全文获取类型
收费全文 | 1413篇 |
免费 | 78篇 |
国内免费 | 2篇 |
出版年
2022年 | 20篇 |
2021年 | 29篇 |
2020年 | 19篇 |
2019年 | 14篇 |
2018年 | 35篇 |
2017年 | 29篇 |
2016年 | 47篇 |
2015年 | 65篇 |
2014年 | 70篇 |
2013年 | 86篇 |
2012年 | 109篇 |
2011年 | 94篇 |
2010年 | 68篇 |
2009年 | 46篇 |
2008年 | 65篇 |
2007年 | 43篇 |
2006年 | 49篇 |
2005年 | 53篇 |
2004年 | 36篇 |
2003年 | 51篇 |
2002年 | 33篇 |
2001年 | 36篇 |
2000年 | 34篇 |
1999年 | 29篇 |
1998年 | 21篇 |
1997年 | 12篇 |
1996年 | 8篇 |
1995年 | 14篇 |
1994年 | 7篇 |
1993年 | 7篇 |
1992年 | 27篇 |
1991年 | 22篇 |
1990年 | 19篇 |
1989年 | 20篇 |
1988年 | 17篇 |
1987年 | 23篇 |
1986年 | 17篇 |
1985年 | 14篇 |
1984年 | 8篇 |
1983年 | 10篇 |
1982年 | 11篇 |
1979年 | 5篇 |
1978年 | 9篇 |
1976年 | 7篇 |
1975年 | 6篇 |
1974年 | 4篇 |
1973年 | 4篇 |
1972年 | 7篇 |
1970年 | 5篇 |
1966年 | 4篇 |
排序方式: 共有1493条查询结果,搜索用时 15 毫秒
171.
Zhang MY Vu BK Choudhary A Lu H Humbert M Ong H Alam M Ruprecht RM Quinnan G Jiang S Montefiori DC Mascola JR Broder CC Haynes BF Dimitrov DS 《Journal of virology》2008,82(14):6869-6879
Broadly cross-reactive human immunodeficiency virus (HIV)-neutralizing antibodies are infrequently elicited in infected humans. The two best-characterized gp41-specific cross-reactive neutralizing human monoclonal antibodies, 4E10 and 2F5, target linear epitopes in the membrane-proximal external region (MPER) and bind to cardiolipin and several other autoantigens. It has been hypothesized that, because of such reactivity to self-antigens, elicitation of 2F5 and 4E10 and similar antibodies by vaccine immunogens based on the MPER could be affected by tolerance mechanisms. Here, we report the identification and characterization of a novel anti-gp41 monoclonal antibody, designated m44, which neutralized most of the 22 HIV type 1 (HIV-1) primary isolates from different clades tested in assays based on infection of peripheral blood mononuclear cells by replication-competent virus but did not bind to cardiolipin and phosphatidylserine in an enzyme-linked immunosorbent assay and a Biacore assay nor to any protein or DNA autoantigens tested in Luminex assays. m44 bound to membrane-associated HIV-1 envelope glycoproteins (Envs), to recombinant Envs lacking the transmembrane domain and cytoplasmic tail (gp140s), and to gp41 structures containing five-helix bundles and six-helix bundles, but not to N-heptad repeat trimers, suggesting that the C-heptad repeat is involved in m44 binding. In contrast to 2F5, 4E10, and Z13, m44 did not bind to any significant degree to denatured gp140 and linear peptides derived from gp41, suggesting a conformational nature of the epitope. This is the first report of a gp41-specific cross-reactive HIV-1-neutralizing human antibody that does not have detectable reactivity to autoantigens. Its novel conserved conformational epitope on gp41 could be helpful in the design of vaccine immunogens and as a target for therapeutics. 相似文献
172.
173.
