全文获取类型
收费全文 | 2857篇 |
免费 | 310篇 |
国内免费 | 4篇 |
出版年
2023年 | 20篇 |
2022年 | 48篇 |
2021年 | 70篇 |
2020年 | 45篇 |
2019年 | 51篇 |
2018年 | 70篇 |
2017年 | 67篇 |
2016年 | 94篇 |
2015年 | 175篇 |
2014年 | 175篇 |
2013年 | 218篇 |
2012年 | 244篇 |
2011年 | 225篇 |
2010年 | 145篇 |
2009年 | 119篇 |
2008年 | 152篇 |
2007年 | 135篇 |
2006年 | 135篇 |
2005年 | 135篇 |
2004年 | 129篇 |
2003年 | 114篇 |
2002年 | 86篇 |
2001年 | 37篇 |
2000年 | 56篇 |
1999年 | 32篇 |
1998年 | 23篇 |
1997年 | 22篇 |
1996年 | 18篇 |
1995年 | 21篇 |
1994年 | 13篇 |
1993年 | 19篇 |
1992年 | 18篇 |
1991年 | 26篇 |
1990年 | 16篇 |
1989年 | 25篇 |
1988年 | 20篇 |
1987年 | 16篇 |
1986年 | 10篇 |
1985年 | 20篇 |
1984年 | 12篇 |
1983年 | 14篇 |
1982年 | 10篇 |
1981年 | 13篇 |
1980年 | 6篇 |
1979年 | 10篇 |
1978年 | 13篇 |
1976年 | 6篇 |
1975年 | 5篇 |
1973年 | 6篇 |
1971年 | 5篇 |
排序方式: 共有3171条查询结果,搜索用时 15 毫秒
141.
Two inhibitors, aviglycine and propargylglycine, were tested for their ability to suppress methionine synthesis thus inhibit
conidial germination and mycelial growth of Czapek-Dox liquid medium grown Fusarium oxysporum f. sp. luffae
μM. The linear inhibition range for mycelial growth was about 7.6–762.9 μM. Although aviglycine did not completely inhibit both conidial germination and mycelial growth, it showed significant inhibitory
effect at 1.5 μM. The inhibition range for propargylglycine against conidial germination and mycelial growth were from 0.08 to 8841 μM and from 0.8 to 884.1 μM, respectively. Propargylglycine inhibited conidial germination and mycelial growth at a concentration of 8841 μM. The EC50 values of aviglycine were 1 μM for conidial growth and 122 μM for mycelial growth, and the EC50 values of propargylglycine were 47.7 μM for conidial growth and 55.6 μM for mycelial growth. Supplement of methionine released inhibition of aviglycine or propargylglycine to conidial germination.
In addition, a mixture of aviglycine (1.5 μM) and propargylglycine (8841 μM) showed additive inhibitive effect than applied alone on 10 isolates. From these results, both aviglycine and propargylglycine
exhibited inhibitory activity, and suggest that they can provide potential tools to design novel fungicide against fungal
pathogens. 相似文献
142.
Taxol is extensively used clinically for chemotherapy of patients with ovarian, breast, and lung cancer. Although taxol induces apoptosis of cancer cells, its exact mechanism of action is not yet known. To determine the mechanism of action of taxol in ovarian cancer, we tested the effects of the drug, on the human ovarian carcinoma cell line, SKOV3. We observed that taxol-induced apoptosis of these cells by phosphatidylserine (PS) externalization and DNA fragmentation. While treatment of cells with taxol resulted in bcl-2 phosphorylation and mitochondrial depolarization, cytochrome c was not released and pro-caspase-3 was not activated. Treatment of SKOV3 cells with taxol, however, resulted in the translocation of AIF from the mitochondria to the nucleus via the cytosol. Taken together, these findings suggest that in SKOV3 cells, taxol induces caspase-independent AIF-dependent apoptosis. 相似文献
143.
