全文获取类型
收费全文 | 11852篇 |
免费 | 973篇 |
国内免费 | 11篇 |
出版年
2023年 | 56篇 |
2022年 | 73篇 |
2021年 | 239篇 |
2020年 | 106篇 |
2019年 | 154篇 |
2018年 | 216篇 |
2017年 | 164篇 |
2016年 | 289篇 |
2015年 | 509篇 |
2014年 | 594篇 |
2013年 | 799篇 |
2012年 | 900篇 |
2011年 | 933篇 |
2010年 | 580篇 |
2009年 | 506篇 |
2008年 | 777篇 |
2007年 | 787篇 |
2006年 | 711篇 |
2005年 | 685篇 |
2004年 | 678篇 |
2003年 | 638篇 |
2002年 | 568篇 |
2001年 | 121篇 |
2000年 | 85篇 |
1999年 | 131篇 |
1998年 | 174篇 |
1997年 | 109篇 |
1996年 | 91篇 |
1995年 | 95篇 |
1994年 | 104篇 |
1993年 | 93篇 |
1992年 | 81篇 |
1991年 | 54篇 |
1990年 | 60篇 |
1989年 | 55篇 |
1988年 | 60篇 |
1987年 | 39篇 |
1986年 | 34篇 |
1985年 | 37篇 |
1984年 | 45篇 |
1983年 | 35篇 |
1982年 | 36篇 |
1981年 | 41篇 |
1980年 | 45篇 |
1979年 | 37篇 |
1978年 | 23篇 |
1977年 | 25篇 |
1976年 | 20篇 |
1974年 | 20篇 |
1973年 | 22篇 |
排序方式: 共有10000条查询结果,搜索用时 62 毫秒
981.
Ryu KY Maehr R Gilchrist CA Long MA Bouley DM Mueller B Ploegh HL Kopito RR 《The EMBO journal》2007,26(11):2693-2706
UbC is one of two stress-inducible polyubiquitin genes in mammals and is thought to supplement the constitutive UbA genes in maintaining cellular ubiquitin (Ub) levels during episodes of cellular stress. We have generated mice harboring a targeted disruption of the UbC gene. UbC(-/-) embryos die between embryonic days 12.5 and 14.5 in utero, most likely owing to a severe defect in liver cell proliferation. Mouse embryonic fibroblasts from UbC(-/-) embryos exhibit reduced growth rates, premature senescence, increased apoptosis and delayed cell-cycle progression, with slightly, but significantly, decreased steady-state Ub levels. UbC(-/-) fibroblasts are hypersensitive to proteasome inhibitors and heat shock, and unable to adequately increase Ub levels in response to these cellular stresses. Most, but not all of the UbC(-/-) phenotypes can be rescued by providing additional Ub from a poly hemagglutinin-tagged Ub minigene expressed from the Hprt locus. We propose that UbC is regulated by a process that senses Ub pool dynamics. These data establish that UbC constitutes an essential source of Ub during cell proliferation and stress that cannot be compensated by other Ub genes. 相似文献
982.
Casein kinase 1 is a novel negative regulator of E-cadherin-based cell-cell contacts 总被引:1,自引:0,他引:1
下载免费PDF全文
![点击此处可从《Molecular and cellular biology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Dupre-Crochet S Figueroa A Hogan C Ferber EC Bialucha CU Adams J Richardson EC Fujita Y 《Molecular and cellular biology》2007,27(10):3804-3816
Cadherins are the most crucial membrane proteins for the formation of tight and compact cell-cell contacts. Cadherin-based cell-cell adhesions are dynamically established and/or disrupted during various physiological and pathological processes. However, the molecular mechanisms that regulate cell-cell contacts are not fully understood. In this paper, we report a novel functional role of casein kinase 1 (CK1) in the regulation of cell-cell contacts. Firstly, we observed that IC261, a specific inhibitor of CK1, stabilizes cadherin-based cell-cell contacts, whereas the overexpression of CK1 disrupts them. CK1 colocalizes with E-cadherin and phosphorylates the cytoplasmic domain of E-cadherin in vitro and in a cell culture system. We show that the major CK1 phosphorylation site of E-cadherin is serine 846, a highly conserved residue between classical cadherins. Constitutively phosphorylated E-cadherin (S846D) is unable to localize at cell-cell contacts and has decreased adhesive activity. Furthermore, phosphorylated E-cadherin (S846D) has weaker interactions with beta-catenin and is internalized more efficiently than wild-type E-cadherin. These data indicate that CK1 is a novel negative regulator of cadherin-based cell-cell contacts. 相似文献
983.
