全文获取类型
收费全文 | 1167篇 |
免费 | 92篇 |
出版年
2023年 | 4篇 |
2022年 | 5篇 |
2021年 | 37篇 |
2020年 | 16篇 |
2019年 | 20篇 |
2018年 | 27篇 |
2017年 | 11篇 |
2016年 | 34篇 |
2015年 | 70篇 |
2014年 | 68篇 |
2013年 | 101篇 |
2012年 | 127篇 |
2011年 | 120篇 |
2010年 | 63篇 |
2009年 | 49篇 |
2008年 | 83篇 |
2007年 | 58篇 |
2006年 | 69篇 |
2005年 | 77篇 |
2004年 | 47篇 |
2003年 | 45篇 |
2002年 | 32篇 |
2001年 | 8篇 |
2000年 | 6篇 |
1999年 | 9篇 |
1998年 | 11篇 |
1997年 | 6篇 |
1996年 | 4篇 |
1995年 | 4篇 |
1994年 | 5篇 |
1993年 | 4篇 |
1992年 | 6篇 |
1991年 | 6篇 |
1990年 | 4篇 |
1989年 | 3篇 |
1988年 | 1篇 |
1986年 | 4篇 |
1985年 | 1篇 |
1983年 | 1篇 |
1979年 | 3篇 |
1976年 | 2篇 |
1973年 | 1篇 |
1963年 | 1篇 |
1960年 | 2篇 |
1959年 | 2篇 |
1956年 | 1篇 |
1954年 | 1篇 |
排序方式: 共有1259条查询结果,搜索用时 171 毫秒
31.
Timothy M. Chapman Simon A. Osborne Nathalie Bouloc Jonathan M. Large Claire Wallace Kristian Birchall Keith H. Ansell Hayley M. Jones Debra Taylor Barbara Clough Judith L. Green Anthony A. Holder 《Bioorganic & medicinal chemistry letters》2013,23(10):3064-3069
A series of imidazopyridazines which are potent inhibitors of Plasmodium falciparum calcium-dependent protein kinase 1 (PfCDPK1) was identified from a high-throughput screen against the isolated enzyme. Subsequent exploration of the SAR and optimisation has yielded leading members which show promising in vitro anti-parasite activity along with good in vitro ADME and selectivity against human kinases. Initial in vivo testing has revealed good oral bioavailability in a mouse PK study and modest in vivo efficacy in a Plasmodium berghei mouse model of malaria. 相似文献
32.
33.
Yi He Qinlong Zheng Ole Simonsen Kristian K. Petersen Thorbjørn G. Christiansen Morten A. Karsdal Anne C. Bay-Jensen 《Matrix biology》2013,32(3-4):143-151
ADAMTS-4 (aggrecanase1) is believed to play an important role in the degradation of aggrecan during the progression of joint diseases. ADAMTS-4 is synthesized as a latent pro-enzyme that requires the removal of the pro-domain, exposing the N-terminal neoepitope, to achieve activity. We developed a monoclonal antibody against this neoepitope of active ADAMTS-4. Furthermore, we established and characterized a competitive ELISA for measuring active ADAMTS-4 form applying the specific antibody. We used this assay to profile the presence of active ADAMTS-4 and its aggrecan degradation product (NITEGE373) in a bovine cartilage ex vivo model. We found that after stimulation with catabolic factors, the cartilage initially released high levels of aggrecanase-derived aggrecan fragments into supernatant but subsequently decreased to background levels. The level of active ADAMTS-4 released into the supernatant and retained in the cartilage matrix increased continuously throughout the 21 days of the study. The activity of ADAMTS-4 on the last day of catabolic stimulation was verified in vitro by adding deglycosylated or native aggrecan to the conditioned medium. Samples of human cartilage affected by varying degrees of osteoarthritis stained strongly for active ADAMTS-4 where surface fibrillation and clustered chondrocytes were observed. This assay could be an effective tool for studying ADAMTS-4 activity and for screening drugs regulating ADAMTS-4 activation. Moreover, it could be a potential biomarker for degenerative joint disease. 相似文献
34.
