全文获取类型
收费全文 | 747篇 |
免费 | 64篇 |
专业分类
811篇 |
出版年
2024年 | 1篇 |
2023年 | 6篇 |
2022年 | 13篇 |
2021年 | 28篇 |
2020年 | 19篇 |
2019年 | 20篇 |
2018年 | 12篇 |
2017年 | 19篇 |
2016年 | 27篇 |
2015年 | 49篇 |
2014年 | 48篇 |
2013年 | 57篇 |
2012年 | 63篇 |
2011年 | 55篇 |
2010年 | 26篇 |
2009年 | 28篇 |
2008年 | 39篇 |
2007年 | 30篇 |
2006年 | 41篇 |
2005年 | 47篇 |
2004年 | 35篇 |
2003年 | 35篇 |
2002年 | 32篇 |
2001年 | 7篇 |
2000年 | 7篇 |
1999年 | 13篇 |
1998年 | 4篇 |
1997年 | 3篇 |
1996年 | 5篇 |
1995年 | 3篇 |
1994年 | 7篇 |
1993年 | 3篇 |
1992年 | 1篇 |
1991年 | 4篇 |
1990年 | 5篇 |
1989年 | 2篇 |
1987年 | 1篇 |
1985年 | 1篇 |
1984年 | 1篇 |
1983年 | 1篇 |
1981年 | 2篇 |
1980年 | 4篇 |
1978年 | 1篇 |
1977年 | 1篇 |
1974年 | 3篇 |
1973年 | 1篇 |
1958年 | 1篇 |
排序方式: 共有811条查询结果,搜索用时 15 毫秒
91.
Crystal structure of human insulin‐regulated aminopeptidase with specificity for cyclic peptides 下载免费PDF全文
Stefan J. Hermans David B. Ascher Nancy C. Hancock Jessica K. Holien Belinda J. Michell Siew Yeen Chai Craig J. Morton Michael W. Parker 《Protein science : a publication of the Protein Society》2015,24(2):190-199
Insulin‐regulated aminopeptidase (IRAP or oxytocinase) is a membrane‐bound zinc‐metallopeptidase that cleaves neuroactive peptides in the brain and produces memory enhancing effects when inhibited. We have determined the crystal structure of human IRAP revealing a closed, four domain arrangement with a large, mostly buried cavity abutting the active site. The structure reveals that the GAMEN exopeptidase loop adopts a very different conformation from other aminopeptidases, thus explaining IRAP's unique specificity for cyclic peptides such as oxytocin and vasopressin. Computational docking of a series of IRAP‐specific cognitive enhancers into the crystal structure provides a molecular basis for their structure–activity relationships and demonstrates that the structure will be a powerful tool in the development of new classes of cognitive enhancers for treating a variety of memory disorders such as Alzheimer's disease. 相似文献
92.
Traditional microbiological methods of cultivation recover less than 1% of the total bacterial species, and the culturable portion of bacteria is not representative of the total phylogenetic diversity. Classical cultivation strategies are now known to supply excessive nutrients to a system and therefore select for fast-growing bacteria that are capable of colony or biofilm formation. New approaches to the cultivation of bacteria which rely on growth in dilute nutrient media or simulated environments are beginning to address this problem of selection. Here we describe a novel microcultivation method for soil bacteria that mimics natural conditions. Our soil slurry membrane system combines a polycarbonate membrane as a growth support and soil extract as the substrate. The result is abundant growth of uncharacterized bacteria as microcolonies. By combining microcultivation with fluorescent in situ hybridization, previously "unculturable" organisms belonging to cultivated and noncultivated divisions, including candidate division TM7, can be identified by fluorescence microscopy. Successful growth of soil bacteria as microcolonies confirmed that the missing culturable majority may have a growth strategy that is not observed when traditional cultivation indicators are used. 相似文献
93.