Hue-Beauvais C Péchoux C Bouguyon E Chat S Truchet S Pauloin A Le Gouar Y Ollivier-Bousquet M 《Cell and tissue research》2007,328(3):521-536
Caveolins, components of caveolae, are expressed in mammary tissue. In order to determine whether caveolins are present in
different mammary cell types and whether their localisation depends on the physiological stage or species, cav-1 and cav-2
were characterised by immunoblotting in mammary tissues from the mouse, ewe and rabbit and localised, by immunofluorescence
and electron microscopy, in mammary tissues from the mouse and ewe. At all the physiological stages studied, cav-1 and cav-2
were present in endothelial and myoepithelial cells in which flask-shaped caveolae were abundant. However, labelling of cav-1
and cav-2 associated with small vesiculo-tubular structures (including those close to lipid droplets) was low in epithelial
cells. To study the possible association of cav-1 with lipid droplets, lactating ewe mammary fragments were treated in vitro
with brefeldin A. This treatment did not modify the association of cav-1-labelled structures with lipid droplets. Finally,
HC11 and MCF-10A mammary cell lines were treated with oleic acid. The total quantity of cav-1 was little affected by the treatment,
although the lipid droplet labelling of cav-1 was amplified in MCF-10A cells. Thus, the synthesis and localisation of caveolins
are mostly dependent upon the cell types of mammary tissue and upon their state of differentiation. 相似文献
984.
The endoribonuclease L (RNase L) is the effector of the 2-5A system, a major enzymatic pathway involved in the molecular mechanism of interferons (IFNs). RNase L is a very unusual nuclease with a complex mechanism of regulation. It is a latent enzyme, expressed in nearly every mammalian cell type. Its activation requires its binding to a small oligonucleotide, 2-5A. 2-5A is a series of unique 5'-triphosphorylated oligoadenylates with 2'-5' phosphodiester bonds. By regulating viral and cellular RNA expression, RNase L plays an important role in the antiviral and antiproliferative activities of IFN and contributes to innate immunity and cell metabolism. The 2-5A/RNase L pathway is implicated in mediating apoptosis in response to viral infections and to several types of external stimuli. Several recent studies have suggested that RNase L could have a role in cancer biology and evidence of a tumor suppressor function of RNase L has emerged from studies on the genetics of hereditary prostate cancer. 相似文献
985.
Massip L Ectors F Deprez P Maleki M Behets C Lengelé B Delahaut P Picard J Rezsöhazy R 《Differentiation; research in biological diversity》2007,75(3):256-267
Vertebrate Hox genes act as developmental architects by patterning embryonic structures like axial skeletal elements, limbs, brainstem territories, or neural crest derivatives. While active during the patterning steps of development, these genes turn out to be down-regulated in specific differentiation programs like that leading to chondrogenesis. To investigate why chondrocyte differentiation is correlated to the silencing of a Hox gene, we generated transgenic mice allowing Cre-mediated conditional misexpression of Hoxa2 and induced this gene in Collagen 2 alpha 1-expressing cells committed to enter chondrogenesis. Persistent Hoxa2 expression in chondrogenic cells resulted in overall chondrodysplasia with delayed cartilage hypertrophy, mineralization, and ossification but without proliferation defects. The absence of skeletal patterning anomaly and the regular migration of precursor cells indicated that the condensation step of chondrogenesis was normal. In contrast, closer examination at the differentiation step showed severely impaired chondrocyte differentiation. In addition, this inhibition affected structures independently of their embryonic origin. In conclusion, for the first time here, by a cell-type specific misexpression, we precisely uncoupled the patterning function of Hoxa2 from its involvement in regulating differentiation programs per se and demonstrate that Hoxa2 displays an anti-chondrogenic activity that is distinct from its patterning function. 相似文献
986.
987.
Community genetics examines how genotypic variation within a species influences the associated ecological community. The inclusion of additional environmental and genotypic factors is a natural extension of the current community genetics framework. However, the extent to which the presence of and genetic variation in associated species influences interspecific interactions (i.e., genotype x genotype x environment [G x G x E] interactions) has been largely ignored. We used a community genetics approach to study the interaction of barley and aphids in the absence and presence of rhizosphere bacteria. We designed a matrix of aphid genotype and barley genotype combinations and found a significant G x G x E interaction, indicating that the barley-aphid interaction is dependent on the genotypes of the interacting species as well as the biotic environment. We discuss the consequences of the strong G x G x E interaction found in our study in relation to its impact on the study of species interactions in a community context. 相似文献
988.
