全文获取类型
收费全文 | 1633篇 |
免费 | 229篇 |
专业分类
1862篇 |
出版年
2022年 | 8篇 |
2021年 | 20篇 |
2020年 | 14篇 |
2019年 | 10篇 |
2018年 | 25篇 |
2017年 | 20篇 |
2016年 | 40篇 |
2015年 | 54篇 |
2014年 | 82篇 |
2013年 | 106篇 |
2012年 | 127篇 |
2011年 | 123篇 |
2010年 | 67篇 |
2009年 | 64篇 |
2008年 | 83篇 |
2007年 | 91篇 |
2006年 | 89篇 |
2005年 | 83篇 |
2004年 | 95篇 |
2003年 | 95篇 |
2002年 | 63篇 |
2001年 | 35篇 |
2000年 | 30篇 |
1999年 | 34篇 |
1998年 | 20篇 |
1997年 | 10篇 |
1996年 | 20篇 |
1995年 | 12篇 |
1994年 | 12篇 |
1993年 | 13篇 |
1992年 | 28篇 |
1991年 | 28篇 |
1990年 | 30篇 |
1989年 | 16篇 |
1988年 | 14篇 |
1987年 | 13篇 |
1986年 | 18篇 |
1985年 | 13篇 |
1984年 | 9篇 |
1983年 | 8篇 |
1982年 | 16篇 |
1981年 | 9篇 |
1980年 | 7篇 |
1979年 | 11篇 |
1978年 | 12篇 |
1977年 | 9篇 |
1976年 | 10篇 |
1975年 | 11篇 |
1974年 | 7篇 |
1973年 | 7篇 |
排序方式: 共有1862条查询结果,搜索用时 11 毫秒
991.
A human nuclear shuttling protein that interacts with human immunodeficiency virus type 1 matrix is packaged into virions 总被引:2,自引:0,他引:2
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)
Active nuclear import of the human immunodeficiency virus type 1 (HIV-1) preintegration complex (PIC) is essential for the productive infection of nondividing cells. Nuclear import of the PIC is mediated by the HIV-1 matrix protein, which also plays several critical roles during viral entry and possibly during virion production facilitating the export of Pr55(Gag) and genomic RNA. Using a yeast two-hybrid screen, we identified a novel human virion-associated matrix-interacting protein (VAN) that is highly conserved in vertebrates and expressed in most human tissues. Its expression is upregulated upon activation of CD4(+) T cells. VAN is efficiently incorporated into HIV-1 virions and, like matrix, shuttles between the nucleus and cytoplasm. Furthermore, overexpression of VAN significantly inhibits HIV-1 replication in tissue culture. We propose that VAN regulates matrix nuclear localization and, by extension, both nuclear import of the PIC and export of Pr55(Gag) and viral genomic RNA during virion production. Our data suggest that this regulatory mechanism reflects a more global process for regulation of nucleocytoplasmic transport. 相似文献
992.
Efficient incorporation of HLA class II onto human immunodeficiency virus type 1 requires envelope glycoprotein packaging
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)
HLA class II DR is one of the most abundant cell surface proteins incorporated onto human immunodeficiency virus type 1 (HIV-1) during budding. The mechanism for HLA class II protein incorporation is not known and may involve a viral protein. To determine whether Env affects HLA class II protein incorporation, HIV-1 virions, either with or without Env on their surface, were produced from HLA class II-expressing cells and analyzed by whole-virus immunoprecipitation with antisera against HLA class II proteins. HLA class II proteins were detected on virions only when wild-type Env was incorporated, while similar experiments showed that HLA class I proteins were incorporated independent of Env packaging. Therefore, the packaging of HIV-1 Env protein is required for the efficient incorporation of HLA class II but not class I proteins into the virion. Analysis of two Env mutants revealed that the presence of a 43-amino-acid sequence between amino acids 708 and 750 in the gp41(TM) cytoplasmic tail was required for efficient incorporation of HLA class II proteins. These data show that HIV-1 actively incorporates HLA class II proteins in a process that, either directly or indirectly, requires Env. 相似文献
993.