The oligomerization domain that is present at the C terminus of Ikaros-family proteins and the protein Trps-1 is important for the proper regulation of developmental processes such as hematopoiesis. Remarkably, this domain is predicted to contain two classical zinc fingers (ZnFs), domains normally associated with the recognition of nucleic acids. The preference for protein binding by these predicted ZnFs is not well-understood. We have used a range of methods to gain insight into the structure of this domain. Circular dichroism, UV-vis, and NMR experiments carried out on the C-terminal domain of Eos (EosC) revealed that the two putative ZnFs (C1 and C2) are separable, i.e., capable of folding independently in the presence of Zn(II). We next determined the structure of EosC2 using NMR spectroscopy, revealing that, although the overall fold of EosC2 is similar to other classical ZnFs, a number of differences exist. For example, the conformation of the C terminus of EosC2 appears to be flexible and may result in a major rearrangement of the zinc ligands. Finally, alanine-scanning mutagenesis was used to identify the residues that are involved in the homo- and hetero-oligomerization of Eos, and these results are discussed in the context of the structure of EosC. These studies provide the first structural insights into how EosC mediates protein-protein interactions and contributes to our understanding of why it does not exhibit high-affinity DNA binding. 相似文献
94.
Bullard B Ferguson C Minajeva A Leake MC Gautel M Labeit D Ding L Labeit S Horwitz J Leonard KR Linke WA 《The Journal of biological chemistry》2004,279(9):7917-7924
alphaB-crystallin, a major component of the vertebrate lens, is a chaperone belonging to the family of small heat shock proteins. These proteins form oligomers that bind to partially unfolded substrates and prevent denaturation. alphaB-crystallin in cardiac muscle binds to myofibrils under conditions of ischemia, and previous work has shown that the protein binds to titin in the I-band of cardiac fibers (Golenhofen, N., Arbeiter, A., Koob, R., and Drenckhahn, D. (2002) J. Mol. Cell. Cardiol. 34, 309-319). This part of titin extends as muscles are stretched and is made up of immunoglobulin-like modules and two extensible regions (N2B and PEVK) that have no well defined secondary structure. We have followed the position of alphaB-crystallin in stretched cardiac fibers relative to a known part of the titin sequence. alphaB-crystallin bound to a discrete region of the I-band that moved away from the Z-disc as sarcomeres were extended. In the physiological range of sarcomere lengths, alphaB-crystallin bound in the position of the N2B region of titin, but not to PEVK. In overstretched myofibrils, it was also in the Ig region between N2B and the Z-disc. Binding between alphaB-crystallin and N2B was confirmed using recombinant titin fragments. The Ig domains in an eight-domain fragment were stabilized by alphaB-crystallin; atomic force microscopy showed that higher stretching forces were needed to unfold the domains in the presence of the chaperone. Reversible association with alphaB-crystallin would protect I-band titin from stress liable to cause domain unfolding until conditions are favorable for refolding to the native state. 相似文献
95.
Background
Repeated blocks of genome sequence have been shown to be associated with genetic diversity and disease risk in humans, and with phenotypic diversity in model organisms and domestic animals. Reliable tests are desirable to determine whether individuals are carriers of copy number variants associated with disease risk in humans and livestock, or associated with economically important traits in livestock. In some cases, copy number variants affect the phenotype through a dosage effect but in other cases, allele combinations have non-additive effects. In the latter cases, it has been difficult to develop tests because assays typically return an estimate of the sum of the copy number counts on the maternally and paternally inherited chromosome segments, and this sum does not uniquely determine the allele configuration. In this study, we show that there is an old solution to this new problem: segregation analysis, which has been used for many years to infer alleles in pedigreed populations.Methods
Segregation analysis was used to estimate copy number alleles from assay data on simulated half-sib sheep populations. Copy number variation at the Agouti locus, known to be responsible for the recessive self-colour black phenotype, was used as a model for the simulation and an appropriate penetrance function was derived. The precision with which carriers and non-carriers of the undesirable single copy allele could be identified, was used to evaluate the method for various family sizes, assay strategies and assay accuracies.Results
Using relationship data and segregation analysis, the probabilities of carrying the copy number alleles responsible for black or white fleece were estimated with much greater precision than by analyzing assay results for animals individually. The proportion of lambs correctly identified as non-carriers of the undesirable allele increased from 7% when the lambs were analysed alone to 80% when the lambs were analysed in half-sib families.Conclusions
When a quantitative assay is used to estimate copy number alleles, segregation analysis of related individuals can greatly improve the precision of the estimates. Existing software for segregation analysis would require little if any change to accommodate the penetrance function for copy number assay data. 相似文献96.