Alistair J. Fielding Kristian Parey Ulrich Ermler Silvan Scheller Bernhard Jaun Marina Bennati 《Journal of biological inorganic chemistry》2013,18(8):905-915
Heterodisulfide reductase (Hdr) is a key enzyme in the energy metabolism of methanogenic archaea. The enzyme catalyzes the reversible reduction of the heterodisulfide (CoM-S-S-CoB) to the thiol coenzymes M (CoM-SH) and B (CoB-SH). Cleavage of CoM-S-S-CoB at an unusual FeS cluster reveals unique substrate chemistry. The cluster is fixed by cysteines of two cysteine-rich CCG domain sequence motifs (CX31–39CCX35–36CXXC) of subunit HdrB of the Methanothermobacter marburgensis HdrABC complex. We report on Q-band (34 GHz) 57Fe electron-nuclear double resonance (ENDOR) spectroscopic measurements on the oxidized form of the cluster found in HdrABC and in two other CCG-domain-containing proteins, recombinant HdrB of Hdr from M. marburgensis and recombinant SdhE of succinate: quinone reductase from Sulfolobus solfataricus P2. The spectra at 34 GHz show clearly improved resolution arising from the absence of proton resonances and polarization effects. Systematic spectral simulations of 34 GHz data combined with previous 9 GHz data allowed the unambiguous assignment of four 57Fe hyperfine couplings to the cluster in all three proteins. 13C Mims ENDOR spectra of labelled CoM-SH were consistent with the attachment of the substrate to the cluster in HdrABC, whereas in the other two proteins no substrate is present. 57Fe resonances in all three systems revealed unusually large 57Fe ENDOR hyperfine splitting as compared to known systems. The results infer that the cluster’s unique magnetic properties arise from the CCG binding motif. 相似文献
35.
Kristian Spilling Ása Brynjólfsdóttir Dagmar Enss Heiko Rischer Halldór Guðfinnur Svavarsson 《Journal of applied phycology》2013,25(5):1435-1439
We tested the hypothesis that increased pH reduces the amount of structural lipids. To do this, we used three different diatoms (Phaeodactylum tricornutum CCAP strain, P. tricornutum TV strain and Amphiprora sp). We tested the effect of rapid increase from pH?7.5 to 10 by adding NaOH. The total lipid content was reduced by 13, 36 and 47 % in the P. tricornutum CCAP strain, TV strain and Amphiprora sp., respectively, 1 h after increasing the pH. The P. tricornutum CCAP strain was used for further testing the effect of pH on the lipid content during active growth. This strain was cultivated at pH?7.5 and 10, and the pH was regulated by the CO2 inflow. The growth rate was similar (0.3 day?1) in both pH treatments, but the lipid content in the pH?10 treatment was on average 28 % lower than in the pH?7.5 treatment. Our data support the hypothesis that structural lipids are reduced when pH increases to high levels. The results suggest that regulating the pH during algae cultivation could be used to refine the lipid composition in the harvested algal biomass. 相似文献
36.
Christoph Scherber David J. Gladbach Karen Stevnbak Rune Juelsborg Karsten Inger Kappel Schmidt Anders Michelsen Kristian Rost Albert Klaus Steenberg Larsen Teis Nørgaard Mikkelsen Claus Beier Søren Christensen 《Ecology and evolution》2013,3(6):1449-1460
The impact of climate change on herbivorous insects can have far‐reaching consequences for ecosystem processes. However, experiments investigating the combined effects of multiple climate change drivers on herbivorous insects are scarce. We independently manipulated three climate change drivers (CO2, warming, drought) in a Danish heathland ecosystem. The experiment was established in 2005 as a full factorial split‐plot with 6 blocks × 2 levels of CO2 × 2 levels of warming × 2 levels of drought = 48 plots. In 2008, we exposed 432 larvae (n = 9 per plot) of the heather beetle (Lochmaea suturalis Thomson ), an important herbivore on heather, to ambient versus elevated drought, temperature, and CO2 (plus all combinations) for 5 weeks. Larval weight and survival were highest under ambient conditions and decreased significantly with the number of climate change drivers. Weight was lowest under the drought treatment, and there was a three‐way interaction between time, CO2, and drought. Survival was lowest when drought, warming, and elevated CO2 were combined. Effects of climate change drivers depended on other co‐acting factors and were mediated by changes in plant secondary compounds, nitrogen, and water content. Overall, drought was the most important factor for this insect herbivore. Our study shows that weight and survival of insect herbivores may decline under future climate. The complexity of insect herbivore responses increases with the number of combined climate change drivers. 相似文献
37.
