全文获取类型
收费全文 | 7328篇 |
免费 | 681篇 |
国内免费 | 6篇 |
出版年
2023年 | 43篇 |
2022年 | 100篇 |
2021年 | 232篇 |
2020年 | 153篇 |
2019年 | 183篇 |
2018年 | 180篇 |
2017年 | 157篇 |
2016年 | 210篇 |
2015年 | 355篇 |
2014年 | 380篇 |
2013年 | 461篇 |
2012年 | 548篇 |
2011年 | 543篇 |
2010年 | 321篇 |
2009年 | 288篇 |
2008年 | 380篇 |
2007年 | 391篇 |
2006年 | 328篇 |
2005年 | 336篇 |
2004年 | 315篇 |
2003年 | 279篇 |
2002年 | 272篇 |
2001年 | 67篇 |
2000年 | 43篇 |
1999年 | 64篇 |
1998年 | 83篇 |
1997年 | 38篇 |
1996年 | 32篇 |
1995年 | 36篇 |
1994年 | 30篇 |
1993年 | 42篇 |
1992年 | 44篇 |
1991年 | 30篇 |
1990年 | 31篇 |
1989年 | 40篇 |
1988年 | 29篇 |
1987年 | 37篇 |
1986年 | 33篇 |
1985年 | 28篇 |
1984年 | 36篇 |
1983年 | 23篇 |
1982年 | 43篇 |
1981年 | 44篇 |
1980年 | 42篇 |
1979年 | 23篇 |
1978年 | 39篇 |
1977年 | 29篇 |
1975年 | 33篇 |
1974年 | 30篇 |
1973年 | 29篇 |
排序方式: 共有8015条查询结果,搜索用时 15 毫秒
991.
992.
Chiu HC Lee SL Kapuriya N Wang D Chen YR Yu SL Kulp SK Teng LJ Chen CS 《Bioorganic & medicinal chemistry》2012,20(15):4653-4660
Methicillin-resistant Staphylococcus aureus (MRSA) poses a serious threat to public health because of its resistance to multiple antibiotics most commonly used to treat infection. In this study, we report the unique ability of the cyclooxygenase-2 (COX-2) inhibitor celecoxib to kill Staphylococcus aureus and MRSA with modest potency. We hypothesize that the anti-Staphylococcus activity of celecoxib could be pharmacologically exploited to develop novel anti-MRSA agents with a distinct mechanism. Examination of an in-house, celecoxib-based focused compound library in conjunction with structural modifications led to the identification of compound 46 as the lead agent with high antibacterial potency against a panel of Staphylococcus pathogens and different strains of MRSA. Moreover, this killing effect is bacteria-specific, as human cancer cells are resistant to 46. In addition, a single intraperitoneal administration of compound 46 at 30 mg/kg improved the survival of MRSA-infected C57BL/6 mice. In light of its high potency in eradicating MRSA in vitro and its in vivo activity, compound 46 and its analogues warrant continued preclinical development as a potential therapeutic intervention against MRSA. 相似文献
993.
An exposed F-type lectin domain fused to the N-terminus of a cholesterol-dependent cytolysin scaffold allows Streptococcus mitis lectinolysin to cluster at fucose-rich sites on target cell membranes, thereby leading to increased pore-forming toxin activity. In this issue of Structure, Feil and coworkers define the structural basis for lectinolysin glycan-binding specificity. 相似文献
994.
Claudia Knief Nathana?l Delmotte Samuel Chaffron Manuel Stark Gerd Innerebner Reiner Wassmann Christian von Mering Julia A Vorholt 《The ISME journal》2012,6(7):1378-1390
The above- and below-ground parts of rice plants create specific habitats for various microorganisms. In this study, we characterized the phyllosphere and rhizosphere microbiota of rice cultivars using a metaproteogenomic approach to get insight into the physiology of the bacteria and archaea that live in association with rice. The metaproteomic datasets gave rise to a total of about 4600 identified proteins and indicated the presence of one-carbon conversion processes in the rhizosphere as well as in the phyllosphere. Proteins involved in methanogenesis and methanotrophy were found in the rhizosphere, whereas methanol-based methylotrophy linked to the genus Methylobacterium dominated within the protein repertoire of the phyllosphere microbiota. Further, physiological traits of differential importance in phyllosphere versus rhizosphere bacteria included transport processes and stress responses, which were more conspicuous in the phyllosphere samples. In contrast, dinitrogenase reductase was exclusively identified in the rhizosphere, despite the presence of nifH genes also in diverse phyllosphere bacteria. 相似文献
995.