Chenine AL Shai-Kobiler E Steele LN Ong H Augostini P Song R Lee SJ Autissier P Ruprecht RM Secor WE 《PLoS neglected tropical diseases》2008,2(7):e265
Background
Individuals living in sub-Saharan Africa represent 10% of the world''s population but almost 2/3 of all HIV-1/AIDS cases. The disproportionate HIV-1 infection rates in this region may be linked to helminthic parasite infections that affect many individuals in the developing world. However, the hypothesis that parasite infection increases an individual''s susceptibility to HIV-1 has never been prospectively tested in a relevant in vivo model.Methodology/Principal Findings
We measured whether pre-existing infection of rhesus monkeys with a parasitic worm would facilitate systemic infection after mucosal AIDS virus exposure. Two groups of animals, one consisting of normal monkeys and the other harboring Schistosoma mansoni, were challenged intrarectally with decreasing doses of R5-tropic clade C simian-human immunodeficiency virus (SHIV-C). Systemic infection occurred in parasitized monkeys at viral doses that remained sub-infectious in normal hosts. In fact, the 50% animal infectious (AID50) SHIV-C dose was 17-fold lower in parasitized animals compared to controls (P<0.001). Coinfected animals also had significantly higher peak viral RNA loads than controls (P<0.001), as well as increased viral replication in CD4+ central memory cells (P = 0.03).Conclusions/Significance
Our data provide the first direct evidence that acute schistosomiasis significantly increases the risk of de novo AIDS virus acquisition, and the magnitude of the effect suggests that control of helminth infections may be a useful public health intervention to help decrease the spread of HIV-1. 相似文献174.
Feng S Okenka GM Bai CX Streets AJ Newby LJ DeChant BT Tsiokas L Obara T Ong AC 《The Journal of biological chemistry》2008,283(42):28471-28479
Autosomal dominant polycystic kidney disease (ADPKD), the most common inherited cause of kidney failure, is caused by mutations in either PKD1 (85%) or PKD2 (15%). The PKD2 protein, polycystin-2 (PC2 or TRPP2), is a member of the transient receptor potential (TRP) superfamily and functions as a non-selective calcium channel. PC2 has been found to form oligomers in native tissues suggesting that it may form functional homo- or heterotetramers with other subunits, similar to other TRP channels. Our experiments unexpectedly revealed that PC2 mutant proteins lacking the known C-terminal dimerization domain were still able to form oligomers and co-immunoprecipitate full-length PC2, implying the possible existence of a proximal dimerization domain. Using yeast two-hybrid and biochemical assays, we have mapped an alternative dimerization domain to the N terminus of PC2 (NT2-1-223, L224X). Functional characterization of this domain demonstrated that it was sufficient to induce cyst formation in zebrafish embryos and inhibit PC2 surface currents in mIMCD3 cells probably by a dominant-negative mechanism. In summary, we propose a model for PC2 assembly as a functional tetramer which depends on both C- and N-terminal dimerization domains. These results have significant implications for our understanding of PC2 function and disease pathogenesis in ADPKD and provide a new strategy for studying PC2 function. 相似文献
175.
Simultaneous ammonium-nitrogen (NH(4)(+)-N) and copper removal, and copper recovery in synthetic wastewater using nitrifying biofilm from an ultra-compact biofilm reactor (UCBR) was demonstrated in batch studies, which consisted of three phases: Phase 1 for NH(4)(+)-N and copper removals, Phase 2 for copper recovery, and Phase 3 for NH(4)(+)-N removal. The results showed that more than 96.3% of copper was removed within 60min, while 60.1% of the adsorbed copper was recovered through rinsing the biofilms with 0.1mM of ethylenediaminetetraacetic acid (EDTA). The nitrifying biofilm was able to adsorb 0.245mg of copper/g of biofilms. After recovery treatment, 29.4% of copper remained bound within the nitrifying biofilms. No significant inhibitory effects towards NH(4)(+)-N removal in the presence of 0.92mg copper/L was noted in Phase 1 compared with the control test. However, lower initial pH condition in the recovery process and the accumulation of copper on the biofilm led to 50% inhibition on NH(4)(+)-N removal efficiency in the subsequent phase. 相似文献
176.
