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991.
Boyd SE Pike RN Rudy GB Whisstock JC Garcia de la Banda M 《Journal of bioinformatics and computational biology》2005,3(3):551-585
Proteases play a fundamental role in the control of intra- and extra-cellular processes by binding and cleaving specific amino acid sequences. Identifying these targets is extremely challenging. Current computational attempts to predict cleavage sites are limited, representing these amino acid sequences as patterns or frequency matrices. Here we present PoPS, a publicly accessible bioinformatics tool (http://pops.csse.monash.edu.au/) that provides a novel method for building computational models of protease specificity, which while still being based on these amino acid sequences, can be built from any experimental data or expert knowledge available to the user. PoPS specificity models can be used to predict and rank likely cleavages within a single substrate, and within entire proteomes. Other factors, such as the secondary or tertiary structure of the substrate, can be used to screen unlikely sites. Furthermore, the tool also provides facilities to infer, compare and test models, and to store them in a publicly accessible database. 相似文献
992.
Dijoux MG Schnabel PC Hallock YF Boswell JL Johnson TR Wilson JA Ireland CM van Soest R Boyd MR Barrows LR Cardellina JH 《Bioorganic & medicinal chemistry》2005,13(21):6035-6044
A detailed analysis of four different collections of the sponge genus Zyzzya yielded nine pyrroloiminoquinones of the makaluvamine, batzelline, and isobatzelline/damirone classes. Dereplication analyses of additional Zyzzya extracts did not disclose more potent or additional new compounds. Comparative testing of these compounds in the National Cancer Institute's 60 cell line human tumor screen revealed varying levels of potency and differential cytotoxicity, apparently related to the unsaturation levels in and substitution patterns on the core ring system. Further studies on the topoisomerase II-mediated DNA cleavage were conducted. Reductive activation of the pyrroloiminoquinones led to DNA damage in vitro, which correlated with half wave potentials and reversibility parameters. DNA damage could be abrogated by ascorbate. Fluorescence displacement was used to measure intercalation with DNA; intercalation efficiency did not correlate with DNA-damaging proficiency. Makaluvamine H (5) emerged as the most potent and differential of our isolates, roughly comparable to makaluvamines C (in vitro) and I (in vivo). 3,7-Dimethyl guanine was isolated from one of the Zyzzya collections and from the sponge Latrunculia purpurea. 相似文献
993.
Franchetti P Cappellacci L Pasqualini M Petrelli R Jayaprakasan V Jayaram HN Boyd DB Jain MD Grifantini M 《Bioorganic & medicinal chemistry》2005,13(6):2045-2053
Thiazole-4-carboxamide adenine dinucleotide (TAD) analogues T-2'-MeAD (1) and T-3'-MeAD (2) containing, respectively, a methyl group at the ribose 2'-C-, and 3'-C-position of the adenosine moiety, were prepared as potential selective human inosine monophosphate dehydrogenase (IMPDH) type II inhibitors. The synthesis of heterodinucleotides was carried out by CDI-catalyzed coupling reaction of unprotected 2'-C-methyl- or 3'-C-methyl-adenosine 5'-monophosphate with 2',3'-O-isopropylidene-tiazofurin 5'-monophosphate, and then deisopropylidenation. Biological evaluation of dinucleotides 1 and 2 as inhibitors of recombinant human IMPDH type I and type II resulted in a good activity. Inhibition of both isoenzymes by T-2'-MeAD and T-3'-MeAD was noncompetitive with respect to NAD substrate. Binding of T-3'-MeAD was comparable to that of parent compound TAD, while T-2'-MeAD proved to be a weaker inhibitor. However, no significant difference was found in inhibition of the IMPDH isoenzymes. T-2'-MeAD and T-3'-MeAD were found to inhibit the growth of K562 cells (IC(50) 30.7 and 65.0muM, respectively). 相似文献
994.
Lin X Yang H Sakuragi T Hu M Mantell LL Hayashi S Al-Abed Y Tracey KJ Ulloa L Miller EJ 《American journal of physiology. Lung cellular and molecular physiology》2005,289(4):L583-L590
High mobility group box 1 (HMGB1) protein, a late mediator of lethality in sepsis, can induce acute inflammatory lung injury. Here, we identify the critical role of alpha-chemokine receptors in the HMGB1-induced inflammatory injury and show that alpha-chemokine receptor inhibition increases survival in sepsis, in a clinically relevant time frame. Intratracheal instillation of recombinant HMGB1 induces a neutrophilic leukocytosis, preceded by alveolar accumulation of the alpha-chemokine macrophage inflammatory protein-2 and accompanied by injury and increased inflammatory potential within the air spaces. To investigate the role of alpha-chemokine receptors in the injury, we instilled recombinant HMGB1 (0.5 microg) directly into the lungs and administered a subcutaneous alpha-chemokine receptor inhibitor, Antileukinate (200 microg). alpha-Chemokine receptor blockade reduced HMGB1-induced inflammatory injury (neutrophils: 2.9 +/- 3.2 vs. 8.1 +/- 2.4 x 10(4) cells; total protein: 120 +/- 48 vs. 311 +/- 129 microg/ml; reactive nitrogen species: 2.3 +/- 0.3 vs. 3.5 +/- 1.3 microM; and macrophage migration inhibitory factor: 6.4 +/- 4.2 vs. 37.4 +/- 15.9 ng/ml) within the bronchoalveolar lavage fluid, indicating that HMGB1-induced inflammation and injury are alpha-chemokine mediated. Because HMGB1 can mediate late septic lethality, we administered Antileukinate to septic mice and observed increased survival (from 58% in controls to 89%) even when the inhibitor treatment was initiated 24 h after the induction of sepsis. These data demonstrate that alpha-chemokine receptor inhibition can reduce HMGB1-induced lung injury and lethality in established sepsis and may provide a novel treatment in this devastating disease. 相似文献
995.
