全文获取类型
收费全文 | 911篇 |
免费 | 66篇 |
专业分类
977篇 |
出版年
2023年 | 4篇 |
2022年 | 18篇 |
2021年 | 28篇 |
2020年 | 13篇 |
2019年 | 16篇 |
2018年 | 25篇 |
2017年 | 17篇 |
2016年 | 32篇 |
2015年 | 47篇 |
2014年 | 52篇 |
2013年 | 54篇 |
2012年 | 86篇 |
2011年 | 92篇 |
2010年 | 65篇 |
2009年 | 41篇 |
2008年 | 52篇 |
2007年 | 64篇 |
2006年 | 56篇 |
2005年 | 42篇 |
2004年 | 32篇 |
2003年 | 30篇 |
2002年 | 27篇 |
2001年 | 3篇 |
2000年 | 4篇 |
1999年 | 4篇 |
1998年 | 4篇 |
1997年 | 8篇 |
1995年 | 2篇 |
1993年 | 3篇 |
1991年 | 2篇 |
1990年 | 2篇 |
1989年 | 2篇 |
1988年 | 4篇 |
1987年 | 3篇 |
1986年 | 4篇 |
1985年 | 4篇 |
1984年 | 2篇 |
1982年 | 4篇 |
1981年 | 2篇 |
1980年 | 2篇 |
1972年 | 3篇 |
1971年 | 2篇 |
1968年 | 1篇 |
1964年 | 2篇 |
1961年 | 1篇 |
1957年 | 1篇 |
1936年 | 2篇 |
1932年 | 1篇 |
1931年 | 1篇 |
1925年 | 1篇 |
排序方式: 共有977条查询结果,搜索用时 15 毫秒
31.
Bonsignori M Hwang KK Chen X Tsao CY Morris L Gray E Marshall DJ Crump JA Kapiga SH Sam NE Sinangil F Pancera M Yongping Y Zhang B Zhu J Kwong PD O'Dell S Mascola JR Wu L Nabel GJ Phogat S Seaman MS Whitesides JF Moody MA Kelsoe G Yang X Sodroski J Shaw GM Montefiori DC Kepler TB Tomaras GD Alam SM Liao HX Haynes BF 《Journal of virology》2011,85(19):9998-10009
V2/V3 conformational epitope antibodies that broadly neutralize HIV-1 (PG9 and PG16) have been recently described. Since an elicitation of previously known broadly neutralizing antibodies has proven elusive, the induction of antibodies with such specificity is an important goal for HIV-1 vaccine development. A critical question is which immunogens and vaccine formulations might be used to trigger and drive the development of memory B cell precursors with V2/V3 conformational epitope specificity. In this paper we identified a clonal lineage of four V2/V3 conformational epitope broadly neutralizing antibodies (CH01 to CH04) from an African HIV-1-infected broad neutralizer and inferred their common reverted unmutated ancestor (RUA) antibodies. While conformational epitope antibodies rarely bind recombinant Env monomers, a screen of 32 recombinant envelopes for binding to the CH01 to CH04 antibodies showed monoclonal antibody (MAb) binding to the E.A244 gp120 Env and to chronic Env AE.CM243; MAbs CH01 and CH02 also bound to transmitted/founder Env B.9021. CH01 to CH04 neutralized 38% to 49% of a panel of 91 HIV-1 tier 2 pseudoviruses, while the RUAs neutralized only 16% of HIV-1 isolates. Although the reverted unmutated ancestors showed restricted neutralizing activity, they retained the ability to bind to the E.A244 gp120 HIV-1 envelope with an affinity predicted to trigger B cell development. Thus, E.A244, B.9021, and AE.CM243 Envs are three potential immunogen candidates for studies aimed at defining strategies to induce V2/V3 conformational epitope-specific antibodies. 相似文献
32.
33.
The N-methyl-D-aspartate receptor (NMDAR) is a key molecule mediating brain plasticity related processes. Knowing that alternative splicing
of the NMDAR1 (NR1) subunit offers molecular diversity to NMDAR, controls the forward trafficking of the NR1 protein and is
important for placing NMDA receptors at synapses, we investigated herein the postnatal developmental expression and the influence
of visual deprivation on NR1 subunit splice variants in rat retina. Real-time PCR was performed using oligonucleotide primers
specific for N- terminal (NR1a, NR1b) and C-terminal splice variants (NR1-1, NR1-2, NR1-3, NR1-4). The developmental profiles
of mRNA expression levels of all NR1 isoforms peaked at the end of the third week. Dark rearing led to reductions in both
N- and C-terminal NR1 variants in several developmental ages and a significant interaction between age and visual experience
was observed for NR1a, NR1-2 and NR1-4 expression. Our results have demonstrated a developmental and visual experience-dependent
regulation of NR1 splicing in rat retina. 相似文献
34.
