全文获取类型
收费全文 | 1251篇 |
免费 | 73篇 |
出版年
2022年 | 7篇 |
2021年 | 18篇 |
2020年 | 10篇 |
2019年 | 17篇 |
2018年 | 24篇 |
2017年 | 9篇 |
2016年 | 26篇 |
2015年 | 49篇 |
2014年 | 62篇 |
2013年 | 56篇 |
2012年 | 85篇 |
2011年 | 67篇 |
2010年 | 36篇 |
2009年 | 56篇 |
2008年 | 59篇 |
2007年 | 49篇 |
2006年 | 58篇 |
2005年 | 69篇 |
2004年 | 47篇 |
2003年 | 43篇 |
2002年 | 35篇 |
2001年 | 34篇 |
2000年 | 42篇 |
1999年 | 21篇 |
1998年 | 19篇 |
1997年 | 18篇 |
1996年 | 16篇 |
1995年 | 7篇 |
1994年 | 9篇 |
1993年 | 9篇 |
1992年 | 23篇 |
1991年 | 11篇 |
1990年 | 13篇 |
1989年 | 13篇 |
1988年 | 11篇 |
1987年 | 7篇 |
1986年 | 7篇 |
1984年 | 8篇 |
1982年 | 7篇 |
1980年 | 11篇 |
1979年 | 10篇 |
1975年 | 9篇 |
1974年 | 7篇 |
1973年 | 12篇 |
1972年 | 9篇 |
1971年 | 10篇 |
1969年 | 11篇 |
1968年 | 8篇 |
1965年 | 7篇 |
1958年 | 6篇 |
排序方式: 共有1324条查询结果,搜索用时 31 毫秒
211.
212.
Bouzid W Stefka J Hypsa V Lek S Scholz T Legal L Ben Hassine OK Loot G 《International journal for parasitology》2008,38(12):1465-1479
Parasite species with global distributions and complex life cycles offer a rare opportunity to study alternative mechanisms of speciation and evolution in a single model. Here, genealogy and genetic structure, with respect to geography and fish host preference, have been analyzed for Ligula intestinalis, a tapeworm affecting freshwater fish. The data analyzed consisted of 109 tapeworms sampled from 13 fish host species in 18 different localities on a macrogeographic scale. Two mitochondrial genes, cytochrome oxidase subunit I and cytochrome B, and the nuclear sequence of intergenic transcribed spacer 2 (ITS2) were used for the genetic reconstruction. Different evolutionary patterns were found at the local and at the global geographic scales. On a local scale, the flat genetic structure was mainly attributed to contiguous range expansion. Migrating birds are the most likely cause of the homogenisation of the whole population, preventing the creation of significant genetic barriers. By contrast, on a global scale, genetically distant and well-separated clusters are present in different geographic areas. Reproductive isolation was found even between clades living in sympatry and infecting the same definitive host, suggesting the existence of efficient biologically determined genetic barriers, and thus possibly separate species. Although the ITS2 sequences were found to display considerable intragenomic variability, their relationships were generally in good agreement with the topology derived from mitochondrial genes. 相似文献
213.
Barley grain maturation and germination: metabolic pathway and regulatory network commonalities and differences highlighted by new MapMan/PageMan profiling tools 总被引:4,自引:0,他引:4 下载免费PDF全文
Sreenivasulu N Usadel B Winter A Radchuk V Scholz U Stein N Weschke W Strickert M Close TJ Stitt M Graner A Wobus U 《Plant physiology》2008,146(4):1738-1758
214.
Elsässer T Brons S Psonka K Scholz M Gudowska-Nowak E Taucher-Scholz G 《Radiation research》2008,169(6):649-659
The investigation of fragment length distributions of plasmid DNA gives insight into the influence of localized energy distribution on the induction of DNA damage, particularly the clustering of double-strand breaks. We present an approach that determines the fragment length distributions of plasmid DNA after heavy-ion irradiation by using the Local Effect Model. We find a good agreement of our simulations with experimental fragment distributions derived from atomic force microscopy (AFM) studies by including experimental constraints typical for AFM. Our calculations reveal that by comparing the fragmentation in terms of fluence, we can uniquely distinguish the effect of different radiation qualities. For very high-LET irradiation using nickel or uranium ions, no difference between their fragment distributions can be expected for the same dose level. However, for carbon ions with an intermediate LET, the fragmentation pattern differs from the distribution for very high-LET particles. The results of the model calculations can be used to determine the optimal experimental parameters for a demonstration of the influence of track structure on primary radiation damage. Additionally, we compare the results of our model for two different plasmid geometries. 相似文献
215.
Sandra J. Bucci Fabian G. Scholz Guillermo Goldstein Frederick C. Meinzer Maria E. Arce 《Oecologia》2009,160(4):631-641
Adaptations of species to capture limiting resources is central for understanding structure and function of ecosystems. We
studied the water economy of nine woody species differing in rooting depth in a Patagonian shrub steppe from southern Argentina
to understand how soil water availability and rooting depth determine their hydraulic architecture. Soil water content and
potentials, leaf water potentials (ΨLeaf), hydraulic conductivity, wood density (ρw), rooting depth, and specific leaf area (SLA) were measured during two summers. Water potentials in the upper soil layers
during a summer drought ranged from −2.3 to −3.6 MPa, increasing to −0.05 MPa below 150 cm. Predawn ΨLeaf was used as a surrogate of weighted mean soil water potential because no statistical differences in ΨLeaf were observed between exposed and covered leaves. Species-specific differences in predawn ΨLeaf were consistent with rooting depths. Predawn ΨLeaf ranged from −4.0 MPa for shallow rooted shrubs to −1.0 MPa for deep-rooted shrubs, suggesting that the roots of the latter
have access to abundant moisture, whereas shallow-rooted shrubs are adapted to use water deposited mainly by small rainfall
events. Wood density was a good predictor of hydraulic conductivity and SLA. Overall, we found that shallow rooted species
had efficient water transport in terms of high specific and leaf specific hydraulic conductivity, low ρw, high SLA and a low minimum ΨLeaf that exhibited strong seasonal changes, whereas deeply rooted shrubs maintained similar minimum ΨLeaf throughout the year, had stems with high ρw and low hydraulic conductivity and leaves with low SLA. These two hydraulic syndromes were the extremes of a continuum with
several species occupying different portions of a gradient in hydraulic characteristics. It appears that the marginal cost
of having an extensive root system (e.g., high ρw and root hydraulic resistance) contributes to low growth rates of the deeply rooted species. 相似文献
216.
