strain expressing only man5K, a large fraction of the recombinant enzyme was truncated and lost the N-terminal dockerin domain, but it remained active towards galactomannan. When man5K was coexpressed with cipC1 in C. acetobutylicum, the recombinant strain secreted almost exclusively full-length mannanase, which bound to the scaffoldin miniCipC1, thus showing that complexation to the scaffoldin stabilized the enzyme. The secreted heterologous complex was found to be functional: it binds to crystalline cellulose via the carbohydrate binding module of the miniscaffoldin, and the complexed mannanase is active towards galactomannan. Taken together, these data show that C. acetobutylicum is a suitable host for the production, assembly, and secretion of heterologous minicellulosomes. 相似文献