全文获取类型
收费全文 | 529篇 |
免费 | 111篇 |
专业分类
640篇 |
出版年
2021年 | 9篇 |
2017年 | 6篇 |
2016年 | 7篇 |
2015年 | 20篇 |
2014年 | 17篇 |
2013年 | 16篇 |
2012年 | 22篇 |
2011年 | 25篇 |
2010年 | 13篇 |
2009年 | 21篇 |
2008年 | 30篇 |
2007年 | 22篇 |
2006年 | 20篇 |
2005年 | 16篇 |
2004年 | 16篇 |
2003年 | 18篇 |
2002年 | 15篇 |
2001年 | 15篇 |
2000年 | 12篇 |
1999年 | 13篇 |
1997年 | 5篇 |
1996年 | 8篇 |
1995年 | 6篇 |
1993年 | 5篇 |
1992年 | 13篇 |
1991年 | 13篇 |
1990年 | 11篇 |
1989年 | 8篇 |
1988年 | 10篇 |
1987年 | 18篇 |
1986年 | 15篇 |
1985年 | 16篇 |
1984年 | 11篇 |
1983年 | 13篇 |
1982年 | 10篇 |
1981年 | 5篇 |
1980年 | 8篇 |
1979年 | 9篇 |
1978年 | 5篇 |
1977年 | 9篇 |
1976年 | 5篇 |
1975年 | 5篇 |
1974年 | 8篇 |
1973年 | 10篇 |
1972年 | 12篇 |
1971年 | 11篇 |
1969年 | 8篇 |
1968年 | 10篇 |
1966年 | 4篇 |
1965年 | 5篇 |
排序方式: 共有640条查询结果,搜索用时 15 毫秒
151.
152.
153.
154.
The differential ability of HLA B*5701+ long-term nonprogressors and progressors to restrict human immunodeficiency virus replication is not caused by loss of recognition of autologous viral gag sequences
下载免费PDF全文
![点击此处可从《Journal of virology》网站下载免费的PDF全文](/ch/ext_images/free.gif)
Migueles SA Laborico AC Imamichi H Shupert WL Royce C McLaughlin M Ehler L Metcalf J Liu S Hallahan CW Connors M 《Journal of virology》2003,77(12):6889-6898
Although the HLA B(*)5701 class I allele is highly overrepresented among human immunodeficiency virus (HIV)-infected long-term nonprogressors (LTNPs), it is also present at the expected frequency (11%) in patients with progressive HIV infection. Whether B57(+) progressors lack restriction of viral replication because of escape from recognition of highly immunodominant B57-restricted gag epitopes by CD8(+) T cells remains unknown. In this report, we investigate the association between restriction of virus replication and recognition of autologous virus sequences in 27 B(*)57(+) patients (10 LTNPs and 17 progressors). Amplification and direct sequencing of single molecules of viral cDNA or proviral DNA revealed low frequencies of genetic variations in these regions of gag. Furthermore, CD8(+) T-cell recognition of autologous viral variants was preserved in most cases. In two patients, responses to autologous viral variants were not demonstrable at one epitope. By using a novel technique to isolate primary CD4(+) T cells expressing autologous viral gene products, it was found that 1 to 13% of CD8(+) T cells were able to respond to these cells by gamma interferon production. In conclusion, escape-conferring mutations occur infrequently within immunodominant B57-restricted gag epitopes and are not the primary mechanism of virus evasion from immune control in B(*)5701(+) HIV-infected patients. Qualitative features of the virus-specific CD8(+) T-cell response not measured by current assays remain the most likely determinants of the differential abilities of HLA B(*)5701(+) LTNPs and progressors to restrict virus replication. 相似文献
155.
Wiedner C Visser PM Fastner J Metcalf JS Codd GA Mur LR 《Applied and environmental microbiology》2003,69(3):1475-1481
Many cyanobacteria produce microcystins, hepatotoxic cyclic heptapeptides that can affect animals and humans. The effects of photosynthetically active radiation (PAR) on microcystin production by Microcystis strain PCC 7806 were studied in continuous cultures. Microcystis strain PCC 7806 was grown under PAR intensities between 10 and 403 micro mol of photons m(-2) s(-1) on a light-dark rhythm of 12 h -12 h. The microcystin concentration per cell, per unit biovolume and protein, was estimated under steady-state and transient-state conditions and on a diurnal timescale. The cellular microcystin content varied between 34.5 and 81.4 fg cell(-1) and was significantly positively correlated with growth rate under PAR-limited growth but not under PAR-saturated growth. Microcystin production and PAR showed a significant positive correlation under PAR-limited growth and a significant negative correlation under PAR-saturated growth. The microcystin concentration, as a ratio with respect to biovolume and protein, correlated neither with growth rate nor with PAR. Adaptation of microcystin production to a higher irradiance during transient states lasted for 5 days. During the period of illumination at a PAR of 10 and 40 micro mol of photons m(-2) s(-1), the intracellular microcystin content increased to values 10 to 20% higher than those at the end of the dark period. Extracellular (dissolved) microcystin concentrations were 20 times higher at 40 micro mol of photons m(-2) s(-1) than at 10 micro mol of photons m(-2) s(-1) and did not change significantly during the light-dark cycles at both irradiances. In summary, our results showed a positive effect of PAR on microcystin production and content of Microcystis strain PCC 7806 up to the point where the maximum growth rate is reached, while at higher irradiances the microcystin production is inhibited. 相似文献
156.
