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151.
152.
Wang J Balog CI Stavenhagen K Koeleman CA Scherer HU Selman MH Deelder AM Huizinga TW Toes RE Wuhrer M 《Molecular & cellular proteomics : MCP》2011,10(5):M110.004655
We have recently shown that IgG1 directed against antigens thought to be involved in the pathogenesis of rheumatoid arthritis harbor different glycan moieties on their Fc-tail, as compared with total sera IgG1. Given the crucial roles of Fc-linked N-glycans for the structure and biological activity of IgG, Fc-glycosylation of antibodies is receiving considerable interest. However, so far little is known about the signals and factors that could influence the composition of these carbohydrate structures on secreted IgG produced by B lymphocytes. Here we show that both "environmental" factors, such as all-trans retinoic acid (a natural metabolite of vitamin A), as well as factors stimulating the innate immune system (i.e. CpG oligodeoxynucleotide, a ligand for toll-like receptor 9) or coming from the adaptive immune system (i.e. interleukin-21, a T-cell derived cytokine) can modulate IgG1 Fc-glycosylation. These factors affect Fc-glycan profiles in different ways. CpG oligodeoxynucleotide and interleukin-21 increase Fc-linked galactosylation and reduce bisecting N-acetylglucosamine levels, whereas all-trans retinoic acid significantly decreases galactosylation and sialylation levels. Moreover, these effects appeared to be stable and specific for secreted IgG1 as no parallel changes of the corresponding glycans in the cellular glycan pool were observed. Interestingly, several other cytokines and molecules known to affect B-cell biology and antibody production did not have an impact on IgG1 Fc-coupled glycan profiles. Together, these data indicate that different stimuli received by B cells during their activation and differentiation can modulate the Fc-linked glycosylation of secreted IgG1 without affecting the general cellular glycosylation machinery. Our study, therefore, furthers our understanding of the regulation of IgG1 glycosylation at the cellular level. 相似文献
153.
154.
Pati A Gronow S Zeytun A Lapidus A Nolan M Hammon N Deshpande S Cheng JF Tapia R Han C Goodwin L Pitluck S Liolios K Pagani I Ivanova N Mavromatis K Chen A Palaniappan K Land M Hauser L Chang YJ Jeffries CD Detter JC Brambilla E Rohde M Göker M Woyke T Bristow J Eisen JA Markowitz V Hugenholtz P Kyrpides NC Klenk HP Lucas S 《Standards in genomic sciences》2011,4(1):45-53
Bacteroides helcogenes Benno et al. 1983 is of interest because of its isolated phylogenetic location and, although it has been found in pig feces and is known to be pathogenic for pigs, occurrence of this bacterium is rare and it does not cause significant damage in intensive animal husbandry. The genome of B. helcogenes P 36-108(T) is already the fifth completed and published type strain genome from the genus Bacteroides in the family Bacteroidaceae. The 3,998,906 bp long genome with its 3,353 protein-coding and 83 RNA genes consists of one circular chromosome and is a part of the Genomic Encyclopedia of Bacteria and Archaea project. 相似文献
155.
156.
Maurer B Mathias U Papatheodorou P Shekfeh S Orth J Jank T Schwan C Sippl W Aktories K Jung M 《Molecular bioSystems》2011,7(3):799-808
ADP-ribosyltransferases (ADP-RTs) use NAD(+) to transfer an ADP-ribosyl group to target proteins. Although some ADP-RTs are bacterial toxins only few inhibitors are known. Here we present the development of fluorescence-based assays and a focussed library screening using kinase inhibitors as a new approach towards inhibitors of ADP-RTs. Different screening setups were established using surrogate small molecule substrates or the quantitation of the cofactor NAD(+). Proof-of-principle screening experiments were performed using a kinase inhibitor library in order to target the NAD(+) binding pockets. This led to the discovery of structurally different lead inhibitors for the mono-ADP-ribosyltransferases Mosquitocidal toxin (MTX) from Bacillus sphaericus SSII-1, C3bot toxin from Clostridium botulinum and CDTa from Clostridium difficile. The interaction of the inhibitors with the toxin proteins was analyzed by means of docking and binding free energy calculations. Binding at the nicotinamide subpocket, which shows a significant difference in the three enzymes, is used to explain the selectivity of the identified inhibitors and offers an opportunity for further development of potent and selective inhibitors. 相似文献
157.