Development of a New, Combined Rapid Method Using Phage and PCR for Detection and Identification of Viable Mycobacterium paratuberculosis Bacteria within 48 Hours
下载免费PDF全文
![点击此处可从《Applied microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Emma C. Stanley Richard J. Mole Rebecca J. Smith Sarah M. Glenn Michael R. Barer Michael McGowan Catherine E. D. Rees 《Applied microbiology》2007,73(6):1851-1857
The FASTPlaqueTB assay is an established diagnostic aid for the rapid detection of Mycobacterium tuberculosis from human sputum samples. Using the FASTPlaqueTB assay reagents, viable Mycobacterium avium subsp. paratuberculosis cells were detected as phage plaques in just 24 h. The bacteriophage used does not infect M. avium subsp. paratuberculosis alone, so to add specificity to this assay, a PCR-based identification method was introduced to amplify M. avium subsp. paratuberculosis-specific sequences from the DNA of the mycobacterial cell detected by the phage. To give further diagnostic information, a multiplex PCR method was developed to allow simultaneous amplification of either M. avium subsp. paratuberculosis or M. tuberculosis complex-specific sequences from plaque samples. Combining the plaque PCR technique with the phage-based detection assay allowed the rapid and specific detection of viable M. avium subsp. paratuberculosis in milk samples in just 48 h. 相似文献
989.
Screening Marine Fungi for Inhibitors of the C4 Plant Enzyme Pyruvate Phosphate Dikinase: Unguinol as a Potential Novel Herbicide Candidate
下载免费PDF全文
![点击此处可从《Applied microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Cherie A. Motti David G. Bourne James N. Burnell Jason R. Doyle Dianne S. Haines Catherine H. Liptrot Lyndon E. Llewellyn Shilo Ludke Andrew Muirhead Dianne M. Tapiolas 《Applied microbiology》2007,73(6):1921-1927
A total of 2,245 extracts, derived from 449 marine fungi cultivated in five types of media, were screened against the C4 plant enzyme pyruvate phosphate dikinase (PPDK), a potential herbicide target. Extracts from several fungal isolates selectively inhibited PPDK. Bioassay-guided fractionation of one isolate led to the isolation of the known compound unguinol, which inhibited PPDK with a 50% inhibitory concentration of 42.3 ± 0.8 μM. Further kinetic analysis revealed that unguinol was a mixed noncompetitive inhibitor of PPDK with respect to the substrates pyruvate and ATP and an uncompetitive inhibitor of PPDK with respect to phosphate. Unguinol had deleterious effects on a model C4 plant but no effect on a model C3 plant. These results indicate that unguinol inhibits PPDK via a novel mechanism of action which also translates to an herbicidal effect on whole plants. 相似文献
990.
Bacteroides sp. Strain D8, the First Cholesterol-Reducing Bacterium Isolated from Human Feces
下载免费PDF全文
![点击此处可从《Applied microbiology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Philippe Grard Pascale Lepercq Marion Leclerc Franoise Gavini Pierre Raibaud Catherine Juste 《Applied microbiology》2007,73(18):5742-5749
The microbial community in the human colon contains bacteria that reduce cholesterol to coprostanol, but the species responsible for this conversion are still unknown. We describe here the first isolation and characterization of a cholesterol-reducing bacterium of human intestinal origin. Strain D8 was isolated from a 10−8 dilution of a fresh stool sample provided by a senior male volunteer with a high capacity to reduce luminal cholesterol to coprostanol. Cholesterol-to-coprostanol conversion by strain D8 started on the third day, while cells were in stationary phase, and was almost complete after 7 days. Intermediate products (4-cholesten-3-one and coprostanone) were occasionally observed, suggesting an indirect pathway for cholesterol-to-coprostanol conversion. Resting-cell assays showed that strain D8 could reduce 1.5 μmol of cholesterol/mg bacterial protein/h. Strain D8 was a gram-negative, non-spore-forming, rod-shaped organism identified as a member of the genus Bacteroides closely related to Bacteroides vulgatus, based on its morphological and biochemical characteristics. The 16S rRNA gene sequence of strain D8 was most similar (>99.5%) to those of two isolates of the recently described species Bacteroides dorei. Phylogenetic tree construction confirmed that Bacteroides sp. strain D8 clustered within an independent clade together with these B. dorei strains. Nevertheless, no cholesterol-reducing activity could be detected in cultures of the B. dorei type strain. Based on Bacteroides group-specific PCR-temporal temperature gradient gel electrophoresis, there was no correlation between the presence of a band comigrating with the band of Bacteroides sp. strain D8 and cholesterol conversion in 11 human fecal samples, indicating that this strain is unlikely to be mainly responsible for cholesterol conversion in the human population. 相似文献