全文获取类型
收费全文 | 448篇 |
免费 | 27篇 |
国内免费 | 1篇 |
出版年
2022年 | 8篇 |
2021年 | 21篇 |
2020年 | 7篇 |
2019年 | 4篇 |
2018年 | 5篇 |
2017年 | 9篇 |
2016年 | 21篇 |
2015年 | 27篇 |
2014年 | 27篇 |
2013年 | 35篇 |
2012年 | 33篇 |
2011年 | 38篇 |
2010年 | 29篇 |
2009年 | 26篇 |
2008年 | 25篇 |
2007年 | 31篇 |
2006年 | 26篇 |
2005年 | 16篇 |
2004年 | 5篇 |
2003年 | 14篇 |
2002年 | 11篇 |
2000年 | 3篇 |
1999年 | 3篇 |
1998年 | 2篇 |
1997年 | 1篇 |
1996年 | 1篇 |
1995年 | 1篇 |
1994年 | 4篇 |
1992年 | 4篇 |
1991年 | 5篇 |
1990年 | 1篇 |
1989年 | 2篇 |
1987年 | 1篇 |
1986年 | 5篇 |
1985年 | 2篇 |
1984年 | 1篇 |
1981年 | 4篇 |
1978年 | 1篇 |
1974年 | 1篇 |
1973年 | 1篇 |
1972年 | 2篇 |
1969年 | 1篇 |
1966年 | 1篇 |
1963年 | 1篇 |
1962年 | 3篇 |
1961年 | 1篇 |
1960年 | 2篇 |
1952年 | 1篇 |
1947年 | 1篇 |
1926年 | 1篇 |
排序方式: 共有476条查询结果,搜索用时 980 毫秒
131.
Rangarajan ES Li Y Ajamian E Iannuzzi P Kernaghan SD Fraser ME Cygler M Matte A 《The Journal of biological chemistry》2005,280(52):42919-42928
Coenzyme A transferases are involved in a broad range of biochemical processes in both prokaryotes and eukaryotes, and exhibit a diverse range of substrate specificities. The YdiF protein from Escherichia coli O157:H7 is an acyl-CoA transferase of unknown physiological function, and belongs to a large sequence family of CoA transferases, present in bacteria to humans, which utilize oxoacids as acceptors. In vitro measurements showed that YdiF displays enzymatic activity with short-chain acyl-CoAs. The crystal structures of YdiF and its complex with CoA, the first co-crystal structure for any Family I CoA transferase, have been determined and refined at 1.9 and 2.0 A resolution, respectively. YdiF is organized into tetramers, with each monomer having an open alpha/beta structure characteristic of Family I CoA transferases. Co-crystallization of YdiF with a variety of CoA thioesters in the absence of acceptor carboxylic acid resulted in trapping a covalent gamma-glutamyl-CoA thioester intermediate. The CoA binds within a well defined pocket at the N- and C-terminal domain interface, but makes contact only with the C-terminal domain. The structure of the YdiF complex provides a basis for understanding the different catalytic steps in the reaction of Family I CoA transferases. 相似文献
132.
Eunice Strelzoff 《Molecular & general genetics : MGG》1962,93(2):287-300
Summary An investigation has been carried out dealing with the incorporation of BU into DNA ofE. coli 15 thy– under conditions of complete thymine deficiency. It was found that exponentially growing cells can increase their DNA 5-fold upon suspension in BU-supplemented medium. DNA increased in a linear fashion and followed the series ×, 2×, 3×, 4× where × is the amount of DNA initially present. If thy– cells were starved for 30 minutes before being provided with BU, DNA appeared to increase stepwise although the increase during each period of synthesis was equal only to the amount of DNA initially present. Paper chromatography revealed that BU totally replaced thymine in the newly-synthesized DNA. Equilibrium density gradient techniques and radioactive labeling made it possible to ascertain that the DNA in which BU fully replaced thymine was functional on the primary level, that of priming or taking iart in the synthesis of new DNA. Cellular inhibition as indicated by lethality was described and possible explanations for the inhibition resulting from incroporation of BU into DNA were discussed. 相似文献
133.
