全文获取类型
收费全文 | 5270篇 |
免费 | 381篇 |
国内免费 | 2篇 |
专业分类
5653篇 |
出版年
2023年 | 31篇 |
2022年 | 60篇 |
2021年 | 139篇 |
2020年 | 60篇 |
2019年 | 95篇 |
2018年 | 119篇 |
2017年 | 94篇 |
2016年 | 177篇 |
2015年 | 179篇 |
2014年 | 247篇 |
2013年 | 316篇 |
2012年 | 341篇 |
2011年 | 332篇 |
2010年 | 193篇 |
2009年 | 187篇 |
2008年 | 218篇 |
2007年 | 239篇 |
2006年 | 189篇 |
2005年 | 194篇 |
2004年 | 167篇 |
2003年 | 132篇 |
2002年 | 145篇 |
2001年 | 141篇 |
2000年 | 123篇 |
1999年 | 101篇 |
1998年 | 45篇 |
1997年 | 42篇 |
1996年 | 34篇 |
1995年 | 42篇 |
1994年 | 40篇 |
1993年 | 29篇 |
1992年 | 89篇 |
1991年 | 69篇 |
1990年 | 87篇 |
1989年 | 70篇 |
1988年 | 80篇 |
1987年 | 74篇 |
1986年 | 72篇 |
1985年 | 68篇 |
1984年 | 56篇 |
1983年 | 33篇 |
1981年 | 27篇 |
1980年 | 35篇 |
1979年 | 45篇 |
1978年 | 31篇 |
1977年 | 35篇 |
1976年 | 34篇 |
1974年 | 31篇 |
1973年 | 33篇 |
1972年 | 31篇 |
排序方式: 共有5653条查询结果,搜索用时 15 毫秒
901.
Das J Sitaram Kumar M Subrahmanyam D Sastry TV Prasad Narasimhulu C Laxman Rao CV Kannan M Roshaiah M Awasthi R Patil SN Sarnaik HM Rao Mamidi NV Selvakumar N Iqbal J 《Bioorganic & medicinal chemistry》2006,14(23):8032-8042
In an effort to discover potent antibacterials based on the entropically favored 'bioactive conformation' approach, a series of novel tricyclic molecules mimicking the conformationally constrained structure of Linezolid is reported. Based on the initial tricyclic molecule 1, the benzazepine derivative 2 was designed where the tricyclic structure had more flexibility around C-N bond compared to 1. While, the molecule 2 was less active, the molecule 3 showed promising antibacterial activity presumably after having obtained rigidity due to pyrrole ring. The syntheses, SAR studies, and evaluation of 3 as a lead compound are reported. 相似文献
902.
Samik Das Dibyendu N. Sengupta Amita Pal 《Journal of plant biochemistry and biotechnology.》2006,15(2):123-129
Differential regeneration response in two cotyledon types (Cot and Cot E) of Vigna radiata was reported earlier. The Cot (one cotyledon) is easily detachable from the germinating embryonal axis, whereas, Cot E (the other cotyledon) remains firmly attached during seed germination or after imbibition. Shoots differentiated directly from the Cot E under the induction of in vitro differentiation, while, under the same milieu, shoot differentiation was preceded by callus differentiation from Cot. In this study, we present comparative analyses of protein profiles from these two explant types recorded at different point of time during induction of differentiation. Cot E always contained higher amounts of soluble protein than the Cot. Likewise, higher de novo protein synthesis was noted in Cot E than in Cot as revealed by 35S methionine labeled study. Two polypeptides of ~37 and 84 kD disappeared earlier from Cot E than Cot and is presumed to be linked with shoot induction. Two marker proteins of ~88 and 158 kD synthesized during shoot differentiation were apparent. It was observed that the labeled protein synthesis initiated within 3h in Cot E under in vitro condition, while, no labeled protein was detected from Cot even at 12h. Irrespective of the mode of differentiation, a large amount of protein was hydrolyzed during the process of differentiation. However, in case of Cot, the process was delayed by a day than Cot E. In all probability, this is an indication of delayed cytokinin induced rejuvenation of Cot. Temporal difference in protein profile was also evident in these two explant types during in vitro differentiation. Yet, three major groups of proteins were consistently present in both the explants. The biochemical differences recorded between these two explants during induction of in vitro differentiation reflects the temporal difference in gene expression. Perhaps Cot E has the distinctiveness due to the temporal differences in certain key gene expression and proved its greater suitability over Cot for shoot regeneration purposes. 相似文献
903.
