全文获取类型
收费全文 | 21386篇 |
免费 | 1500篇 |
国内免费 | 28篇 |
出版年
2023年 | 57篇 |
2022年 | 228篇 |
2021年 | 414篇 |
2020年 | 249篇 |
2019年 | 312篇 |
2018年 | 531篇 |
2017年 | 394篇 |
2016年 | 684篇 |
2015年 | 1131篇 |
2014年 | 1229篇 |
2013年 | 1398篇 |
2012年 | 1834篇 |
2011年 | 1714篇 |
2010年 | 1101篇 |
2009年 | 917篇 |
2008年 | 1360篇 |
2007年 | 1189篇 |
2006年 | 1063篇 |
2005年 | 980篇 |
2004年 | 967篇 |
2003年 | 781篇 |
2002年 | 785篇 |
2001年 | 627篇 |
2000年 | 633篇 |
1999年 | 423篇 |
1998年 | 168篇 |
1997年 | 129篇 |
1996年 | 120篇 |
1995年 | 87篇 |
1994年 | 82篇 |
1993年 | 69篇 |
1992年 | 158篇 |
1991年 | 125篇 |
1990年 | 88篇 |
1989年 | 103篇 |
1988年 | 71篇 |
1987年 | 65篇 |
1986年 | 69篇 |
1985年 | 53篇 |
1984年 | 47篇 |
1983年 | 37篇 |
1982年 | 27篇 |
1981年 | 24篇 |
1978年 | 28篇 |
1977年 | 23篇 |
1976年 | 32篇 |
1975年 | 29篇 |
1973年 | 33篇 |
1971年 | 23篇 |
1969年 | 24篇 |
排序方式: 共有10000条查询结果,搜索用时 15 毫秒
931.
932.
Structural mechanism for inactivation and activation of CAD/DFF40 in the apoptotic pathway 总被引:6,自引:0,他引:6
CAD/DFF40 is responsible for the degradation of chromosomal DNA into nucleosomal fragments and subsequent chromatin condensation during apoptosis. It exists as an inactive complex with its inhibitor ICAD/DFF45 in proliferating cells but becomes activated upon cleavage of ICAD/DFF45 into three domains by caspases in dying cells. The molecular mechanism underlying the control and activation of CAD/DFF40 was unknown. Here, the crystal structure of activated CAD/DFF40 reveals that it is a pair of molecular scissors with a deep active-site crevice that appears ideal for distinguishing internucleosomal DNA from nucleosomal DNA. Ensuing studies show that ICAD/DFF45 sequesters the nonfunctional CAD/DFF40 monomer and is also able to disassemble the functional CAD/DFF40 dimer. This capacity requires the involvement of the middle domain of ICAD/DFF45, which by itself cannot remain bound to CAD/DFF40 due to low binding affinity for the enzyme. Thus, the consequence of the caspase-cleavage of ICAD/DFF45 is a self-assembly of CAD/DFF40 into the active dimer. 相似文献
933.
Park S Mazina O Kitagawa A Wong P Matsumura F 《Journal of biochemical and molecular toxicology》2004,18(6):322-331
One of the proposed mechanisms of carcinogenic action of TCDD (=dioxin) on breast cells is that it causes significant inhibition of proper differentiation of mammary duct epithelial cells and thereby increases the number of terminal end buds, which are susceptible to other carcinogens (Fenton et al., Toxicol Sci 2002;67:63-74; Brown et al., Carcinogenesis 1998; 19:1623-1629; Lamartiniere, J Mammary Gland Biol Neoplasia 2002;7:67-76). To address this topic, we selected MCF10A, a line of immortalized normal human breast epithelial cells as an in vitro model. An initial effort was made to optimize the cultural condition of MCF10A cells to promote the cell differentiation effect of insulin. Under this condition, TCDD clearly antagonized the action of insulin only in the presence of cholera toxin that is known to promote the differentiation of normal human breast epithelial cells. To test the hypothesis that TCDD-induced c-Src kinase activation is casually related to this compound's antagonistic action against insulin, we treated MCF10A cells with two c-Src blocking agents, an anti-Src antisense oligonucleotides blocker and a known specific inhibitor of c-Src kinase, PP-2 and studied the effect of insulin and TCDD on cell proliferation. The results showed that, in cells treated with either of these two c-Src blocking agents, the antagonistic effect of TCDD disappeared. It was also found that agents which specifically block the activation of ERK could also abrogate the action of TCDD to suppress insulin signaling. Together, these results indicate that the mechanism of the antagonistic action of TCDD on insulin signaling is mainly mediated through c-Src signaling through activation of ERK. 相似文献
934.
935.
Kim SU Lee KM Park SK Yoo KY Noh DY Choe KJ Ahn SH Hirvonen A Kang D 《Journal of biochemistry and molecular biology》2004,37(5):582-585
To evaluate the potential association between the GSTP1 genotype and the development of breast cancer, a hospital based case-control study was conducted on Korean women. The study population consisted of 171 histologically confirmed incident breast cancer cases and 171 age-matched controls with no present or previous history of cancer. PCR-RFLP was used for the GSTP1 genotyping and statistical evaluations were performed using an unconditional logistic regression model. Postmenopausal women with the GSTP1 Val allele were found to have a reduced risk of breast cancer (OR = 0.3, 95 % CI = 0.10-0.74). A significant interaction was observed between the GSTP1 genotype and alcohol consumption (p for interaction = 0.01); compared with never-drinking women with Ile/Ile genotype, ever-drinking women with the GSTP1 Val allele had almost a three-fold risk of breast cancer (OR = 2.9, 95 % CI = 1.05-7.85), whereas never-drinking women with Val allele had half this risk (OR = 0.5, 95 % CI = 0.27-0.93). Our findings suggest that the GSTP1 polymorphism influences individual susceptibility to breast cancer in the Korean women and this effect may be modified by alcohol consumption. 相似文献
936.
