全文获取类型
收费全文 | 374篇 |
免费 | 62篇 |
国内免费 | 1篇 |
出版年
2022年 | 2篇 |
2021年 | 4篇 |
2020年 | 2篇 |
2019年 | 3篇 |
2018年 | 3篇 |
2017年 | 5篇 |
2016年 | 6篇 |
2015年 | 11篇 |
2014年 | 17篇 |
2013年 | 19篇 |
2012年 | 30篇 |
2011年 | 25篇 |
2010年 | 19篇 |
2009年 | 23篇 |
2008年 | 21篇 |
2007年 | 11篇 |
2006年 | 17篇 |
2005年 | 23篇 |
2004年 | 14篇 |
2003年 | 13篇 |
2002年 | 21篇 |
2001年 | 13篇 |
2000年 | 16篇 |
1999年 | 8篇 |
1998年 | 10篇 |
1997年 | 5篇 |
1996年 | 2篇 |
1995年 | 3篇 |
1993年 | 3篇 |
1992年 | 9篇 |
1991年 | 5篇 |
1990年 | 7篇 |
1989年 | 5篇 |
1988年 | 7篇 |
1987年 | 5篇 |
1986年 | 4篇 |
1985年 | 4篇 |
1984年 | 4篇 |
1983年 | 5篇 |
1982年 | 2篇 |
1981年 | 4篇 |
1978年 | 2篇 |
1976年 | 2篇 |
1975年 | 2篇 |
1971年 | 3篇 |
1969年 | 1篇 |
1968年 | 10篇 |
1967年 | 1篇 |
1964年 | 1篇 |
1958年 | 1篇 |
排序方式: 共有437条查询结果,搜索用时 15 毫秒
101.
Transcriptome profile of human colorectal adenomas 总被引:2,自引:0,他引:2
102.
Karen E Sullam Benjamin ER Rubin Christopher M Dalton Susan S Kilham Alexander S Flecker Jacob A Russell 《The ISME journal》2015,9(7):1508-1522
Diverse microbial consortia profoundly influence animal biology, necessitating an understanding of microbiome variation in studies of animal adaptation. Yet, little is known about such variability among fish, in spite of their importance in aquatic ecosystems. The Trinidadian guppy, Poecilia reticulata, is an intriguing candidate to test microbiome-related hypotheses on the drivers and consequences of animal adaptation, given the recent parallel origins of a similar ecotype across streams. To assess the relationships between the microbiome and host adaptation, we used 16S rRNA amplicon sequencing to characterize gut bacteria of two guppy ecotypes with known divergence in diet, life history, physiology and morphology collected from low-predation (LP) and high-predation (HP) habitats in four Trinidadian streams. Guts were populated by several recurring, core bacteria that are related to other fish associates and rarely detected in the environment. Although gut communities of lab-reared guppies differed from those in the wild, microbiome divergence between ecotypes from the same stream was evident under identical rearing conditions, suggesting host genetic divergence can affect associations with gut bacteria. In the field, gut communities varied over time, across streams and between ecotypes in a stream-specific manner. This latter finding, along with PICRUSt predictions of metagenome function, argues against strong parallelism of the gut microbiome in association with LP ecotype evolution. Thus, bacteria cannot be invoked in facilitating the heightened reliance of LP guppies on lower-quality diets. We argue that the macroevolutionary microbiome convergence seen across animals with similar diets may be a signature of secondary microbial shifts arising some time after host-driven adaptation. 相似文献
103.