Park IY Eidsness MK Lin IJ Gebel EB Youn B Harley JL Machonkin TE Frederick RO Markley JL Smith ET Ichiye T Kang C 《Proteins》2004,57(3):618-625
Understanding the structural origins of differences in reduction potentials is crucial to understanding how various electron transfer proteins modulate their reduction potentials and how they evolve for diverse functional roles. Here, the high-resolution structures of several Clostridium pasteurianum rubredoxin (Cp Rd) variants with changes in the vicinity of the redox site are reported in order to increase this understanding. Our crystal structures of [V44L] (at 1.8 A resolution), [V44A] (1.6 A), [V44G] (2.0 A) and [V44A, G45P] (1.5 A) Rd (all in their oxidized states) show that there is a gradual decrease in the distance between Fe and the amide nitrogen of residue 44 upon reduction in the size of the side chain of residue 44; the decrease occurs from leucine to valine, alanine or glycine and is accompanied by a gradual increase in their reduction potentials. Mutation of Cp Rd at position 44 also changes the hydrogen-bond distance between the amide nitrogen of residue 44 and the sulfur of cysteine 42 in a size-dependent manner. Our results suggest that residue 44 is an important determinant of Rd reduction potential in a manner dictated by side-chain size. Along with the electric dipole moment of the 43-44 peptide bond and the 44-42 NH--S type hydrogen bond, a modulation mechanism for solvent accessibility through residue 41 might regulate the redox reaction of the Rds. 相似文献
144.
Amegbey G Chang Z Stothard P Yee A Arrowsmith C Wishart DS 《Journal of biomolecular NMR》2004,30(4):459-460
145.
Il?Yeong?Park Buhyun?Youn Jill?L.?Harley Marly?K.?Eidsness Eugene?Smith Toshiko?Ichiye ChulHee?KangEmail author 《Journal of biological inorganic chemistry》2004,9(4):423-428
Rubredoxin is a small iron-sulfur (FeS4) protein involved in oxidation–reduction reactions. The side chain of Leu41 near the iron-sulfur center has two conformations, which we suggested previously serve as a gate for a water molecule during the electron transfer process. To establish the role of residue 41 in electron transfer, an [L41A] mutant of Clostridium pasteurianum rubredoxin was constructed and crystallized in both oxidation states. Despite the lack of the gating side chain in this protein, the structure of the reduced [L41A] rubredoxin reveals a specific water molecule in the same position as observed in the reduced wild-type rubredoxin. In contrast, both the wild-type and [L41A] rubredoxins in the oxidized state do not have water molecules in this location. The reduction potential of the [L41A] variant was ~50 mV more positive than wild-type. Based on these observations, it is proposed that the site around the S of Cys9 serves as a port for an electron acceptor. Lastly, the Fe–S distances of the reduced rubredoxin are expanded, while the hydrogen bonds between S of the cysteines and the backbone amide nitrogens are shortened compared to its oxidized counterpart. This small structural perturbation in the Fe(II)/Fe(III) transition is closely related to the small energy difference which is important in an effective electron transfer agent. 相似文献
146.
Bettoun DJ Lu J Khalifa B Yee Y Chin WW Nagpal S 《The Journal of steroid biochemistry and molecular biology》2004,(1-5):195-198
We have recently shown that in colon cancer cells, Vitamin D receptor (VDR) interacts with the catalytic subunit of Ser/Thr protein phosphatases, PP1c and PP2Ac, and induces their enzymatic activity in a ligand-dependent manner. The VDR-PP1c and VDR-PP2Ac interactions were ligand independent in vivo, and 1,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3))-mediated increase in VDR-associated phosphatase activity resulted in dephosphorylation and inactivation of p70S6 kinase in colon cancer cells. Here, we demonstrate that in myeloid leukemia cells, 1,25(OH)(2)D(3) treatment increased the Thr389 phosphorylation of p70S6 kinase. Accordingly, 1,25(OH)(2)D(3) decreased VDR-associated Ser/Thr protein phosphatase activity by dissociating VDR-PP1c and VDR-PP2Ac interactions. Further, 1,25(OH)(2)D(3) increased the association between VDR and Thr389 phosphorylated p70S6 kinase. Finally, by using non-secosteroidal VDR ligands, we demonstrate a separation between transactivation and p70S6 kinase phosphorylation activities of VDR and show pharmacologically that p70S6 kinase phosphorylation correlates with HL-60 cell differentiation. 相似文献
147.