Kim SH Lee DG Yoo JH Choi SM Choi JH Shin WS Lee K Yong D Lee WG Youn BS Kang MW 《Journal of microbiology (Seoul, Korea)》2004,42(2):143-146
Vancomycin-resistant Enterococcus faecium (VREFM) is becoming a threatening pathogen. We identified a gene called DD1.5K by differential display-PCR, which was preferentially expressed in the bloodstream isolates of VREFM. Due to its amino acid similarity to transfer complex protein, trsE, and tissue-specific expression, this gene may be involved in virulence of VREFM. 相似文献
937.
Lee J Nam S Hwang SB Hong M Kwon JY Joeng KS Im SH Shim J Park MC 《Journal of biochemistry and molecular biology》2004,37(1):107-113
Since the completion of the genome project of the nematode C. elegans in 1998, functional genomic approaches have been applied to elucidate the gene and protein networks in this model organism. The recent completion of the whole genome of C. briggsae, a close sister species of C. elegans, now makes it possible to employ the comparative genomic approaches for identifying regulatory mechanisms that are conserved in these species and to make more precise annotation of the predicted genes. RNA interference (RNAi) screenings in C. elegans have been performed to screen the whole genome for the genes whose mutations give rise to specific phenotypes of interest. RNAi screens can also be used to identify genes that act genetically together with a gene of interest. Microarray experiments have been very useful in identifying genes that exhibit co-regulated expression profiles in given genetic or environmental conditions. Proteomic approaches also can be applied to the nematode, just as in other species whose genomes are known. With all these functional genomic tools, genetics will still remain an important tool for gene function studies in the post genome era. New breakthroughs in C. elegans biology, such as establishing a feasible gene knockout method, immortalized cell lines, or identifying viruses that can be used as vectors for introducing exogenous gene constructs into the worms, will augment the usage of this small organism for genome-wide biology. 相似文献
938.
A halophilic bacterium was isolated from fermented seafood. The 16S rDNA sequence identity between the isolate and Halomonas subglaciescola AJ306801 was above 95%. The isolate that did not grow in the condition without NaCl or in the condition with other sodium (Na+) or chloride ions (Cl-) instead of NaCl was named H. subglaciescola DH-1. Two mutants capable of growing without NaCl were obtained by random mutagenesis, of which their total soluble protein profiles were compared with those of the wild type by two-dimensional electrophoresis. The external compatible solutes (betaine and choline) and cell extract of the wild type did not function as osmoprotectants, and these parameters within the mutants did not enhance their growth in the saline environment. In the proton translocation test, rapid acidification of the reactant was not detected for the wild type, but it was detected for the mutant in the condition without NaCl. From these results, we derived the hypothesis that NaCl may be absolutely required for the energy metabolism of H. subglaciescola DH-1 but not for its osmoregulation, and the mutants may have another modified proton translocation system that is independent of NaCl, except for those mutants with an NaCl-dependent system. 相似文献
939.
Rho J Shin JH Song JW Park MR Kee SJ Jang SJ Park YK Suh SP Ryang DW 《Journal of microbiology (Seoul, Korea)》2004,42(2):80-86
Pulsed-field gel electrophoresis (PFGE) typing was applied to the epidemiological investigation of 21 Candida tropicalis isolates collected from urine specimens of 11 patients and one healthcare worker, in an intensive care unit (ICU) over a 4-month period. Seventeen epidemiologically unrelated strains from 14 patients were also tested to determine the discriminatory power of PFGE. PFGE typing consisted of electrophoretic karyotyping (EK) and restriction endonuclease analysis of genomic DNA (REAG), using two restriction enzymes (BssHII and SfiI). The EK pattern was the same in all 38 isolates, while REAG using SfiI separated the isolates into nine types. However, 16 different PFGE types were identified by REAG with BssHII, and the same results were obtained when the results of both REAG tests were combined. In serial urinary isolates from 10 patients, all strains from each patient had the same PFGE pattern. While the epidemiologically unrelated strains from 14 patients consisted of 13 different PFGE types, the 20 isolates from the 11 ICU patients fell into only two PFGE types (types C1 and C2), and these apparently originated from the two different outbreaks. All strains of type C1 (n = 12) were isolated from six patients, between November 1999 and January 2000, and all of the type C2 strains (n=8) were isolated from five patients, during January and February 2000. This study shows two consecutive clusters of C. tropicalis candiduria in an ICU, defined by PFGE typing, and also demonstrates that a PFGE typing method using BssHII is perhaps the most useful method for investigating C. tropicalis candiduria. 相似文献
940.
Kim YM Park K Jung SH Choi JH Kim WC Joo GJ Rhee IK 《Journal of microbiology (Seoul, Korea)》2004,42(1):42-46
It has recently been reported that one of the most important factors of yeast resistance to the fungicide chlorothalonil is the glutathione contents and the catalytic efficiency of glutathione S-transferase (GST) (Shin et al, 2003). GST is known to catalyze the conjugation of glutathione to a wide variety of xenobiotics, resulting in detoxification. In an attempt to elucidate the relation between chlorothalonil-detoxification and GST, the GST of Escherichia coli was expressed and purified. The drug-hypersensitive E. coli KAM3 cells harboring a plasmid for the overexpression of the GST gene can grow in the presence of chlorothalonil. The purified GST showed chlorothalonil-biotransformation activity in the presence of glutathione. Thus, chlorothalonil is detoxified by the mechanism of glutathione conjugation catalyzed by GST. 相似文献