To characterize the importance of infection of epithelial cells for morbillivirus pathogenesis, we took advantage of the severe disease caused by canine distemper virus (CDV) in ferrets. To obtain a CDV that was unable to enter epithelial cells but retained the ability to enter immune cells, we transferred to its attachment (H) protein two mutations shown to interfere with the interaction of measles virus H with its epithelial receptor, human nectin-4. As expected for an epithelial receptor (EpR)-blind CDV, this virus infected dog and ferret epithelial cells inefficiently and did not cause cell fusion or syncytium formation. On the other hand, the EpR-blind CDV replicated in cells expressing canine signaling lymphocyte activation molecule (SLAM), the morbillivirus immune cell receptor, with similar kinetics to those of wild-type CDV. While ferrets infected with wild-type CDV died within 12 days after infection, after developing severe rash and fever, animals infected with the EpR-blind virus showed no clinical signs of disease. Nevertheless, both viruses spread rapidly and efficiently in immune cells, causing similar levels of leukopenia and inhibition of lymphocyte proliferation activity, two indicators of morbillivirus immunosuppression. Infection was documented for airway epithelia of ferrets infected with wild-type CDV but not for those of animals infected with the EpR-blind virus, and only animals infected with wild-type CDV shed virus. Thus, epithelial cell infection is necessary for clinical disease and efficient virus shedding but not for immunosuppression. 相似文献
104.
Chanakha K. Navaratnarajah Surendra Negi Werner Braun Roberto Cattaneo 《The Journal of biological chemistry》2012,287(46):38543-38551
The measles virus (MV) fusion apparatus consists of a fusion protein and an attachment protein named hemagglutinin (H). After receptor-binding through its cuboidal head, the H-protein transmits the fusion-triggering signal through its stalk to the fusion protein. However, the structural basis of signal transmission is unclear because only structures of H-heads without their stalk have been solved. On the other hand, the entire ectodomain structure of the hemagglutinin-neuraminidase protein of another Paramyxovirus revealed a four-helix bundle stalk. To probe the structure of the 95-residue MV H-stalk we individually substituted head-proximal residues (positions 103–153) with cysteine, and biochemically and functionally characterized the resultant proteins. Our results indicate that most residues in the central segment (positions 103–117) can be cross-linked by engineered disulfide bonds, and thus may be engaged in a tetrameric structure. While covalent tetramerization disrupts fusion triggering function, disulfide bond reduction restores it in most positions except Asp-113. The next stalk segment (residues 123–138) also has high propensity to form covalent tetramers, but since these cross-links have little or no effect on function, it can conduct the fusion-triggering signal while remaining in a stabilized tetrameric configuration. This segment may act as a spacer, maintaining H-heads at an optimal height. Finally, the head-proximal segment (residues 139–154) has very limited propensity to trap tetramers, suggesting bifurcation into two flexible linkers clamped by inter-subunit covalent links formed by natural Cys-139 and Cys-154. We discuss the modular structure of the MV H-stalk in the context of membrane fusion triggering and cell entry by Paramyxoviruses. 相似文献
105.
doi: 10.1111/j.1741‐2358.2011.00536.x Effect of ill‐fitting dentures on the swallowing duration in patients using polygraphy Background: Surface electromyography (SEMG) has been widely used in the recent years to study swallowing physiology, offering a valid and reliable tool for identifying normal swallowing. The goal of our study was to assess the contribution of denture fitness in the age‐related increase of swallowing duration. Methods: Twenty denture wearers and 20 dentate individuals were analysed using SEMG and a computerised kinesiography of mandibular movement. Three spontaneous saliva swallowings were recorded for each patient with both their old and new prostheses. Three spontaneous saliva swallowings were recorded for each dentate person in two different recording sessions. Results: Old prosthesis mean swallowing time was 1.84 (SD ± 0.85) seconds while the new well‐fitting prostheses needed a 1.28 (SD ± 0.55) (p = 0.0009) swallowing time. The difference in swallowing time was significant (p = 0.01) between dentate subjects and individuals wearing an old prosthesis. No significant difference was found between dentate subjects and the same prosthesis wearers when a new well‐fitting prosthesis was worn. Conclusion: Data presented in this work suggest that part of the increased duration of swallowing showed by elderly and healthy people is because of incorrect an dental prosthesis. Prolongation of swallowing duration in the elderly population could be reconsidered in the light of the quality of dental device worn by the aged population. 相似文献
106.