Kristian Soltesz Jin-Oh Hahn Tore Hägglund Guy A. Dumont J. Mark Ansermino 《Biomedical signal processing and control》2013,8(6):500-508
This paper proposes an individualized approach to closed-loop control of depth of hypnosis during propofol anesthesia. The novelty of the paper lies in the individualization of the controller at the end of the induction phase of anesthesia, based on a patient model identified from the dose–response relationship during induction of anesthesia. The proposed approach is shown to be superior to administration of propofol based on population-based infusion schemes tailored to individual patients. This approach has the potential to outperform fully adaptive approaches in regards to controller robustness against measurement variability due to surgical stimulation. To streamline controller synthesis, two output filters were introduced (inverting the Hill dose–response model and the linear time-invariant sensor model), which yield a close-to-linear representation of the system dynamics when used with a compartmental patient model. These filters are especially useful during the induction phase of anesthesia in which a nonlinear dose–response relationship complicates the design of an appropriate controller. The proposed approach was evaluated in simulation on pharmacokinetic and pharmacodynamic models of 44 patients identified from real clinical data. A model of the NeuroSense, a hypnotic depth monitor based on wavelet analysis of EEG, was also included. This monitor is similar to the well-known BIS, but has linear time-invariant dynamics and does not introduce a delay. The proposed scheme was compared with a population-based controller, i.e. a controller only utilizing models based on demographic covariates for its tuning. On average, the proposed approach offered 25% improvement in disturbance attenuation, measured as the integrated absolute error following a step disturbance. The corresponding standard deviation from the reference was also decreased by 25%. Results are discussed and possible directions of future work are proposed. 相似文献
38.
Background
Poor self-rated health (SRH) has been connected to immunological changes, and pregnancy complications have been suggested in the etiology of autoimmune diseases including inflammatory bowel disease (IBD). We evaluated the impact of self-rated pre-pregnancy health and pregnancy course, hyperemesis, gestational hypertension, and preeclampsia on risk of IBD.Methods
Information was collected by questionnaires from The Danish National Birth Cohort (enrolment 1996–2002) at 16th and 30th week of pregnancy and 6 months postpartum. A total of 55,699 women were followed from childbirth until development of IBD (using validated National Hospital Discharge Register diagnoses), emigration, death, or end of follow-up, 31st of October, 2011. Hazard ratios (HR) with 95% confidence intervals (CI) were calculated using Cox proportional hazards models adjusting for age and evaluating pre-pregnancy BMI, parity, alcohol and tobacco consumption, and socio-occupational status as potential confounders.Results
Risk of IBD increased with decreasing level of self-rated pre-pregnancy health (p = 0.002) and was elevated in women with poor self-rated pregnancy course (HR, 1.61, 95% CI 1.22–2.12). Associations persisted for more than 5 years postpartum. Hyperemesis and preeclampsia were not significantly associated with risk of IBD.Conclusions
This is the first prospective observational study to suggest that poor self-rated health – in general and in relation to pregnancy – is associated with increased risk of IBD even in the long term though results needs further confirmation. Symptoms of specific pregnancy complications were, on the other hand, not significantly associated with risk of IBD. 相似文献39.
40.