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61.
Li S Jiang J Zou J Qiao J Xue S Wei L Long R Wang L Castiblanco A White N Ngo J Mao H Liu ZR Yang JJ 《Journal of inorganic biochemistry》2012,107(1):111-118
Magnetic resonance imaging (MRI) has emerged as a leading diagnostic technique in clinical and preclinical settings. However, the application of MRI to assess specific disease markers for diagnosis and monitoring drug effect has been severely hampered by the lack of desired contrast agents with high relaxivities, and optimized in vivo retention time. We have reported the development of protein-based MRI contrast agents (ProCA1) by rational design of Gd3 + binding sites into a stable protein resulting in significantly increased longitudinal (r1) and transverse (r2) relaxivities compared to Gd-DTPA. Here, we report a further improvement of protein contrast agents ProCA1 for in vivo imaging by protein modification with various sizes of polyethylene glycol (PEG) chain. PEGylation results in significant increases of both r1 and r2 relaxivities (up to 200%), and these high relaxivities persist even at field strengths up to 9.4 T. In addition, our experimental results demonstrate that modified contrast agents have significant improvement of in vivo MR imaging and biocompatibilities including dose efficiency, protein solubility, blood retention time and decreased immunogenicity. Such improvement can be important to the animal imaging and pre-clinical research at high or ultra-high field where there is an urgent need for molecular imaging probes and optimized contrast agent. 相似文献
62.
A bidirectional relationship between obesity and depression may exist, though previous results are conflicting. The objectives of our study were to determine whether there is a bidirectional relationship between obesity and symptoms of depression in younger adults and whether this relationship varies with sociodemographic factors. We used data from 7,980 participants in the National Longitudinal Survey of Youth 1979 to examine whether baseline depressive symptoms (score ≥ 10 on a seven-item subscale of the CES-D) in 1992, predicted adjusted percent change in BMI between 1992 and 1994. We then examined whether obesity in 1992 predicted the development of symptoms of depression in 1994, after adjustment for confounders. We found that the presence of baseline depressive symptoms was not prospectively associated with increase in percent BMI, except in Hispanic women. Additionally, baseline obesity was not associated with higher risk of future symptoms of depression in the sample overall (adjusted risk ratio (RR) 1.20; 99% CI 0.91-1.60). However, in those of higher socioeconomic status, obesity was associated with almost double the risk of depressive symptoms compared to nonobese (highest income category: adjusted RR 1.97; 99% CI 1.14-3.40). We concluded that although obesity was not associated with risk of depression symptoms in the population overall, obesity was associated with an increased risk of developing depressive symptoms in those of higher socioeconomic status. Sociodemographic factors may be important modifiers of the relationship between obesity and depression. 相似文献
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65.
Natarajan S Kim JK Jung TK Doan TT Ngo HP Hong MK Kim S Tan VP Ahn SJ Lee SH Han Y Ahn YJ Kang LW 《Molecules and cells》2012,33(1):19-25
Xanthomonas oryzae pv. oryzae (Xoo) is a plant bacterial pathogen that causes bacterial blight (BB) disease, resulting in serious production losses of rice. The crystal structure of malonyl CoA-acyl carrier protein transacylase (XoMCAT), encoded by the gene fabD (Xoo0880) from Xoo, was determined at 2.3 Å resolution in complex with N-cyclohexyl-2-aminoethansulfonic acid. Malonyl CoA-acyl carrier protein transacylase transfers malonyl group from malonyl CoA to acyl carrier protein (ACP). The transacylation step is essential in fatty acid synthesis. Based on the rationale, XoMCAT has been considered as a target for antibacterial agents against BB. Protein-protein interaction between XoMCAT and ACP was also extensively investigated using computational docking, and the proposed model revealed that ACP bound to the cleft between two XoMCAT subdomains. 相似文献
66.
Quy A. Ngo Celia Baroux Daniela Guth?rl Peter Mozerov Margaret A. Collinge Venkatesan Sundaresan Ueli Grossniklaus 《The Plant cell》2012,24(10):4026-4043
The proper balance of parental genomic contributions to the fertilized embryo and endosperm is essential for their normal growth and development. The characterization of many gametophytic maternal effect (GME) mutants affecting seed development indicates that there are certain classes of genes with a predominant maternal contribution. We present a detailed analysis of the GME mutant zak ixik (zix), which displays delayed and arrested growth at the earliest stages of embryo and endosperm development. ZIX encodes an Armadillo repeat (Arm) protein highly conserved across eukaryotes. Expression studies revealed that ZIX manifests a GME through preferential maternal expression in the early embryo and endosperm. This parent-of-origin–dependent expression is regulated by neither the histone and DNA methylation nor the DNA demethylation pathways known to regulate some other GME mutants. The ZIX protein is localized in the cytoplasm and nucleus of cells in reproductive tissues and actively dividing root zones. The maternal ZIX allele is required for the maternal expression of MINISEED3. Collectively, our results reveal a reproductive function of plant Arm proteins in promoting early seed growth, which is achieved through a distinct GME of ZIX that involves mechanisms for maternal allele-specific expression that are independent of the well-established pathways. 相似文献
67.