Curnis F Longhi R Crippa L Cattaneo A Dondossola E Bachi A Corti A 《The Journal of biological chemistry》2006,281(47):36466-36476
Isoaspartate formation in extracellular matrix proteins, by aspartate isomerization or asparagine deamidation, is generally viewed as a degradation reaction occurring in vivo during tissue aging. For instance, non-enzymatic isoaspartate formation at RGD-integrin binding sites causes loss of cell adhesion sites, which in turn can be enzymatically "repaired" to RGD by protein-l-isoAsp-O-methyltransferase. We show here that isoaspartate formation is also a mechanism for extracellular matrix activation. In particular, we show that deamidation of Asn263 at the Asn-Gly-Arg (NGR) site in fibronectin N-terminal region generates an alpha(v)beta3-integrin binding site containing the L-isoDGR sequence, which is enzymatically "deactivated" to DGR by protein-L-isoAsp-O-methyltransferase. Furthermore, rapid NGR-to-isoDGR sequence transition in fibronectin fragments generates alpha(v)beta3 antagonists (named "isonectins") that competitively bind RGD binding sites and inhibit endothelial cell adhesion, proliferation, and tumor growth. Time-dependent generation of isoDGR may represent a sort of molecular clock for activating latent integrin binding sites in proteins. 相似文献
107.
108.
Minuz P Fumagalli L Gaino S Tommasoli RM Degan M Cavallini C Lecchi A Cattaneo M Lechi Santonastaso C Berton G 《The Biochemical journal》2006,400(1):127-134
Signals ensuing from trimeric G-protein-coupled receptors synergize to induce platelet activation. At low doses, the thromboxane A2 analogue U46619 does not activate integrin alphaIIbbeta3 or trigger platelet aggregation, but it induces shape changes. In the present study, we addressed whether low doses of U46619 trigger tyrosine phosphorylation independently of integrin alphaIIbbeta3 activation and ADP secretion, and synergize with adrenaline (epinephrine) to induce aggregation in acetylsalicylic acid (aspirin)-treated platelets. Low doses of U46619 triggered tyrosine phosphorylation of different proteins, including FAK (focal adhesion kinase), Src and Syk, independently of signals ensuing from integrin alphaIIbbeta3 or ADP receptors engaged by secreted ADP. The G(12/13)-mediated Rho/Rho-kinase pathway was also increased by low doses of U46619; however, this pathway was not upstream of tyrosine phosphorylation, because this occurred in the presence of the Rho-kinase inhibitor Y-27632. Although low doses of U46619 or adrenaline alone were unable to trigger platelet aggregation and integrin alphaIIbbeta3 activation, the combination of the two stimuli effectively induced these responses. PP2, a tyrosine kinase inhibitor, and Y-27632 inhibited platelet activation induced by low doses of U46619 plus adrenaline and, when used in combination, totally suppressed this platelet response. In addition, the two inhibitors selectively blocked tyrosine kinases and the Rho/Rho-kinase pathway respectively. These findings suggest that both tyrosine phosphorylation and the Rho/Rho-kinase pathway are required to activate platelet aggregation via G(12/13) plus G(z) signalling. 相似文献
109.
Wang X Narayanan M Bruey JM Rigamonti D Cattaneo E Reed JC Friedlander RM 《Biochimica et biophysica acta》2006,1762(8):742-754
CARD only protein (Cop) was recently identified as a protein with significant homology with the CARD of caspase-1. We have conducted functional studies on Cop and report on its role as an inhibitor of cell death in a broad range of cell death paradigms. A notable exception in the ability of Cop to inhibit cell death pertains to its inability to inhibit ER stress-mediated cell death. Furthermore, in addition to the known interaction of Cop and caspase-1, we demonstrated a novel interaction of Cop with caspase-4. We propose that Cop's action to prevent TNF-alpha-induced cell death may operate independently of the mitochondrial death pathway. Furthermore, Cop overexpression inhibits Bid cleavage. In summary, Cop inhibition of cell death, at least to a certain extent, results from its interference with the activation of caspase-1 and caspase-4. Understanding the mechanistic details modulating caspase cell death pathways should provide important information for the development of therapies for diseases featuring aberrant caspase activation. Cop, as an inhibitor of an important apical caspase cell death axis, may provide a tool for modulating pathological cell death. 相似文献
110.