全文获取类型
收费全文 | 601篇 |
免费 | 65篇 |
出版年
2023年 | 3篇 |
2022年 | 12篇 |
2021年 | 23篇 |
2020年 | 5篇 |
2019年 | 11篇 |
2018年 | 13篇 |
2017年 | 17篇 |
2016年 | 23篇 |
2015年 | 41篇 |
2014年 | 53篇 |
2013年 | 56篇 |
2012年 | 65篇 |
2011年 | 46篇 |
2010年 | 32篇 |
2009年 | 28篇 |
2008年 | 34篇 |
2007年 | 33篇 |
2006年 | 35篇 |
2005年 | 30篇 |
2004年 | 23篇 |
2003年 | 24篇 |
2002年 | 11篇 |
2001年 | 3篇 |
2000年 | 2篇 |
1999年 | 4篇 |
1998年 | 4篇 |
1997年 | 3篇 |
1996年 | 4篇 |
1995年 | 1篇 |
1994年 | 1篇 |
1993年 | 4篇 |
1992年 | 2篇 |
1991年 | 2篇 |
1989年 | 2篇 |
1988年 | 2篇 |
1986年 | 2篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1982年 | 4篇 |
1977年 | 1篇 |
1973年 | 2篇 |
1968年 | 1篇 |
1963年 | 1篇 |
1962年 | 1篇 |
排序方式: 共有666条查询结果,搜索用时 15 毫秒
51.
Hanan Shamseldin Anas?M. Alazami Melanie Manning Amal Hashem Oana Caluseiu Brahim Tabarki Edward Esplin Susan Schelley A.?Micheil Innes Jillian?S. Parboosingh Ryan Lamont CareRare Canada Consortium Jacek Majewski Francois?P. Bernier Fowzan?S. Alkuraya 《American journal of human genetics》2015,97(6):862-868
Primary microcephaly is a developmental brain anomaly that results from defective proliferation of neuroprogenitors in the germinal periventricular zone. More than a dozen genes are known to be mutated in autosomal-recessive primary microcephaly in isolation or in association with a more generalized growth deficiency (microcephalic primordial dwarfism), but the genetic heterogeneity is probably more extensive. In a research protocol involving autozygome mapping and exome sequencing, we recruited a multiplex consanguineous family who is affected by severe microcephalic primordial dwarfism and tested negative on clinical exome sequencing. Two candidate autozygous intervals were identified, and the second round of exome sequencing revealed a single intronic variant therein (c.2885+8A>G [p.Ser963∗] in RTTN exon 23). RT-PCR confirmed that this change creates a cryptic splice donor and thus causes retention of the intervening 7 bp of the intron and leads to premature truncation. On the basis of this finding, we reanalyzed the exome file of a second consanguineous family affected by a similar phenotype and identified another homozygous change in RTTN as the likely causal mutation. Combined linkage analysis of the two families confirmed that RTTN maps to the only significant linkage peak. Finally, through international collaboration, a Canadian multiplex family affected by microcephalic primordial dwarfism and biallelic mutation of RTTN was identified. Our results expand the phenotype of RTTN-related disorders, hitherto limited to polymicrogyria, to include microcephalic primordial dwarfism with a complex brain phenotype involving simplified gyration. 相似文献
52.
53.
Yelton AP Thomas BC Simmons SL Wilmes P Zemla A Thelen MP Justice N Banfield JF 《PLoS computational biology》2011,7(10):e1002230
During microbial evolution, genome rearrangement increases with increasing sequence divergence. If the relationship between synteny and sequence divergence can be modeled, gene clusters in genomes of distantly related organisms exhibiting anomalous synteny can be identified and used to infer functional conservation. We applied the phylogenetic pairwise comparison method to establish and model a strong correlation between synteny and sequence divergence in all 634 available Archaeal and Bacterial genomes from the NCBI database and four newly assembled genomes of uncultivated Archaea from an acid mine drainage (AMD) community. In parallel, we established and modeled the trend between synteny and functional relatedness in the 118 genomes available in the STRING database. By combining these models, we developed a gene functional annotation method that weights evolutionary distance to estimate the probability of functional associations of syntenous proteins between genome pairs. The method was applied to the hypothetical proteins and poorly annotated genes in newly assembled acid mine drainage Archaeal genomes to add or improve gene annotations. This is the first method to assign possible functions to poorly annotated genes through quantification of the probability of gene functional relationships based on synteny at a significant evolutionary distance, and has the potential for broad application. 相似文献
54.
Characterization of the interaction of lassa fever virus with its cellular receptor alpha-dystroglycan
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The cellular receptor for the Old World arenaviruses Lassa fever virus (LFV) and lymphocytic choriomeningitis virus (LCMV) has recently been identified as alpha-dystroglycan (alpha-DG), a cell surface receptor that provides a molecular link between the extracellular matrix and the actin-based cytoskeleton. In the present study, we show that LFV binds to alpha-DG with high affinity in the low-nanomolar range. Recombinant vesicular stomatitis virus pseudotyped with LFV glycoprotein (GP) adopted the receptor binding characteristics of LFV and depended on alpha-DG for infection of cells. Mapping of the binding site of LFV on alpha-DG revealed that LFV binding required the same domains of alpha-DG that are involved in the binding of LCMV. Further, LFV was found to efficiently compete with laminin alpha1 and alpha2 chains for alpha-DG binding. Together with our previous studies on receptor binding of the prototypic immunosuppressive LCMV isolate LCMV clone 13, these findings indicate a high degree of conservation in the receptor binding characteristics between the highly human-pathogenic LFV and murine-immunosuppressive LCMV isolates. 相似文献
55.