Bone-targeted 2,6,9-trisubstituted purines: novel inhibitors of Src tyrosine kinase for the treatment of bone diseases 总被引:2,自引:0,他引:2
Wang Y Metcalf CA Shakespeare WC Sundaramoorthi R Keenan TP Bohacek RS van Schravendijk MR Violette SM Narula SS Dalgarno DC Haraldson C Keats J Liou S Mani U Pradeepan S Ram M Adams S Weigele M Sawyer TK 《Bioorganic & medicinal chemistry letters》2003,13(18):3067-3070
Novel bone-targeted 2,6,9-trisubstituted purine template-based inhibitors of Src tyrosine kinase are described. Drug design studies of known purine compounds revealed that both positions-2 and -6 were suitable for incorporating bone-seeking moieties. A variety of bone-targeting groups with different affinity to hydroxyapatite were utilized in the study. Compound 3d was determined to be a potent Src inhibitor and was quite selective against a panel of other protein kinases. 相似文献
157.
158.
Suppressor of cytokine signaling-1 has IFN-gamma-independent actions in T cell homeostasis 总被引:5,自引:0,他引:5
Cornish AL Davey GM Metcalf D Purton JF Corbin JE Greenhalgh CJ Darwiche R Wu L Nicola NA Godfrey DI Heath WR Hilton DJ Alexander WS Starr R 《Journal of immunology (Baltimore, Md. : 1950)》2003,170(2):878-886
Suppressor of cytokine signaling (SOCS)-1 is a member of a family of proteins that negatively regulate cytokine signaling pathways. We have previously established that SOCS-1 is a key regulator of IFN-gamma signaling and that IFN-gamma is responsible for the complex inflammatory disease that leads to the death of SOCS-1-deficient mice. In this study, we provide evidence that SOCS-1 is also a critical regulator of IFN-gamma-independent immunoregulatory factors. Mice lacking both SOCS-1 and IFN-gamma, although outwardly healthy, have clear abnormalities in their immune system, including a reduced ratio of CD4:CD8 T cells in lymphoid tissues and increased expression of T cell activation markers. To examine the contribution of TCR Ag specificity to these immune defects, we have generated two lines of SOCS-1-deficient mice expressing a transgenic TCR specific for an exogenous Ag, OVA (OT-I and OT-II). Although TCR transgenic SOCS-1(-/-) mice have a longer lifespan than nontransgenic SOCS-1(-/-) mice, they still die as young adults with inflammatory disease and the TCR transgenic SOCS-1(-/-) T cells appear activated despite the absence of OVA. This suggests that both Ag-dependent and -independent mechanisms contribute to the disease in SOCS-1-deficient mice. Thus, SOCS-1 is a critical regulator of T cell activation and homeostasis, and its influence extends beyond regulating IFN-gamma signaling. 相似文献
159.
SOCS-6 binds to insulin receptor substrate 4, and mice lacking the SOCS-6 gene exhibit mild growth retardation 总被引:3,自引:0,他引:3
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)
Krebs DL Uren RT Metcalf D Rakar S Zhang JG Starr R De Souza DP Hanzinikolas K Eyles J Connolly LM Simpson RJ Nicola NA Nicholson SE Baca M Hilton DJ Alexander WS 《Molecular and cellular biology》2002,22(13):4567-4578
SOCS-6 is a member of the suppressor of cytokine signaling (SOCS) family of proteins (SOCS-1 to SOCS-7 and CIS) which each contain a central SH2 domain and a carboxyl-terminal SOCS box. SOCS-1, SOCS-2, SOCS-3, and CIS act to negatively regulate cytokine-induced signaling pathways; however, the actions of SOCS-4, SOCS-5, SOCS-6, and SOCS-7 remain less clear. Here we have used both biochemical and genetic approaches to examine the action of SOCS-6. We found that SOCS-6 and SOCS-7 are expressed ubiquitously in murine tissues. Like other SOCS family members, SOCS-6 binds to elongins B and C through its SOCS box, suggesting that it might act as an E3 ubiquitin ligase that targets proteins bound to its SH2 domain for ubiquitination and proteasomal degradation. We investigated the binding specificity of the SOCS-6 and SOCS-7 SH2 domains and found that they preferentially bound to phosphopeptides containing a valine in the phosphotyrosine (pY) +1 position and a hydrophobic residue in the pY +2 and pY +3 positions. In addition, these SH2 domains interacted with a protein complex consisting of insulin receptor substrate 4 (IRS-4), IRS-2, and the p85 regulatory subunit of phosphatidylinositol 3-kinase. To investigate the physiological role of SOCS-6, we generated mice lacking the SOCS-6 gene. SOCS-6(-/-) mice were born in a normal Mendelian ratio, were fertile, developed normally, and did not exhibit defects in hematopoiesis or glucose homeostasis. However, both male and female SOCS-6(-/-) mice weighed approximately 10% less than wild-type littermates. 相似文献
160.
The Escherichia coli disulfide bond isomerase DsbC rearranges incorrect disulfide bonds during oxidative protein folding. It is specifically activated by the periplasmic N-terminal domain (DsbDalpha) of the transmembrane electron transporter DsbD. An intermediate of the electron transport reaction was trapped, yielding a covalent DsbC-DsbDalpha complex. The 2.3 A crystal structure of the complex shows for the first time the specific interactions between two thiol oxidoreductases. DsbDalpha is a novel thiol oxidoreductase with the active site cysteines embedded in an immunoglobulin fold. It binds into the central cleft of the V-shaped DsbC dimer, which assumes a closed conformation on complex formation. Comparison of the complex with oxidized DsbDalpha reveals major conformational changes in a cap structure that regulates the accessibility of the DsbDalpha active site. Our results explain how DsbC is selectively activated by DsbD using electrons derived from the cytoplasm. 相似文献