HLA-B63 presents HLA-B57/B58-restricted cytotoxic T-lymphocyte epitopes and is associated with low human immunodeficiency virus load 下载免费PDF全文
Frahm N Adams S Kiepiela P Linde CH Hewitt HS Lichterfeld M Sango K Brown NV Pae E Wurcel AG Altfeld M Feeney ME Allen TM Roach T St John MA Daar ES Rosenberg E Korber B Marincola F Walker BD Goulder PJ Brander C 《Journal of virology》2005,79(16):10218-10225
Several HLA class I alleles have been associated with slow human immunodeficiency virus (HIV) disease progression, supporting the important role HLA class I-restricted cytotoxic T lymphocytes (CTL) play in controlling HIV infection. HLA-B63, the serological marker for the closely related HLA-B*1516 and HLA-B*1517 alleles, shares the epitope binding motif of HLA-B57 and HLA-B58, two alleles that have been associated with slow HIV disease progression. We investigated whether HIV-infected individuals who express HLA-B63 generate CTL responses that are comparable in breadth and specificity to those of HLA-B57/58-positive subjects and whether HLA-B63-positive individuals would also present with lower viral set points than the general population. The data show that HLA-B63-positive individuals indeed mounted responses to previously identified HLA-B57-restricted epitopes as well as towards novel, HLA-B63-restricted CTL targets that, in turn, can be presented by HLA-B57 and HLA-B58. HLA-B63-positive subjects generated these responses early in acute HIV infection and were able to control HIV replication in the absence of antiretroviral treatment with a median viral load of 3,280 RNA copies/ml. The data support an important role of the presented epitope in mediating relative control of HIV replication and help to better define immune correlates of controlled HIV infection. 相似文献
134.
Wu HY Yuen EY Lu YF Matsushita M Matsui H Yan Z Tomizawa K 《The Journal of biological chemistry》2005,280(22):21588-21593
The N-methyl-D-aspartate (NMDA) receptor is a cation channel highly permeable to calcium and plays critical roles in governing normal and pathologic functions in neurons. Calcium entry through NMDA receptors (NMDARs) can lead to the activation of the Ca2+-dependent protease, calpain. Here we investigated the involvement of calpain in regulation of NMDAR channel function. After prolonged (5-min) treatment with NMDA or glutamate, the whole-cell NMDAR-mediated current was significantly reduced in both acutely dissociated and cultured cortical pyramidal neurons. The down-regulation of NMDAR current was blocked by bath application of selective calpain inhibitors. Intracellular injection of a specific calpain inhibitory peptide also eliminated the down-regulation of NMDAR current induced by prolonged NMDA treatment. In contrast, dynamin inhibitory peptide had no effect on the depression of NMDAR current, suggesting the lack of involvement of dynamin/clathrin-mediated NMDAR internalization in this process. Immunoblotting analysis showed that the NR2A and NR2B subunits of NMDARs were markedly degraded in cultured cortical neurons treated with glutamate, and the degradation of NR2 subunits was prevented by calpain inhibitors. Taken together, our results suggest that prolonged activation of NMDARs in neurons activates calpain, and activated calpain in turn down-regulates the function of NMDARs, which provides a neuroprotective mechanism against NMDAR overstimulation accompanying ischemia and stroke. 相似文献
135.
Protein structures can be encoded into binary sequences (Gabarro-Arpa et al., Comput Chem 2000;24:693-698) these are used to define a Hamming distance in conformational space: the distance between two different molecular conformations is the number of different bits in their sequences. Each bit in the sequence arises from a partition of conformational space in two halves. Thus, the information encoded in the binary sequences is also used to characterize the regions of conformational space visited by the system. We apply this distance and their associated geometric structures to the clustering and analysis of conformations sampled during a 4-ns molecular dynamics simulation of the HIV-1 integrase catalytic core. The cluster analysis of the simulation shows a division of the trajectory into two segments of 2.6 and 1.4 ns length, which are qualitatively different: the data points to the fact that equilibration is only reached at the end of the first segment. The Hamming distance is compared also to the r.m.s. deviation measure. The analysis of the cases studied so far shows that under the same conditions the two measures behave quite differently, and that the Hamming distance appears to be more robust than the r.m.s. deviation. 相似文献
136.
P Cottin J L Azanza P Vidalenc A Ducastaing C Valin A Ouali 《Reproduction, nutrition, development》1981,21(2):309-317
This paper describes the isolation, purification and properties of a specific inhibitor of calcium-activated neutral proteinase (CaANP) in rabbit skeletal muscle. The inhibitor was a thermo-acid-stable protein degraded by trypsin and chymotrypsin and seemed to contain two polypeptide chains with molecular weights of 70 000 and 13 000 daltons. Maximal inhibitory activity was obtained at neutral pH. High salt concentrations were needed to suppressinhibition. Inhibitor concentration had no effect on the optimal Ca++ ion levels for CaANP. These experiments also show that enzyme inhibitor association was instantaneous and did not need any incubation. 相似文献
137.
138.