Chester VL Biden EN Tingley M 《Biomedical instrumentation & technology / Association for the Advancement of Medical Instrumentation》2005,39(1):64-74
Gait analysis, or the study of locomotion, has changed dramatically over the last few decades. Advances in computer technology and data analysis techniques have contributed greatly to the progress of this field. Gait analysis has become a valuable tool in the clinical setting. The ability to objectively quantify motion is essential to our understanding of normal and abnormal movement patterns and the evaluation of treatment effectiveness. This paper will discuss the various experimental and analytical techniques currently used for performing clinical gait analyses at the University of New Brunswick, Fredericton, New Brunswick, Canada. 相似文献
996.
Kunji ER Chan KW Slotboom DJ Floyd S O'Connor R Monné M 《Current opinion in biotechnology》2005,16(5):546-551
Eukaryotic membrane proteins play many vital roles in the cell and are important drug targets. Approximately 25% of all genes identified in the genome are known to encode membrane proteins, but the vast majority have no assigned function. Although the generation of structures of soluble proteins has entered the high-throughput stage, for eukaryotic membrane proteins only a dozen high-resolution structures have been obtained so far. One major bottleneck for the functional and structural characterisation of membrane proteins is the overproduction of biologically active material. Recent advances in the development of the Lactococcus lactis expression system have opened the way for the high-throughput functional expression of eukaryotic membrane proteins. 相似文献
997.
Interhemispheric transport of viable fungi and bacteria from Africa to the Caribbean with soil dust 总被引:2,自引:0,他引:2
Joseph?M.?ProsperoEmail author Edmund?Blades George?Mathison Raana?Naidu 《Aerobiologia》2005,21(1):1-19
Daily aerosol samples collected in trade winds at Barbados, West Indies, throughout 1996–1997 yielded significant concentrations of viable (culture-forming) bacteria and fungi only when African dust was present. Air masses from the North Atlantic, North America, and Europe yielded no cultivable organisms. The strong association of cultivable organisms with African dust suggests various factors that might be relevant to viability. Although we did not specifically look for pathogens, these same mechanisms could protect them as well. Our results suggest that arid regions could be an important source for the long-range transport of viable microorganisms. The transport of microorganisms to Barbados follows a clear meteorological and seasonal pattern, which suggests that it should be possible to model the transport process and to predict events. Microorganism and dust concentrations were unusually great in 1997, possibly in response to the strong El Niño. This suggests that the long-range transport of microorganisms might be particularly responsive to climate variability in general. 相似文献
998.
999.
Boyd AP Ross PJ Conroy H Mahon N Lavelle EC Mills KH 《Journal of immunology (Baltimore, Md. : 1950)》2005,175(2):730-738
Adenylate cyclase toxin (CyaA) of Bordetella pertussis belongs to the repeat in toxin family of pore-forming toxins, which require posttranslational acylation to lyse eukaryotic cells. CyaA modulates dendritic cell (DC) and macrophage function upon stimulation with LPS. In this study, we examined the roles of acylation and enzymatic activity in the immunomodulatory and lytic effects of CyaA. The adenylate cyclase activity of CyaA was necessary for its modulatory effects on murine innate immune cells. In contrast, acylation was not essential for the immunomodulatory function of CyaA, but was required for maximal caspase-3 activation and cytotoxic activity. The wild-type acylated toxin (A-CyaA) and nonacylated CyaA (NA-CyaA), but not CyaA with an inactive adenylate cyclase domain (iAC-CyaA), enhanced TLR-ligand-induced IL-10 and inhibited IL-12, TNF-alpha, and CCL3 production by macrophages and DC. In addition, both A-CyaA and NA-CyaA, but not iAC-CyaA, enhanced surface expression of CD80 and decreased CpG-stimulated CD40 and ICAM-1 expression on immature DC. Furthermore, both A-CyaA and NA-CyaA promoted the induction of murine IgG1 Abs, Th2, and regulatory T cells against coadministered Ags in vivo, whereas iAC-CyaA had more limited adjuvant activity. In contrast, A-CyaA and iAC-CyaA induced caspase-3 activation and cell death in macrophages, but these effects were considerably reduced or absent with NA-CyaA. Our findings demonstrate that the enzymatic activity plays a critical role in the immunomodulatory effects of CyaA, whereas acylation facilitates the induction of apoptosis and cell lysis, and as such, NA-CyaA has considerable potential as a nontoxic therapeutic molecule with potent anti-inflammatory properties. 相似文献
1000.
Frank Schuster Rainer Müller Edmund Hartung Norbert Roewer Martin Anetseder 《BMC anesthesiology》2005,5(1):1-5