Although methylation-specific PCR (MSP) is a sensitive technique in the detection of DNA hypermethylation, it is not quantitative. Here we described a modified PCR protocol to quantify methylated SOCS-1 gene by real time MSP using SYBR green, which involves an additional PCR step after the 72 degrees C extension step. This modified protocol is also useful in the quantitative detection of methylated SOCS-1 gene in serum samples of gastric cancer patients. 相似文献
148.
Hu YJ Dolan ME Bae R Yee H Roy M Glickman R Kiremidjian-Schumacher L Diamond AM 《Biological trace element research》2004,101(2):97-106
Glutathione peroxidase is a selenium-containing, antioxidant enzyme previously implicated in the risk and development of lung
and breast cancer, in part the result of allelic loss at the GPx-1 locus. This study examined allelic loss at the same locus in squamous cell carcinomas of the head and neck. The frequency
of a polymorphism at codon 198 resulting in either a leucine or a proline at that position was surveyed by comparing 133 DNA
samples obtained from head and neck tumors and 517 samples obtained from cancer-free individuals. Tumor DNAs exhibited fewer
pro/leu heterozygotes as compared to DNA obtained from the cancer-free population. Fewer GPx-1 heterozygotes were verified by determining the frequency of highly polymorphic alanine repeat sequences in the same gene.
The analysis revealed an approximately 42% reduction in heterozygosity in the DNA from the tumor samples. In order to assess
loss of heterozygosity (LOH) at the GPx-1 locus, DNA was genotyped from peripheral lymphocytes, tumor tissue, and microscopically normal tissues adjacent to the tumor,
derived from the same patients. These studies indicated LOH at the GPx-1 locus in each of the three tumor/normal tissues sample sets examined. Furthermore, LOH in the microscopically normal tissues
at the tumor margin occurred in two of the three sample sets examined. These data implicate GPx-1 in the development of squamous cell carcinoma the head and neck and suggest that allelic loss of this gene, or one tightly
linked to it, is an early event in the development of this type of malignancy.
Author to whom all correspondence and reprint requests should be addressed. These authors contributed equally to this work. 相似文献
149.
Wong KY Chuan YC Aggarwal A Tham L Kong WM Tan P 《Journal of bioinformatics and computational biology》2004,2(3):569-587
Amplified Fragment Length Polymorphism (AFLP) screening is a genome-wide genotyping strategy that has been widely used in plants and bacteria, but little has been reported concerning its use in humans. We investigated if the AFLP procedure could be coupled with high-throughput capillary electrophoresis (CE) for use in tumor diagnosis and classification. Using CE-AFLP, a series of molecular 'fingerprints' were generated for a set of gastric tumor and normal genomic DNA samples. The CE-AFLP procedure was qualitatively and quantitatively robust, and a variety of clustering tools were used to identify a specific DNA marker 'pattern' of 20 features that classified the tumor and normal samples to reasonable degrees of accuracy (Sensitivity 95%, Specificity 80%). The CE-AFLP-based approach also correctly classified 16 tumor samples, which in a previous study had exhibited no detectable genomic aberrations by comparative genome hybridization (CGH). This is the first reported application of CE-AFLP screening in tumor diagnosis. As the procedure is relatively inexpensive and requires minimal prior sequence knowledge and biological material, we suggest that CE-AFLP-based protocols may represent a promising new approach for DNA-based cancer screening and diagnosis. 相似文献
150.
Lowe DB Magnuson S Qi N Campbell AM Cook J Hong Z Wang M Rodriguez M Achebe F Kluender H Wong WC Bullock WH Salhanick AI Witman-Jones T Bowling ME Keiper C Clairmont KB 《Bioorganic & medicinal chemistry letters》2004,14(12):3155-3159
A series of (5-(2H)-isoxazolonyl) ureas were developed as nanomolar inhibitors of hormone-sensitive lipase, an enzyme of potential importance in the treatment of diabetes. 相似文献