904.
The human cytomegalovirus (HCMV) US12 gene family is a group of predicted seven-transmembrane, G-protein-coupled receptor-related proteins, about which little is known. Specific rabbit polyclonal antibodies detected US17 and US18 beginning 54 and 36 h after infection, respectively, with expression of both proteins dependent on viral DNA synthesis. While US14 and US18 are expressed exclusively in the cytoplasm, we unexpectedly found abundant expression of US17 in both the cytoplasm and nucleoplasm. N- and C-terminally tagged versions of US17 were readily detected in the cytoplasm of transfected mammalian cells, but not in nuclei, suggesting that nuclear localization involves other viral proteins or an infection-triggered cellular process. There was no specific colocalization between US17 and other nuclear expressed HCMV-encoded proteins (IE-2, DNA polymerase processivity factor, and pp28/UL99). To determine whether the observed nuclear localization might be the product of a process by which a soluble C-terminal segment of the full-length protein is expressed, we constructed a recombinant virus that incorporates a synthetic epitope at its N terminus, which in conjunction with the antipeptide antibody that targets its predicted cytoplasmic C-terminal segment, enables simultaneous independent detection of both termini. In cells infected with the recombinant, the US17 N and C termini had limited colocalization, with the N-terminal segment not detected in nuclei, supporting the segmentation hypothesis. Consistent with this, a fragment with an apparent molecular size of 10 kDa was detected by immunoblotting. We have identified the first viral example of a seven-transmembrane protein that is either segmented or expressed in nuclei. Further study will be required to learn the mechanism by which this occurs and the function of the nuclear localizing segment. This likely represents yet another mechanism by which a virus has hijacked or modified cellular regulatory pathways for its benefit. 相似文献
905.
Maeda K Das D Ogata-Aoki H Nakata H Miyakawa T Tojo Y Norman R Takaoka Y Ding J Arnold GF Arnold E Mitsuya H 《The Journal of biological chemistry》2006,281(18):12688-12698
We have characterized the structural and molecular interactions of CC-chemokine receptor 5 (CCR5) with three CCR5 inhibitors active against R5 human immunodeficiency virus type 1 (HIV-1) including the potent in vitro and in vivo CCR5 inhibitor aplaviroc (AVC). The data obtained with saturation binding assays and structural analyses delineated the key interactions responsible for the binding of CCR5 inhibitors with CCR5 and illustrated that their binding site is located in a predominantly lipophilic pocket in the interface of extracellular loops and within the upper transmembrane (TM) domain of CCR5. Mutations in the CCR5 binding sites of AVC decreased gp120 binding to CCR5 and the susceptibility to HIV-1 infection, although mutations in TM4 and TM5 that also decreased gp120 binding and HIV-1 infectivity had less effects on the binding of CC-chemokines, suggesting that CCR5 inhibition targeting appropriate regions might render the inhibition highly HIV-1-specific while preserving the CC chemokine-CCR5 interactions. The present data delineating residue by residue interactions of CCR5 with CCR5 inhibitors should not only help design more potent and more HIV-1-specific CCR5 inhibitors, but also give new insights into the dynamics of CC-chemokine-CCR5 interactions and the mechanisms of CCR5 involvement in the process of cellular entry of HIV-1. 相似文献
906.
907.
