全文获取类型
收费全文 | 2276篇 |
免费 | 225篇 |
国内免费 | 1篇 |
出版年
2024年 | 3篇 |
2023年 | 30篇 |
2022年 | 90篇 |
2021年 | 156篇 |
2020年 | 66篇 |
2019年 | 81篇 |
2018年 | 79篇 |
2017年 | 66篇 |
2016年 | 110篇 |
2015年 | 174篇 |
2014年 | 156篇 |
2013年 | 168篇 |
2012年 | 208篇 |
2011年 | 174篇 |
2010年 | 102篇 |
2009年 | 100篇 |
2008年 | 129篇 |
2007年 | 92篇 |
2006年 | 96篇 |
2005年 | 72篇 |
2004年 | 55篇 |
2003年 | 49篇 |
2002年 | 57篇 |
2001年 | 16篇 |
2000年 | 11篇 |
1999年 | 7篇 |
1998年 | 12篇 |
1997年 | 7篇 |
1996年 | 6篇 |
1995年 | 6篇 |
1994年 | 11篇 |
1993年 | 6篇 |
1992年 | 5篇 |
1991年 | 5篇 |
1990年 | 3篇 |
1989年 | 4篇 |
1988年 | 6篇 |
1986年 | 4篇 |
1985年 | 4篇 |
1983年 | 3篇 |
1980年 | 3篇 |
1977年 | 4篇 |
1975年 | 3篇 |
1974年 | 4篇 |
1971年 | 3篇 |
1967年 | 3篇 |
1966年 | 3篇 |
1955年 | 4篇 |
1946年 | 2篇 |
1926年 | 2篇 |
排序方式: 共有2502条查询结果,搜索用时 15 毫秒
131.
Conserved and nonconserved features of the folding pathway of hisactophilin, a beta-trefoil protein 下载免费PDF全文
Liu C Gaspar JA Wong HJ Meiering EM 《Protein science : a publication of the Protein Society》2002,11(3):669-679
Based on previous studies of interleukin-1beta (IL-1beta) and both acidic and basic fibroblast growth factors (FGFs), it has been suggested that the folding of beta-trefoil proteins is intrinsically slow and may occur via the formation of essential intermediates. Using optical and NMR-detected quenched-flow hydrogen/deuterium exchange methods, we have measured the folding kinetics of hisactophilin, another beta-trefoil protein that has < 10% sequence identity and unrelated function to IL-1beta and FGFs. We find that hisactophilin can fold rapidly and with apparently two-state kinetics, except under the most stabilizing conditions investigated where there is evidence for formation of a folding intermediate. The hisactophilin intermediate has significant structural similarities to the IL-1beta intermediate that has been observed experimentally and predicted theoretically using a simple, topology-based folding model; however, it appears to be different from the folding intermediate observed experimentally for acidic FGF. For hisactophilin and acidic FGF, intermediates are much less prominent during folding than for IL-1beta. Considering the structures of the different beta-trefoil proteins, it appears that differences in nonconserved loops and hydrophobic interactions may play an important role in differential stabilization of the intermediates for these proteins. 相似文献
132.
133.
Chen YG Lui HM Lin SL Lee JM Ying SY 《Experimental biology and medicine (Maywood, N.J.)》2002,227(2):75-87
The aim of this review is to provide insight into the molecular mechanisms by which activin A modulates cell proliferation, apoptosis, and carcinogenesis in vitro and in vivo. Activin A, a member of the TGFbeta superfamily, has various effects on diverse biological systems, including cell growth inhibition in many cell types. However, the mechanism(s) by which activin exerts its inhibitory effects are not yet understood. This review highlights activin's effects on activin receptors and signaling pathway, modulation of activin signaling, and regulation of cell proliferation and apoptosis by activin. Based on the experiences of all the authors, we emphasized cell cycle inhibitors such as p16 and p21 and regulators of apoptosis such as p53 and members of the bcl-2 family. Aside from activin's inhibition of cell proliferation and enhancement of apoptosis, other newly developed methods for molecular studies of apoptosis by activin were briefly presented that support the role of activin as an inhibitor of carcinogenesis and cancer progression. These methods include subtractive hybridization based on covalent bonding, a simple and accurate means to determine molecular profile of as few as 20 cells based on an RNA-PCR approach, and a messenger RNA-antisense DNA interference phenomenon (D-RNAi), resulting in a long-term gene knockout effects. 相似文献
134.