Ong PL Yao YF Weng YM Hsu WH Lin LL 《Biochemical and biophysical research communications》2008,366(2):294-300
To evaluate the importance of conserved Arg114 and Arg337 residues of Escherichia coli γ-glutamyltranspeptidase (EcGGT), Lys, Leu, or Asp-substituted mutants were constructed by site-directed mutagenesis. The wild-type and mutant enzymes were overexpressed in the recombinant E. coli M15 and purified by nickel-chelate chromatography to near homogeneity. With the exception of R114K, all the other mutants significantly lost GGT activity, confirming the importance of these two residues in EcGGT. Kinetic analysis of R114L, R114D, R337K, and R337L revealed a significant increase in Km with a minor change in kcat, leading to more than an 8-fold decrease in kcat/Km values. Mutations of Arg337 impaired the capability of autocatalytic processing of the enzyme. In vitro maturation experiments revealed that EcGGT precursor mutants, pro-R337K and pro-R337L, could precede a time-dependent autocatalytic process to generate the small and large subunits, while no autocatalytic processing was observed in pro-R337D. Computer modeling showed that the critical bonding distance of Gln390 O-Thr391 HG1 and Gln390 C-Thr391 OG1 are significantly increased in Arg337 replacements, implying that these distance changes might be responsible for the lack of enzyme maturation. 相似文献
177.
Previous studies show that aqueous garlic extract and its derivatives (e.g. S-allylcysteine [SAC]) prevent carcinogen-induced breast tumorigenesis. However, investigations testing the effect of SAC on later stages of breast tumorigenesis and/or metastasis have produced mixed results. Here we show that SAC significantly reduced anchorage-dependent and -independent growth of MDA-MB-231 breast tumor cells in a dose- and time-dependent fashion, and sub-lethal SAC-treatment altered mammary tumor cell adhesion and invasion through components of the extracellular matrix. We provide evidence to suggest increased expression of E-cadherin and reduced MMP-2 expression and activity are partially responsible for inhibition of mammary tumor cell invasion by SAC. Because E-cadherin and MMP-2 are important in cancer metastasis, these results suggest a link between SAC induction of E-cadherin and reduction of MMP2 activity with the inhibition of cell motility and invasion; thus providing evidence that events leading to breast cancer metastasis are repressed by sub-lethal SAC-treatment. 相似文献
178.
179.
AU binding proteins recruit the exosome to degrade ARE-containing mRNAs. 总被引:45,自引:0,他引:45
C Y Chen R Gherzi S E Ong E L Chan R Raijmakers G J Pruijn G Stoecklin C Moroni M Mann M Karin 《Cell》2001,107(4):451-464
Inherently unstable mammalian mRNAs contain AU-rich elements (AREs) within their 3' untranslated regions. Although found 15 years ago, the mechanism by which AREs dictate rapid mRNA decay is not clear. In yeast, 3'-to-5' mRNA degradation is mediated by the exosome, a multisubunit particle. We have purified and characterized the human exosome by mass spectrometry and found its composition to be similar to its yeast counterpart. Using a cell-free RNA decay system, we demonstrate that the mammalian exosome is required for rapid degradation of ARE-containing RNAs but not for poly(A) shortening. The mammalian exosome does not recognize ARE-containing RNAs on its own. ARE recognition requires certain ARE binding proteins that can interact with the exosome and recruit it to unstable RNAs, thereby promoting their rapid degradation. 相似文献
180.
Wan Yun Ho Jer-Cherng Chang Kenneth Lim Amaury Cazenave-Gassiot Aivi T. Nguyen Juat Chin Foo Sneha Muralidharan Ashley Viera-Ortiz Sarah J.M. Ong Jin Hui Hor Ira Agrawal Shawn Hoon Olubankole Aladesuyi Arogundade Maria J. Rodriguez Su Min Lim Seung Hyun Kim John Ravits Shi-Yan Ng Markus R. Wenk Edward B. Lee Greg Tucker-Kellogg Shuo-Chien Ling 《The Journal of cell biology》2021,220(9)