Tregoning JS Yamaguchi Y Wang B Mihm D Harker JA Bushell ES Zheng M Liao G Peltz G Openshaw PJ 《Journal of immunology (Baltimore, Md. : 1950)》2010,185(9):5384-5391
Respiratory syncytial virus (RSV) is a major cause of respiratory morbidity, resulting in hospitalization for bronchiolitis in some infected infants that is associated with wheeze in later life. Genetic factors are known to affect the severity of the sequelae after RSV infection, but the complexity of the temporal and genetic effects makes it difficult to analyze this response in studies in man. Therefore, we developed a murine genetic model to analyze the sequelae occurring after RSV infection in early life. Haplotype-based genetic analysis of interstrain differences in severity identified the MHC as an important genetic determinant. This was confirmed by analysis of responses in congenic mice with different MHC haplotypes. We also found that susceptible strains had high CD8 levels during secondary infection. Analysis of first filial generation, second filial generation, and back-cross progeny produced by intercrossing resistant (H-2(k), C3H/HeN) and sensitive (H-2(b), BALB/c) strains indicated that susceptibility to sequelae after RSV infection was dominantly inherited but also segregated in a non-MHC-dependent manner. Thus, MHC haplotype and its effect on CD8 cell response is an important determinant of the outcome of neonatal RSV infection. 相似文献
97.
Mai-Prochnow A Webb JS Ferrari BC Kjelleberg S 《Applied and environmental microbiology》2006,72(8):5414-5420
In the ubiquitous marine bacterium Pseudoalteromonas tunicata, subpopulations of cells are killed by the production of an autocidal protein, AlpP, during biofilm development. Our data demonstrate an involvement of this process in two parameters, dispersal and phenotypic diversification, which are of importance for the ecology of this organism and for its survival within the environment. Cell death in P. tunicata wild-type biofilms led to a major reproducible dispersal event after 192 h of biofilm development. The dispersal was not observed with a DeltaAlpP mutant strain. Using flow cytometry and the fluorescent dye DiBAC4(3), we also show that P. tunicata wild-type cells that disperse from biofilms have enhanced metabolic activity compared to those cells that disperse from DeltaAlpP mutant biofilms, possibly due to nutrients released from dead cells. Furthermore, we report that there was considerable phenotypic variation among cells dispersing from wild-type biofilms but not from the DeltaAlpP mutant. Wild-type cells that dispersed from biofilms showed significantly increased variations in growth, motility, and biofilm formation, which may be important for successful colonization of new surfaces. These findings suggest for the first time that the autocidal events mediated by an antibacterial protein can confer ecological advantages to the species by generating a metabolically active and phenotypically diverse subpopulation of dispersal cells. 相似文献
98.
Endocytic systems within eukaryotic cells are a diverse set of intracellular transport pathways responsible for uptake, recycling, interaction with the exocytic system and degradation of molecules. Each of these pathways requires the interaction of distinct protein components that function in macromolecule sorting, control of transport rates and in membrane biogenesis. In the second of two articles on kinetoplastida endocytosis, the endocytic system in Trypanosoma brucei is considered as a model, and the molecules that control this system and the protein components of the endocytic pathway are discussed. We also consider novel mechanisms for sorting that have been proposed to operate in trypanosomes. 相似文献
99.
100.
Debbie Cavers Belinda Hacking Sara E. Erridge Marilyn Kendall Paul G. Morris Scott A. Murray 《CMAJ》2012,184(7):E373-E382