Lützelberger M Reinert LS Das AT Berkhout B Kjems J 《The Journal of biological chemistry》2006,281(27):18644-18651
Productive infection and successful replication of human immunodeficiency virus 1 (HIV-1) requires the balanced expression of all viral genes. This is achieved by a combination of alternative splicing events and regulated nuclear export of viral RNA. Because viral splicing is incomplete and intron-containing RNAs must be exported from the nucleus where they are normally retained, it must be ensured that the unspliced HIV-1 RNA is actively exported from the nucleus and protected from degradation by processes such as nonsense-mediated decay. Here we report the identification of a novel 178-nt-long exon located in the gag-pol gene of HIV-1 and its inclusion in at least two different mRNA species. Although efficiently spliced in vitro, this exon appears to be tightly repressed and infrequently used in vivo. The splicing is activated or repressed in vitro by the splicing factors ASF/SF2 and heterogeneous nuclear ribonucleoprotein A1, respectively, suggesting that splicing is controlled by these factors. Interestingly, mutations in the 5'-splice site resulted in a dramatic reduction in the steady-state level of HIV-1 RNA, and this effect was partially reversed by expression of U1 small nuclear RNA harboring the compensatory mutation. This implies that U1 small nuclear RNA binding to optimal but non-functional splice sites might have a role in protecting unspliced HIV-1 mRNA from degradation. 相似文献
908.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) and T-cell responses: what we do and don't know 总被引:7,自引:0,他引:7
Shi Y Liu CH Roberts AI Das J Xu G Ren G Zhang Y Zhang L Yuan ZR Tan HS Das G Devadas S 《Cell research》2006,16(2):126-133
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is an important hematopoietic growth factor and immune modulator. GM-CSF also has profound effects on the functional activities of various circulating leukocytes. It is produced by a variety of cell types including T cells, macrophages, endothelial cells and fibroblasts upon receiving immune stimuli. Although GM-CSF is produced locally, it can act in a paracrine fashion to recruit circulating neutrophils, monocytes and lymphocytes to enhance their functions in host defense. Recent intensive investigations are centered on the application of GM-CSF as an immune adjuvant for its ability to increase dendritic cell (DC) maturation and function as well as macrophage activity. It is used clinically to treat neutropenia in cancer patients undergoing chemotherapy, in AIDS patients during therapy, and in patients after bone marrow transplantation. Interestingly, the hematopoietic system of GM-CSF-deficient mice appears to be normal; the most significant changes are in some specific T cell responses. Although molecular cloning of GM-CSF was carried out using cDNA library oft cells and it is well known that the T cells produce GM-CSF after activation, there is a lack of systematic investigation of this cytokine in production by T cells and its effect on T cell function. In this article, we will focus mainly on the immunobiology of GM-CSF in T cells. 相似文献
909.
Background
Nitrate and nitrite (jointly referred to herein as NOx) are ubiquitous environmental contaminants to which aquatic organisms are at particularly high risk of exposure. We tested the hypothesis that NOx undergo intracellular conversion to the potent signaling molecule nitric oxide resulting in the disruption of endocrine-regulated processes.Methodology/Principal Findings
These experiments were performed with insect cells (Drosophila S2) and whole organisms Daphnia magna. We first evaluated the ability of cells to convert nitrate (NO3 −) and nitrite (NO2 −) to nitric oxide using amperometric real-time nitric oxide detection. Both NO3 − and NO2 − were converted to nitric oxide in a substrate concentration-dependent manner. Further, nitric oxide trapping and fluorescent visualization studies revealed that perinatal daphnids readily convert NO2 − to nitric oxide. Next, daphnids were continuously exposed to concentrations of the nitric oxide-donor sodium nitroprusside (positive control) and to concentrations of NO3 − and NO2 −. All three compounds interfered with normal embryo development and reduced daphnid fecundity. Developmental abnormalities were characteristic of those elicited by compounds that interfere with ecdysteroid signaling. However, no compelling evidence was generated to indicate that nitric oxide reduced ecdysteroid titers.Conclusions/Significance
Results demonstrate that nitrite elicits developmental and reproductive toxicity at environmentally relevant concentrations due likely to its intracellular conversion to nitric oxide. 相似文献910.
Dinesh DS Das ML Picado A Roy L Rijal S Singh SP Das P Boelaert M Coosemans M 《PLoS neglected tropical diseases》2010,4(10):e859