The enzymatic processes underlying the degradation of aggrecan in cartilage and the corresponding changes in the biomechanical properties of the tissue are an important part of the pathophysiology of osteoarthritis. Recent studies have demonstrated that the hexosamines glucosamine (GlcN) and mannosamine (ManN) can inhibit aggrecanase-mediated cleavage of aggrecan in IL-1-treated cartilage cultures. The term aggrecanase describes two or more members of the ADAMTS family of metalloproteinases whose glutamyl endopeptidase activity is known to be responsible for much of the aggrecan degradation seen in human arthritides. In this study we examined the effect of ManN and GlcN on aggrecanase-mediated degradation of aggrecan induced by IL-1alpha and the corresponding tissue mechanical properties in newborn bovine articular cartilage. After 6 days of culture in 10 ng/ml IL-1 plus ManN, mechanical testing of explants in confined compression demonstrated that ManN inhibited the IL-1alpha-induced degradation in tissue equilibrium modulus, dynamic stiffness, streaming potential, and hydraulic permeability, in a dose-dependent fashion, with peak inhibition ( approximately 75-100% inhibition) reached by a concentration of 1.35 mM. Aggrecan from explants cultured in IL-1 was found by Western analysis to be almost entirely processed down to the G1-NITEGE(373) end product. Addition of ManN or GlcN was found to produce 75-90% inhibition of this cleavage, but the proportion of aggrecan remaining in the tissue which was cleaved at aggrecanase sites in the chondroitin sulfate (CS)-rich region (Glu(1501) and Glu(1687)) was higher than with IL-1 alone. This result suggests that the preservation of mechanical properties by hexosamines in explants is primarily due to inhibition of cleavage at the Glu(373) site in the interglobular domain. While the precise mechanism by which hexosamines function in this system is unclear, the present analysis suggests that the mechanical properties examined may be predominantly a function of electrostatic repulsion due to the charged CS chains in the tightly packed repetitive sequences of the CS-1 region. 相似文献
994.
Enzymes of the arylamine N-acetyltransferase (NAT) family are found in species ranging from Escherichia coli to humans. In humans they are known to be responsible for the acetylation of a number of arylamine and hydrazine drugs, and they are strongly linked to the carcinogenic potentiation of certain foreign substances. In prokaryotes their substrate specificities may vary and members of the gene family have been linked to pathways including amide synthesis during rifamycin production. Here we report the crystal structure at 2.8 A resolution of a representative member of this family from Salmonella typhimurium in the presence and absence of a covalently bound product analog. The structure reveals surprising mechanistic information including the presence of a Cys-His-Asp catalytic triad. The fold can be described in terms of three domains of roughly equal length with the second and third domains linked by an interdomain helix. The first two domains, a helical bundle and a beta-barrel, make up the catalytic triad using a structural motif identical to that of the cysteine protease superfamily. 相似文献
995.
H B Nielsen M A Febbraio P Ott P Krustrup N H Secher 《Journal of applied physiology》2007,103(4):1227-1233
The exponential rise in blood lactate with exercise intensity may be influenced by hepatic lactate uptake. We compared muscle-derived lactate to the hepatic elimination during 2 h prolonged cycling (62 +/- 4% of maximal O(2) uptake, (.)Vo(2max)) followed by incremental exercise in seven healthy men. Hepatic blood flow was assessed by indocyanine green dye elimination and leg blood flow by thermodilution. During prolonged exercise, the hepatic glucose output was lower than the leg glucose uptake (3.8 +/- 0.5 vs. 6.5 +/- 0.6 mmol/min; mean +/- SE) and at an arterial lactate of 2.0 +/- 0.2 mM, the leg lactate output of 3.0 +/- 1.8 mmol/min was about fourfold higher than the hepatic lactate uptake (0.7 +/- 0.3 mmol/min). During incremental exercise, the hepatic glucose output was about one-third of the leg glucose uptake (2.0 +/- 0.4 vs. 6.2 +/- 1.3 mmol/min) and the arterial lactate reached 6.0 +/- 1.1 mM because the leg lactate output of 8.9 +/- 2.7 mmol/min was markedly higher than the lactate taken up by the liver (1.1 +/- 0.6 mmol/min). Compared with prolonged exercise, the hepatic lactate uptake increased during incremental exercise, but the relative hepatic lactate uptake decreased to about one-tenth of the lactate released by the legs. This drop in relative hepatic lactate extraction may contribute to the increase in arterial lactate during intense exercise. 相似文献
996.