Miguel A. Garcia-Knight Eunice Nduati Amin S. Hassan Faith Gambo Dennis Odera Timothy J. Etyang Nassim J. Hajj James Alexander Berkley Britta C. Urban Sarah L. Rowland-Jones 《PloS one》2015,10(11)
Implementation of successful prevention of mother-to-child transmission of HIV strategies has resulted in an increased population of HIV-exposed uninfected (HEU) infants. HEU infants have higher rates of morbidity and mortality than HIV-unexposed (HU) infants. Numerous factors may contribute to poor health in HEU infants including immunological alterations. The present study assessed T-cell phenotype and function in HEU infants with a focus on memory Th1 responses to vaccination. We compared cross-sectionally selected parameters at 3 and 12 months of age in HIV-exposed (n = 42) and HU (n = 28) Kenyan infants. We measured ex vivo activated and bulk memory CD4 and CD8 T-cells and regulatory T-cells by flow cytometry. In addition, we measured the magnitude, quality and memory phenotype of antigen-specific T-cell responses to Bacillus Calmette-Guerin and Tetanus Toxoid vaccine antigens, and the magnitude and quality of the T cell response following polyclonal stimulation with staphylococcal enterotoxin B. Finally, the influence of maternal disease markers on the immunological parameters measured was assessed in HEU infants. Few perturbations were detected in ex vivo T-cell subsets, though amongst HEU infants maternal HIV viral load positively correlated with CD8 T cell immune activation at 12 months. Conversely, we observed age-dependent differences in the magnitude and polyfunctionality of IL-2 and TNF-α responses to vaccine antigens particularly in Th1 cells. These changes mirrored those seen following polyclonal stimulation, where at 3 months, cytokine responses were higher in HEU infants compared to HU infants, and at 12 months, HEU infant cytokine responses were consistently lower than those seen in HU infants. Finally, reduced effector memory Th1 responses to vaccine antigens were observed in HEU infants at 3 and 12 months and higher central memory Th1 responses to M. tuberculosis antigens were observed at 3 months only. Long-term monitoring of vaccine efficacy and T-cell immunity in this vulnerable population is warranted. 相似文献
139.
Rodrigo?González-Barrios Ernesto?Soto-Reyes Ricardo?Quiroz-Baez Eunice?Fabián-Morales José?Díaz-Chávez Victor?del Castillo Julia?Mendoza Alejandro?López-Saavedra Clementina?Castro Luis?A?HerreraEmail author 《Cell division》2014,9(1):6
Background
Heterochromatin protein 1 (HP1) is important in the establishment, propagation, and maintenance of constitutive heterochromatin, especially at the pericentromeric region. HP1 might participate in recruiting and directing Mis12 to the centromere during interphase, and HP1 disruption or abrogation might lead to the loss of Mis12 incorporation into the kinetochore. Therefore, the centromere structure and kinetochore relaxation that are promoted in the absence of Mis12 could further induce chromosome instability (CIN) by reducing the capacity of the kinetochore to anchor microtubules. The aim of this study was to determine whether alterations in the localization of HP1 proteins induced by trichostatin A (TSA) modify Mis12 and Centromere Protein A (CENP-A) recruitment to the centromere and whether changes in the expression of HP1 proteins and H3K9 methylation at centromeric chromatin increase CIN in HCT116 and WI-38 cells.Methods
HCT116 and WI-38 cells were cultured and treated with TSA to evaluate CIN after 24 and 48 h of exposure. Immunofluorescence, Western blot, ChIP, and RT-PCR assays were performed in both cell lines to evaluate the localization and abundance of HP1α/β, Mis12, and CENP-A and to evaluate chromatin modifications during interphase and mitosis, as well as after 24 and 48 h of TSA treatment.Results
Our results show that the TSA-induced reduction in heterochromatic histone marks on centromeric chromatin reduced HP1 at the centromere in the non-tumoral WI-38 cells and that this reduction was associated with cell cycle arrest and CIN. However, in HCT116 cells, HP1 proteins, together with MIS12 and CENP-A, relocated to centromeric chromatin in response to TSA treatment, even after H3K9me3 depletion in the centromeric nucleosomes. The enrichment of HP1 and the loss of H3K9me3 were associated with an increase in CIN, suggesting a response mechanism at centromeric and pericentromeric chromatin that augments the presence of HP1 proteins in those regions, possibly ensuring chromosome segregation despite serious CIN. Our results provide new insight into the epigenetic landscape of centromeric chromatin and the role of HP1 proteins in CIN.140.
Radek Bukowski Nellie I. Hansen Marian Willinger Uma M. Reddy Corette B. Parker Halit Pinar Robert M. Silver Donald J. Dudley Barbara J. Stoll George R. Saade Matthew A. Koch Carol J. Rowland Hogue Michael W. Varner Deborah L. Conway Donald Coustan Robert L. Goldenberg for the Eunice Kennedy Shriver National Institute of Child Health Human Development Stillbirth Collaborative Research Network 《PLoS medicine》2014,11(4)