H Attar K Bedard E Migliavacca M Gagnebin Y Dupré P Descombes C Borel S Deutsch H Prokisch T Meitinger D Mehta E Wichmann JM Delabar ET Dermitzakis KH Krause SE Antonarakis 《PloS one》2012,7(8):e43566
Natural variation in DNA sequence contributes to individual differences in quantitative traits. While multiple studies have shown genetic control over gene expression variation, few additional cellular traits have been investigated. Here, we investigated the natural variation of NADPH oxidase-dependent hydrogen peroxide (H2O2 release), which is the joint effect of reactive oxygen species (ROS) production, superoxide metabolism and degradation, and is related to a number of human disorders. We assessed the normal variation of H2O2 release in lymphoblastoid cell lines (LCL) in a family-based 3-generation cohort (CEPH-HapMap), and in 3 population-based cohorts (KORA, GenCord, HapMap). Substantial individual variation was observed, 45% of which were associated with heritability in the CEPH-HapMap cohort. We identified 2 genome-wide significant loci of Hsa12 and Hsa15 in genome-wide linkage analysis. Next, we performed genome-wide association study (GWAS) for the combined KORA-GenCord cohorts (n = 279) using enhanced marker resolution by imputation (>1.4 million SNPs). We found 5 significant associations (p<5.00×10−8) and 54 suggestive associations (p<1.00×10−5), one of which confirmed the linked region on Hsa15. To replicate our findings, we performed GWAS using 58 HapMap individuals and ∼2.1 million SNPs. We identified 40 genome-wide significant and 302 suggestive SNPs, and confirmed genome signals on Hsa1, Hsa12, and Hsa15. Genetic loci within 900 kb from the known candidate gene p67phox on Hsa1 were identified in GWAS in both cohorts. We did not find replication of SNPs across all cohorts, but replication within the same genomic region. Finally, a highly significant decrease in H2O2 release was observed in Down Syndrome (DS) individuals (p<2.88×10−12). Taken together, our results show strong evidence of genetic control of H2O2 in LCL of healthy and DS cohorts and suggest that cellular phenotypes, which themselves are also complex, may be used as proxies for dissection of complex disorders. 相似文献
996.
Danger signaling through the inflammasome acts as a master switch between tolerance and sensitization 总被引:1,自引:0,他引:1
Watanabe H Gehrke S Contassot E Roques S Tschopp J Friedmann PS French LE Gaide O 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(9):5826-5832
Efficient priming of adaptive immunity depends on danger signals provided by innate immune pathways. As an example, inflammasome-mediated activation of caspase-1 and IL-1beta is crucial for the development of reactive T cells targeting sensitizers like dinitrofluorobenzene (DNFB). Surprisingly, DNFB and dinitrothiocyanobenzene provide cross-reactive Ags yet drive opposing, sensitizing vs tolerizing, T cell responses. In this study, we show that, in mice, inflammasome-signaling levels can be modulated to turn dinitrothiocyanobenzene into a sensitizer and DNFB into a tolerizer, and that it correlates with the IL-6 and IL-12 secretion levels, affecting Th1, Th17, and regulatory T cell development. Hence, our data provide the first evidence that the inflammasome can define the type of adaptive immune response elicited by an Ag, and hint at new strategies to modulate T cell responses in vivo. 相似文献
997.
998.