Huang L Mao X Abdulaev NG Ngo T Liu W Ridge KD 《Protein expression and purification》2012,82(1):55-60
Desensitization of agonist-activated G protein-coupled receptors (GPCRs) requires phosphorylation followed by the binding of arrestin, a ~48 kDa soluble protein. While crystal structures for the inactive, 'basal' state of various arrestins are available, the conformation of 'activated' arrestin adopted upon interaction with activated GPCRs remains unknown. As a first step towards applying high-resolution structural methods to study arrestin conformation and dynamics, we have utilized the subtilisin prodomain/Profinity eXact? fusion-tag system for the high-level bacterial expression and one-step purification of wild-type visual arrestin (arrestin 1) as well as a mutant form (R175E) of the protein that binds to non-phosphorylated, light-activated rhodopsin (Rho?). The results show that both prodomain/Profinity eXact? fusion-tagged wild-type and R175E arrestins can be expressed to levels approaching 2-3 mg/l in Luria-Bertani media, and that the processed, tag-free mature forms can be purified to near homogeneity using a Bio-Scale? Mini Profinity eXact? cartridge on the Profinia? purification system. Functional analysis of R175E arrestin generated using this approach shows that it binds to non-phosphorylated rhodopsin in a light-dependent manner. These findings should facilitate the structure determination of this 'constitutively activated' state of arrestin 1 as well as the monitoring of conformational changes upon interaction with Rho?. 相似文献
68.
Kentsis A Reed C Rice KL Sanda T Rodig SJ Tholouli E Christie A Valk PJ Delwel R Ngo V Kutok JL Dahlberg SE Moreau LA Byers RJ Christensen JG Woude GV Licht JD Kung AL Staudt LM Look AT 《Nature medicine》2012,18(7):1118-1122
Although the treatment of acute myeloid leukemia (AML) has improved substantially in the past three decades, more than half of all patients develop disease that is refractory to intensive chemotherapy. Functional genomics approaches offer a means to discover specific molecules mediating the aberrant growth and survival of cancer cells. Thus, using a loss-of-function RNA interference genomic screen, we identified the aberrant expression of hepatocyte growth factor (HGF) as a crucial element in AML pathogenesis. We found HGF expression leading to autocrine activation of its receptor tyrosine kinase, MET, in nearly half of the AML cell lines and clinical samples we studied. Genetic depletion of HGF or MET potently inhibited the growth and survival of HGF-expressing AML cells. However, leukemic cells treated with the specific MET kinase inhibitor crizotinib developed resistance resulting from compensatory upregulation of HGF expression, leading to the restoration of MET signaling. In cases of AML where MET is coactivated with other tyrosine kinases, such as fibroblast growth factor receptor 1 (FGFR1), concomitant inhibition of FGFR1 and MET blocked this compensatory HGF upregulation, resulting in sustained logarithmic cell killing both in vitro and in xenograft models in vivo. Our results show a widespread dependence of AML cells on autocrine activation of MET, as well as the key role of compensatory upregulation of HGF expression in maintaining leukemogenic signaling by this receptor. We anticipate that these findings will lead to the design of additional strategies to block adaptive cellular responses that drive compensatory ligand expression as an essential component of the targeted inhibition of oncogenic receptors in human cancers. 相似文献
69.
Madiraju C Welsh K Cuddy MP Godoi PH Pass I Ngo T Vasile S Sergienko EA Diaz P Matsuzawa S Reed JC 《Journal of biomolecular screening》2012,17(2):163-176
UBC13 is a noncanonical ubiquitin conjugating enzyme (E2) that has been implicated in a variety of cellular signaling processes due to its ability to catalyze formation of lysine 63-linked polyubiquitin chains on various substrates. In particular, UBC13 is required for signaling by a variety of receptors important in immune regulation, making it a candidate target for inflammatory diseases. UBC13 is also critical for double-strand DNA repair and thus a potential radiosensitizer and chemosensitizer target for oncology. The authors developed a high-throughput screening (HTS) assay for UBC13 based on the method of time-resolved fluorescence resonance energy transfer (TR-FRET). The TR-FRET assay combines fluorochrome (Fl)-conjugated ubiquitin (fluorescence acceptor) with terbium (Tb)-conjugated ubiquitin (fluorescence donor), such that the assembly of mixed chains of Fl- and Tb-ubiquitin creates a robust TR-FRET signal. The authors defined conditions for optimized performance of the TR-FRET assay in both 384- and 1536-well formats. Chemical library screens (total 456 865 compounds) were conducted in high-throughput mode using various compound collections, affording superb Z' scores (typically >0.7) and thus validating the performance of the assays. Altogether, the HTS assays described here are suitable for large-scale, automated screening of chemical libraries in search of compounds with inhibitory activity against UBC13. 相似文献
70.
Nancy J. Ames Pawel Sulima Thoi Ngo Jennifer Barb Peter J. Munson Bruce J. Paster Thomas C. Hart 《PloS one》2012,7(10)