Schneider EM Flacke S Liu F Lorenz MR Schilling P Nass ME Foehr KJ Huber-Lang M Weiss ME 《Journal of cell communication and signaling》2011,5(2):145-156
Severe trauma and the systemic inflammatory response syndrome (SIRS) occur as a result of a cytokine storm which is in part
due to ATP released from damaged tissue. This pathology also leads to increased numbers of immature antigen presenting cells
(APC) sharing properties of dendritic cells (DC) or macrophages (MΦ). The occurrence of immature APC appears to coincide with
the reactivation of herpes virus infections such as Epstein Barr virus (EBV). The aim of this study was the comparative analysis
of the ultrastructural and functional characteristics of such immature APC. In addition, we investigated EBV infection/ reactivation
and whether immature APC might be targets for natural killers (NK). Significant macroautophagy, mitochondrial degradation
and multivesicular body formation together with the identification of herpes virus particles were morphological findings associated
with immature APC. Exogenous stressors such as ATP further increased morphological signs of autophagy, including LC3 expression.
Functional tests using fluorescent bacteria proved impaired phagolysosome fusion. However, immature APC were susceptible to
NK-92-mediated cytolysis. We found evidence for EBV latency state II infection by detecting EBV-specific LMP1 and EBNA2 in
immature APC and in whole blood of these patients. In summary, trauma-induced cytokine storms may induce maturation arrest
of APC, promote ATP-induced autophagy, support EBV persistence and impair the degradation of phagocytozed bacteria through
inefficient phagolysosome fusion. The susceptibility to NK-mediated cytolysis supports the hypothesis that NK function is
likely to contribute to immune reconstitution after major trauma by regulating immature APC, and ATP-induced autophagy and
survival. 相似文献
158.
Organelle transport in eukaryotes employs both microtubule and actin tracks to deliver cargo effectively to their destinations, but the question of how the two systems cooperate is still largely unanswered. Recently, in vitro studies revealed that the actin-based processive motor myosin V also binds to, and diffuses along microtubules. This biophysical trick enables cells to exploit both tracks for the same transport process without switching motors. The detailed mechanisms underlying this behavior remain to be solved. By means of single molecule Total Internal Reflection Microscopy (TIRFM), we show here that electrostatic tethering between the positively charged loop 2 and the negatively charged C-terminal E-hooks of microtubules is dispensable. Furthermore, our data indicate that in addition to charge-charge interactions, other interaction forces such as non-ionic attraction might account for myosin V diffusion. These findings provide evidence for a novel way of myosin tethering to microtubules that does not interfere with other E-hook-dependent processes. 相似文献
159.
Liu F Struchalin MV Duijn Kv Hofman A Uitterlinden AG Duijn Cv Aulchenko YS Kayser M 《PloS one》2011,6(11):e28145
Multiple loss-of-function (LOF) alleles at the same gene may influence a phenotype not only in the homozygote state when alleles are considered individually, but also in the compound heterozygote (CH) state. Such LOF alleles typically have low frequencies and moderate to large effects. Detecting such variants is of interest to the genetics community, and relevant statistical methods for detecting and quantifying their effects are sorely needed. We present a collapsed double heterozygosity (CDH) test to detect the presence of multiple LOF alleles at a gene. When causal SNPs are available, which may be the case in next generation genome sequencing studies, this CDH test has overwhelmingly higher power than single SNP analysis. When causal SNPs are not directly available such as in current GWA settings, we show the CDH test has higher power than standard single SNP analysis if tagging SNPs are in linkage disequilibrium with the underlying causal SNPs to at least a moderate degree (r2>0.1). The test is implemented for genome-wide analysis in the publically available software package GenABEL which is based on a sliding window approach. We provide the proof of principle by conducting a genome-wide CDH analysis of red hair color, a trait known to be influenced by multiple loss-of-function alleles, in a total of 7,732 Dutch individuals with hair color ascertained. The association signals at the MC1R gene locus from CDH were uniformly more significant than traditional GWA analyses (the most significant P for CDH = 3.11×10−142 vs. P for rs258322 = 1.33×10−66). The CDH test will contribute towards finding rare LOF variants in GWAS and sequencing studies. 相似文献
160.