Gammaherpesvirus 68 (γHV68, or MHV68) is a naturally occurring rodent pathogen that replicates to high titer in cell culture and is amenable to in vivo experimental evaluation of viral and host determinants of gammaherpesvirus disease. However, the inability of MHV68 to transform primary murine B cells in culture, the absence of a robust cell culture latency system, and the paucity of MHV68-positive tumor cell lines have limited an understanding of the molecular mechanisms by which MHV68 modulates the host cell during latency and reactivation. To facilitate a more complete understanding of viral and host determinants that regulate MHV68 latency and reactivation in B cells, we generated a recombinant MHV68 virus that encodes a hygromycin resistance protein fused to enhanced green fluorescent protein as a means to select cells in culture that harbor latent virus. We utilized this virus to infect the A20 murine mature B-cell line and evaluate reactivation competence following treatment with diverse stimuli to reveal viral gene expression, DNA replication, and production of progeny virions. Comparative analyses of parental and infected A20 cells indicated a correlation between infection and alterations in DNA damage signaling following etoposide treatment. The data described in this study highlight the potential utility of this new cell culture-based system to dissect molecular mechanisms that regulate MHV68 latency and reactivation, as well as having the potential of illuminating biochemical alterations that contribute to gammaherpesvirus pathogenesis. In addition, such cell lines may be of value in evaluating targeted therapies to gammaherpesvirus-related tumors. 相似文献
999.
Murine gammaherpesvirus 68 (MHV68) infection of inbred mice represents a genetically tractable small-animal model for assessing the requirements for the establishment of latency, as well as reactivation from latency, within the lymphoid compartment. By day 16 postinfection, MHV68 latency in the spleen is found in B cells, dendritic cells, and macrophages. However, as with Epstein-Barr virus, by 3 months postinfection MHV68 latency is predominantly found in isotype-switched memory B cells. The MHV68 M2 gene product is a latency-associated antigen with no discernible homology to any known cellular or viral proteins. However, depending on experimental conditions, the M2 protein has been shown to play a critical role in both the efficient establishment of latency in splenic B cells and reactivation from latently infected splenic B cells. Inspection of the sequence of the M2 protein reveals several hallmarks of a signaling molecule, including multiple PXXP motifs and two potential tyrosine phosphorylation sites. Here, we report the generation of a panel of recombinant MHV68 viruses harboring mutations in the M2 gene that disrupt putative functional motifs. Subsequent analyses of the panel of M2 mutant viruses revealed a functionally important cluster of PXXP motifs in the C-terminal region of M2, which have previously been implicated in binding Vav proteins (P. A. Madureira, P. Matos, I. Soeiro, L. K. Dixon, J. P. Simas, and E. W. Lam, J. Biol. Chem. 280:37310-37318, 2005; L. Rodrigues, M. Pires de Miranda, M. J. Caloca, X. R. Bustelo, and J. P. Simas, J. Virol. 80:6123-6135, 2006). Further characterization of two adjacent PXXP motifs in the C terminus of the M2 protein revealed differences in the functions of these domains in M2-driven expansion of primary murine B cells in culture. Finally, we show that tyrosine residues 120 and 129 play a critical role in both the establishment of splenic latency and reactivation from latency upon explant of splenocytes into tissue culture. Taken together, these analyses will aide future studies for identifying M2 interacting partners and B-cell signaling pathways that are manipulated by the M2 protein. 相似文献
1000.
The distribution of predators is widely recognized to be intimately linked to the distribution of their prey. Foraging theory
suggests that predators will modify their behaviors, including movements, to optimize net energy intake when faced with variation
in prey attributes or abundance. While many studies have documented changes in movement patterns of animals in response to
temporal changes in food, very few have contrasted movements of a single predator species naturally occurring in dramatically
different prey landscapes. We documented variation in the winter movements, foraging range size, site fidelity, and distribution
patterns of a molluscivorous sea duck, the surf scoter (Melanitta perspicillata), in two areas of coastal British Columbia with very different shellfish prey features. Baynes Sound has extensive tidal
flats with abundant clams, which are high-quality and temporally stable prey for scoters. Malaspina Inlet is a rocky fjord-like
inlet where scoters consume mussels that are superabundant and easily accessible in some patches but are heavily depleted
over the course of winter. We used radio telemetry to track surf scoter movements in both areas and found that in the clam
habitats of Baynes Sound, surf scoters exhibited limited movement, small winter ranges, strong foraging site fidelity, and
very consistent distribution patterns. By contrast, in mussel habitats in the Malaspina Inlet, surf scoters displayed more
movement, larger ranges, little fidelity to specific foraging sites, and more variable distribution patterns. We conclude
that features associated with the different prey types, particularly the higher depletion rates of mussels, strongly influenced
seasonal space use patterns. These findings are consistent with foraging theory and confirm that predator behavior, specifically
movements, is environmentally mediated. 相似文献