Feruloyltyramine (FT) and 4-coumaroyltyramine (4CT) participate in the defense of plants against pathogens through their extracellular peroxidative polymerization, which is thought to reduce cell wall digestibility. Hydroxycinnamoyl-CoA:tyramine N-(hydroxycinnamoyl)transferase (THT; EC 2.3.1.110) and tyrosine decarboxylase (TYDC; EC 4.1.1.25) are purported to play key roles in the stress-induced regulation of tyramine-derived hydroxycinnamic acid amide (HCAAT) metabolism. Transgenic tobacco (Nicotiana tabacum cv. Xanthi) was engineered to constitutively express tobacco THT. A T1 plant over-expressing THT was crossbred with T1 tobacco expressing opium poppy TYDC2, to produce a T2 line with elevated THT and TYDC activities compared with wild type plants. The effects of an independent increase in TYDC or THT activity, or a dual increase in both TYDC and THT on the cellular pools of HCAAT pathway intermediates and the accumulation of soluble and cell wall-bound FT and 4CT were examined. Increased TYDC activity resulted in a larger cellular pool of tyramine and lower levels of L-phenylalanine in transgenic leaves. In contrast, elevated THT activity reduced tyramine levels. HCAAT levels were low in healthy leaves, but were induced in response to wounding and accumulated around wound sites. Similarly, endogenous THT and TYDC activities were wound-induced. The rate of wound-induced HCAAT accumulation was highest in transgenic plants with elevated THT and TYDC activities showing that both enzymes exert control over the flux of intermediates involved in HCAAT biosynthesis under some conditions. 相似文献
56.
Jillian?Johnston Robert?Chan Maria?Calderon-Segura Sarah?McFarlane Leon?W?BrowderEmail author 《BMC developmental biology》2005,5(1):20
Background
Apoptosis is a common and essential aspect of development. It is particularly prevalent in the central nervous system and during remodelling processes such as formation of the digits and in amphibian metamorphosis. Apoptosis, which is dependent upon a balance between pro- and anti-apoptotic factors, also enables the embryo to rid itself of cells damaged by gamma irradiation. In this study, the roles of the anti-apoptotic factor Bcl-xL in protecting cells from apoptosis were examined in Xenopus laevis embryos using transgenesis to overexpress the XR11 gene, which encodes Bcl-xL. The effects on developmental, thyroid hormone-induced and γ-radiation-induced apoptosis in embryos were examined in these transgenic animals. 相似文献57.
Pietrak BL Crouthamel MC Tugusheva K Lineberger JE Xu M DiMuzio JM Steele T Espeseth AS Stachel SJ Coburn CA Graham SL Vacca JP Shi XP Simon AJ Hazuda DJ Lai MT 《Analytical biochemistry》2005,342(1):144-151
The deposition of beta-amyloid peptides (A beta42 and A beta40) in neuritic plaques is one of the hallmarks of Alzheimer's disease (AD). A beta peptides are derived from sequential cleavage of amyloid precursor protein (APP) by beta- and gamma-secretases. BACE-1 has been shown to be the major beta-secretase and is a primary therapeutic target for AD. In this article, two novel assays for the characterization of BACE-1 inhibitors are reported. The first is a sensitive 96-well HPLC biochemical assay that uses a unique substrate containing an optimized peptide cleavage sequence, NFEV, spanning from the P2-P2' positions This substrate was processed by BACE-1 approximately 10 times more efficiently than was the widely used substrate containing the Swedish (NLDA) sequence. As a result, the concentration of the enzyme required for the assay can be as low as 100 pM, permitting the evaluation of inhibitors with subnanomolar potency. The assay has also been applied to related aspartyl proteases such as cathepsin D (Cat D) and BACE-2. The second assay is a homogeneous electrochemiluminescence assay for the evaluation of BACE-1 inhibition in cultured cells that assesses the level of secreted amyloid EV40_NF from HEK293T cells stably transfected with APP containing the novel NFEV sequence. To illustrate the use of these assays, the properties of a potent, cell-active BACE-1 inhibitor are described. 相似文献
58.
59.
IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4+CD25+ regulatory T cells 总被引:21,自引:0,他引:21
60.
Contribution of ebola virus glycoprotein, nucleoprotein, and VP24 to budding of VP40 virus-like particles
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
The VP40 matrix protein of Ebola virus buds from cells in the form of virus-like particles (VLPs) and plays a central role in virus assembly and budding. In this study, we utilized a functional budding assay and cotransfection experiments to examine the contributions of the glycoprotein (GP), nucleoprotein (NP), and VP24 of Ebola virus in facilitating release of VP40 VLPs. We demonstrate that VP24 alone does not affect VP40 VLP release, whereas NP and GP enhance release of VP40 VLPs, individually and to a greater degree in concert. We demonstrate further the following: (i). VP40 L domains are not required for GP-mediated enhancement of budding; (ii). the membrane-bound form of GP is necessary for enhancement of VP40 VLP release; (iii). NP appears to physically interact with VP40 as judged by detection of NP in VP40-containing VLPs; and (iv). the C-terminal 50 amino acids of NP may be important for interacting with and enhancing release of VP40 VLPs. These findings provide a more complete understanding of the role of VP40 and additional Ebola virus proteins during budding. 相似文献