Messenger RNA localization involves the assembly of ribonucleoprotein particles (RNPs) and their subsequent transport along the cytoskeleton to their final destination. Here, we provide new evidence that microtubule-associated protein 2 (MAP2), calcium/calmodulin-dependent protein kinase II (CaMKIIα) and β-actin RNAs localize to dendrites in distinct RNPs, which contain--unexpectedly--very few RNA molecules. The number of MAP2 molecules per particle is affected by synaptic activity and Staufen 2, indicating that RNP composition is tightly controlled. Our data suggest that the independent localization of individual RNAs in low copy numbers could contribute to tighter temporal and spatial control of expression in neurons and synapse-specific plasticity. 相似文献
35.
FoxO3a transcriptional regulation of Bim controls apoptosis in paclitaxel-treated breast cancer cell lines 总被引:15,自引:0,他引:15
36.
Fu, G., Perona-Wright, G., and Barker, D. C. 1998.Leishmania braziliensis: Characterisation of a complex specific subtelomeric repeat sequence and its use in the detection of parasites.Experimental Parasitology90, 236–243. A 1.6-kb tandem repeat sequence had previously been identified in the subtelomeric region of mini- and megabase chromosomes fromLeishmania braziliensis.Southern hybridisation was used to demonstrate that the repeat is complex specific. The sequence was characterised in strains representing four species of theL. braziliensiscomplex. This data allowed an assessment of the evolutionary relationship of the four species. PCR primers targeted to the repeat amplify only DNA from species of theL. braziliensiscomplex. Titration assays indicate that a minimum of 50 fg of parasite DNA can be detected by PCR alone. Southern hybridisation increases the limit of detection to 5 fg. Interspecies variation in the repeat sequence enabled restriction enzyme digestion of PCR products to distinguish individual species within theL. braziliensiscomplex. 相似文献
37.
38.
Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism 总被引:1,自引:0,他引:1
Hitosugi T Fan J Chung TW Lythgoe K Wang X Xie J Ge Q Gu TL Polakiewicz RD Roesel JL Chen GZ Boggon TJ Lonial S Fu H Khuri FR Kang S Chen J 《Molecular cell》2011,44(6):864-877
Many tumor cells rely on aerobic glycolysis instead of oxidative phosphorylation for their continued proliferation and survival. Myc and HIF-1 are believed to promote such a metabolic switch by, in part, upregulating gene expression of pyruvate dehydrogenase (PDH) kinase 1 (PDHK1), which phosphorylates and inactivates mitochondrial PDH and consequently pyruvate dehydrogenase complex (PDC). Here we report that tyrosine phosphorylation enhances PDHK1 kinase activity by promoting ATP and PDC binding. Functional PDC can form in mitochondria outside of the matrix in some cancer cells and PDHK1 is commonly tyrosine phosphorylated in human cancers by diverse oncogenic tyrosine kinases localized to different mitochondrial compartments. Expression of phosphorylation-deficient, catalytic hypomorph PDHK1 mutants in cancer cells leads to decreased cell proliferation under hypoxia and increased oxidative phosphorylation with enhanced mitochondrial utilization of pyruvate and reduced tumor growth in xenograft nude mice. Together, tyrosine phosphorylation activates PDHK1 to promote the Warburg effect and tumor growth. 相似文献
39.
40.
Birgit Schiller Georgia Makrypidi Ebrahim Razzazi-Fazeli Katharina Paschinger Julia Walochnik Iain B. H. Wilson 《The Journal of biological chemistry》2012,287(52):43191-43204
Glycans play key roles in host-pathogen interactions; thus, knowing the N-glycomic repertoire of a pathogen can be helpful in deciphering its methods of establishing and sustaining a disease. Therefore, we sought to elucidate the glycomic potential of the facultative amoebal parasite Acanthamoeba. This is the first study of its asparagine-linked glycans, for which we applied biochemical tools and various approaches of mass spectrometry. An initial glycomic screen of eight strains from five genotypes of this human pathogen suggested, in addition to the common eukaryotic oligomannose structures, the presence of pentose and deoxyhexose residues on their N-glycans. A more detailed analysis was performed on the N-glycans of a genotype T11 strain (4RE); fractionation by HPLC and tandem mass spectrometric analyses indicated the presence of a novel mannosylfucosyl modification of the reducing terminal core as well as phosphorylation of mannose residues, methylation of hexose and various forms of pentosylation. The largest N-glycan in the 4RE strain contained two N-acetylhexosamine, thirteen hexose, one fucose, one methyl, and two pentose residues; however, in this and most other strains analyzed, glycans with compositions of Hex8–9HexNAc2Pnt0–1 tended to dominate in terms of abundance. Although no correlation between pathogenicity and N-glycan structure can be proposed, highly unusual structures in this facultative parasite can be found which are potential virulence factors or therapeutic targets. 相似文献