Buchanan-Smith HM Shand C Morris K 《Journal of applied animal welfare science : JAAWS》2002,5(2):139-149
Determining appropriate feeding regimes has important welfare implications for captive primates. This study examined the preference of food bowl heights in 6 pairs of common marmosets (Callithrix jacchus) housed in a 2-tier cage system. Given that marmosets are arboreal and spend most of their time in the upper half of their cages, we predicted that the marmosets would prefer a food bowl positioned at the top of the cage over one positioned at the bottom. We further predicted that this would be more apparent for the marmosets housed in lower tier than upper tier cages. Given a choice regarding where to feed, marmosets did prefer the top bowl to the bottom bowl; however, when only 1 food bowl was presented, its position had no significant effect on the marmosets' feeding behavior. In addition, contrary to the prediction, there were few differences in the marmosets' feeding behavior in the upper and lower tier cages. Feeding the marmosets in a bowl at the bottom of their cage did not result in greater cage use. On the basis of this study, we recommend positioning captive marmosets' food bowls high in the cage. 相似文献
135.
Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3) 总被引:28,自引:0,他引:28
Feldmann J Callebaut I Raposo G Certain S Bacq D Dumont C Lambert N Ouachée-Chardin M Chedeville G Tamary H Minard-Colin V Vilmer E Blanche S Le Deist F Fischer A de Saint Basile G 《Cell》2003,115(4):461-473
Secretion of cytolytic granules content at the immunological synapse is a highly regulated process essential for lymphocyte cytotoxicity. This process requires the rapid transfer of perforin containing lytic granules to the target cell interface, followed by their docking and fusion with the plasma membrane. Defective cytotoxicity characterizes a genetically heterogeneous condition named familial hemophagocytic lymphohistiocytosis (FHL), which can be associated with perforin deficiency. The locus of a perforin (+) FHL subtype (FHL3), observed in 10 patients, was mapped to 17q25. This region contains hMunc13-4, a member of the Munc13 family of proteins involved in vesicle priming function. HMunc13-4 mutations were shown to cause FHL3. HMunc13-4 deficiency results in defective cytolytic granule exocytosis, despite polarization of the secretory granules and docking with the plasma membrane. Expressed tagged hMunc13-4 localizes with cytotoxic granules at the immunological synapse. HMunc13-4 is therefore essential for the priming step of cytolytic granules secretion preceding vesicle membrane fusion. 相似文献
136.
Cyclin E in complex with CDK2 is a positive regulator of the G1 to S phase transition of the cell cycle and is responsible for cells passing the restriction point, committing the cell to another round of cell division. Cyclin E is overexpressed and proteolytically cleaved into low molecular weight (LMW) isoforms in breast cancer cell lines and tumor tissues compared to normal cells and tissues. These alterations in cyclin E are linked to poor prognosis in breast cancer patients. In order to evaluate the biological effects of the LMW cyclin E, immortalized mammary epithelial cells, 76NE6, were stably transfected with each of the three cyclin E constructs. Our results reveal that the LMW forms of cyclin E (T1 and T2) are biologically functional, as their overexpression in the immortalized cells increases the ability of these cells to enter S and G2/M phase by 2 fold over full length or vector-alone transfected cells, concomitant with an increased rate of cell proliferation. In addition, these LMW isoforms are biochemically hyperactive, shown by their ability to phosphorylate substrates such as histone H1 4 fold more in cells transfected with T1 or T2 versus cells transfected with the full length form. These results suggest that overexpression of the LMW forms of cyclin E is mitogenic, stimulating the cells to progress through the cell cycle much more efficiently than the full length cyclin E. 相似文献
137.