Fritz M Lokstein H Hackenberg D Welti R Roth M Zähringer U Fulda M Hellmeyer W Ott C Wolter FP Heinz E 《The Journal of biological chemistry》2007,282(7):4613-4625
Plastidial glycolipids contain diacylglycerol (DAG) moieties, which are either synthesized in the plastids (prokaryotic lipids) or originate in the extraplastidial compartment (eukaryotic lipids) necessitating their transfer into plastids. In contrast, the only phospholipid in plastids, phosphatidylglycerol (PG), contains exclusively prokaryotic DAG backbones. PG contributes in several ways to the functions of chloroplasts, but it is not known to what extent its prokaryotic nature is required to fulfill these tasks. As a first step toward answering this question, we produced transgenic tobacco plants that contain eukaryotic PG in thylakoids. This was achieved by targeting a bacterial DAG kinase into chloroplasts in which the heterologous enzyme was also incorporated into the envelope fraction. From lipid analysis we conclude that the DAG kinase phosphorylated eukaryotic DAG forming phosphatidic acid, which was converted into PG. This resulted in PG with 2-3 times more eukaryotic than prokaryotic DAG backbones. In the newly formed PG the unique Delta3-trans-double bond, normally confined to 3-trans-hexadecenoic acid, was also found in sn-2-bound cis-unsaturated C18 fatty acids. In addition, a lipidomics technique allowed the characterization of phosphatidic acid, which is assumed to be derived from eukaryotic DAG precursors in the chloroplasts of the transgenic plants. The differences in lipid composition had only minor effects on measured functions of the photosynthetic apparatus, whereas the most obvious phenotype was a significant reduction in growth. 相似文献
997.
Ott M Norberg E Walter KM Schreiner P Kemper C Rapaport D Zhivotovsky B Orrenius S 《The Journal of biological chemistry》2007,282(38):27633-27639
Cytochrome c release from mitochondria is a key event in apoptosis signaling that is regulated by Bcl-2 family proteins. Cleavage of the BH3-only protein Bid by multiple proteases leads to the formation of truncated Bid (tBid), which, in turn, promotes the oligomerization/insertion of Bax into the mitochondrial outer membrane and the resultant release of proteins residing in the intermembrane space. Bax, a monomeric protein in the cytosol, is targeted by a yet unknown mechanism to the mitochondria. Several hypotheses have been put forward to explain this targeting specificity. Using mitochondria isolated from different mutants of the yeast Saccharomyces cerevisiae and recombinant proteins, we have now investigated components of the mitochondrial outer membrane that might be required for tBid/Bax-induced cytochrome c release. Here, we show that the protein translocase of the outer mitochondrial membrane is required for Bax insertion and cytochrome c release. 相似文献
998.
Distinct transcriptional profiles in ex vivo CD4+ and CD8+ T cells are established early in human immunodeficiency virus type 1 infection and are characterized by a chronic interferon response as well as extensive transcriptional changes in CD8+ T cells
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)
Hyrcza MD Kovacs C Loutfy M Halpenny R Heisler L Yang S Wilkins O Ostrowski M Der SD 《Journal of virology》2007,81(7):3477-3486
999.
Laura A. Lewis Krzysztof Polanski Marta de Torres-Zabala Siddharth Jayaraman Laura Bowden Jonathan Moore Christopher A. Penfold Dafyd J. Jenkins Claire Hill Laura Baxter Satish Kulasekaran William Truman George Littlejohn Justyna Prusinska Andrew Mead Jens Steinbrenner Richard Hickman David Rand David L. Wild Sascha Ott Vicky Buchanan-Wollaston Nick Smirnoff Jim Beynon Katherine Denby Murray Grant 《The Plant cell》2015,27(11):3038-3064
1000.
Liu L Sun H Valji WY Pang KS 《American journal of physiology. Gastrointestinal and liver physiology》2007,293(5):G1078-G1088
Temporal changes in physiological spaces, protein expression of transporters and enzymes, and enalapril removal were appraised in the metastatic liver tumor model developed from male Wag/Rij rats after the intraportal injection of CC531 colon adenocarcinoma cells; sham-operated preparations received PBS. Liver tissue spaces, investigated with multiple indicator dilution technique in liver perfusion studies, were unchanged at week 3 after tumor induction. At week 4, however, the sinusoidal blood volume and albumin Disse space in tumor-bearing livers were slightly lower compared with those of shams. Increased levels of the canalicular ATP transporters, P-glycoprotein, multidrug resistance-associated protein 2 (Mrp2), and bile salt export pump (Bsep) at week 2 (P < 0.05), unchanged levels of Ntcp, Oatp1a1, Oatp1a4, and Mct2, but decreased levels of cytochrome P450 3a2 (Cyp3a2) and glutathione S-transferase (Gst4-4) at week 4 (P < 0.05) were observed in peritumor vs. sham-operated liver tissues with Western blotting. The steady-state extraction ratio of enalapril, a substrate that enters the liver rapidly via Oatp1a1 and primarily undergoes metabolism by the carboxylesterases, was unaffected by liver metastasis at week 4 regardless of its delivery via the portal vein or hepatic artery into the perfused liver preparations. 相似文献