The program of multicellular development in Dictyostelium discoideum culminates with the assembly of a rugged, environmentally resistant spore coat around each spore cell. After synthesis, the proteins that will constitute the coat are stored in prespore vesicles (PSVs) until an unknown developmental signal triggers the PSVs to move to the cell surface where they fuse with the plasma membrane and secrete their cargo by exocytosis. These events occur synchronously in 80% of the cells in each developing multicellular aggregate, and thus the system offers a unique opportunity to study the developmental regulation of protein secretion in situ. Proteomic analysis of purified PSVs identified many of the constituent proteins, which in turn has lead to novel hypotheses and new experimental avenues regarding the molecular mechanisms regulating secretion from the PSVs. 相似文献
138.
Holzmann M Habura A Giles H Bowser SS Pawlowski J 《The Journal of eukaryotic microbiology》2003,50(2):135-139
Sediment-dwelling protists are among the most abundant meiobenthic organisms, ubiquitous in all types of aquatic ecosystems. Yet, because their isolation and identification are difficult, their diversity remains largely unknown. In the present work, we applied molecular methods to examine the diversity of freshwater Foraminifera, a group of granuloreticulosan protists largely neglected until now. By using specific PCR primers, we detected the presence of Foraminifera in all sediment samples examined. Phylogenetic analysis of amplified SSU rDNA sequences revealed two distinct groups of freshwater foraminiferans. All obtained sequences branched within monothalamous (single-chambered), marine Foraminifera, suggesting a repeated colonization of freshwater environments. The results of our study challenge the traditional view of Foraminifera as essentially marine organisms, and provide a conceptual framework for charting the molecular diversity of freshwater granuloreticulosan protists. 相似文献
139.
Neuropathology of human Alzheimer disease after immunization with amyloid-beta peptide: a case report 总被引:25,自引:0,他引:25
Amyloid-beta peptide (Abeta) has a key role in the pathogenesis of Alzheimer disease (AD). Immunization with Abeta in a transgenic mouse model of AD reduces both age-related accumulation of Abeta in the brain and associated cognitive impairment. Here we present the first analysis of human neuropathology after immunization with Abeta (AN-1792). Comparison with unimmunized cases of AD (n = 7) revealed the following unusual features in the immunized case, despite diagnostic neuropathological features of AD: (i) there were extensive areas of neocortex with very few Abeta plaques; (ii) those areas of cortex that were devoid of Abeta plaques contained densities of tangles, neuropil threads and cerebral amyloid angiopathy (CAA) similar to unimmunized AD, but lacked plaque-associated dystrophic neurites and astrocyte clusters; (iii) in some regions devoid of plaques, Abeta-immunoreactivity was associated with microglia; (iv) T-lymphocyte meningoencephalitis was present; and (v) cerebral white matter showed infiltration by macrophages. Findings (i)-(iii) strongly resemble the changes seen after Abeta immunotherapy in mouse models of AD and suggest that the immune response generated against the peptide elicited clearance of Abeta plaques in this patient. The T-lymphocyte meningoencephalitis is likely to correspond to the side effect seen in some other patients who received AN-1792 (refs. 7-9). 相似文献
140.
McKinley J Buchanan-Smith HM Bassett L Morris K 《Journal of applied animal welfare science : JAAWS》2003,6(3):209-220
The first author trained 12 laboratory-housed common marmosets (Callithrix jacchus) in pairs to assess the practicality of positive reinforcement training as a technique in the management of these nonhuman animals. Behaviors taught were (a) target training to allow in homecage weighing and (b) providing urine samples. Between 2 to 13, 10-minute training sessions established desired behaviors. Training aggressive animals only after they had been fed eliminated aggression during training. Trained animals proved extremely reliable, and data collection using trained animals was considerably faster than collection using current laboratory techniques. The results suggest that positive reinforcement training is a practical option in the management of laboratory-housed marmosets. 相似文献