Thao Nguyen Dominic De Nardo Paul Masendycz John A. Hamilton Glen M. Scholz 《Cellular signalling》2009,21(5):719-726
Macrophages are important mediators of the immune response to infection by virtue of their ability to secrete cytokines that trigger inflammation. Toll-like receptors (TLRs) are largely responsible for meditating the activation of macrophages by pathogens. IRAK-1 is a proximal protein kinase in TLR signalling pathways and hence its activation must be tightly regulated. However, the mechanisms which control the activation of IRAK-1 are poorly understood. IRAK-1 contains a death domain at its N-terminus that mediates its interaction with other death domain containing proteins, a central Ser/Thr kinase domain, and a C-terminal domain that contains binding motifs for TRAF6. We show here that deletion of the death domain or the majority of the C-terminal domain markedly enhanced the capacity of IRAK-1 to activate NF-κB in a TLR-independent manner in RAW 264.7 macrophages. Furthermore, the C-terminal truncation mutant spontaneously oligomerised and formed complexes with the negative regulator IRAK-M in the absence of TLR activation. In contrast to the binding of IRAK-M to IRAK-1, the death domain of IRAK-1 was not required for the interaction of IRAK-4 with IRAK-1. On the basis of these results we propose a model in which IRAK-1 is held in a closed, inactive conformation via an intramolecular mechanism involving its C-terminal domain and possibly the death domain. Phosphorylation of IRAK-1 by IRAK-4 in response to TLR activation may then release IRAK-1 from the inhibitory constraint exerted by its C-terminal domain. 相似文献
217.
Macrophages are important mediators of the immune response to infection by virtue of, amongst other things, their ability to secrete cytokines (e.g. TNF) that trigger inflammation. However, excessive systemic release of inflammatory cytokines can cause septic shock and ultimately death. Tolerance is an adaptive mechanism that prevents macrophage activation and inflammatory cytokine production. The activation of macrophages by pathogens is largely mediated by Toll-like receptors (TLRs). IRAK-4 and IRAK-1 are proximal protein kinases in TLR signalling pathways; IRAK-1 is activated via its phosphorylation by IRAK-4. The rapid degradation of IRAK-1 following its TLR-induced activation has been proposed to represent a major mechanism for tolerance. Here, we established that IRAK-1 degradation is insufficient to cause tolerance; in the absence of IRAK-1, IRAK-4 likely activates downstream signalling proteins (e.g. NF-kappaB) via IRAK-2. Significantly, tolerance coincided with IRAK-4 down-regulation, which occurred at the protein level via proteolytic degradation as well as at the mRNA level. Gene silencing experiments confirmed the importance of IRAK-4 for the regulation of TNF expression. The different kinetics of IRAK-4 and IRAK-1 down-regulation may result in both quantitative and qualitative differences in TLR signalling and potentially allow macrophages to temporally modify their inflammatory responses. Furthermore, differences in the kinetics and extent of IRAK-4 down-regulation by TLR ligands may provide a mechanism whereby macrophages can tailor their inflammatory response according to the location and/or type of pathogen detected. 相似文献
218.
Jeschke U Mylonas I Kunert-Keil C Stahn R Scholz C Janni W Kuhn C Schröder E Mayr D Friese K 《Histochemistry and cell biology》2009,131(2):283-295
Glycodelins (Gds) are glycoproteins with a gender specific glycosylation. Glycodelin A (GdA) is primarily produced in endometrial
and decidual tissue and secreted to amniotic fluid. Glycodelins were also identified in several cancer types, including serous
ovarian cancer. Gds act as a T-cell inhibitor and are involved in inactivation of human monocytes. With a Gd peptide antibody,
derived from a 15 amino acid sequence of human Gd and in situ hybridization experiments, the expression of Gd in serous, mucinous,
endometrioid and clear cell ovarian tumors was identified. In contrast to former investigations with antibodies against GdA,
a positive immunohistochemical reaction for Gd was observed in all forms of epithelium ovarian cancer. These results were
confirmed with in situ hybridization. In addition, Gd is expressed in granulose cell tumors, a non-epithelial form of ovarian
cancer. Furthermore, Gd was purified from ascites fluid of ovarian cancer patients. Ascites Gd showed significant differences
in its structure of sialyl Lewis-type oligosaccharides compared to GdA. Additionally, ascites Gd inhibits IL-2 stimulated
proliferation of peripheral blood leucocytes and inhibits adhesion of SLeX-positive cells to E-selectin. Therefore, Gd could act as an inhibitor of lymphocyte activation and/or adhesion in ovarian
cancer.
U. Jeschke, I. Mylonas and C. Kunert-Keil contributed equally to this work. 相似文献
219.
M. Scholz M. Ackermann†‡ C. Engel F. Emmrich† M. Loeffler M. Kamprad† 《Cell proliferation》2009,42(6):813-822
Objectives: Recombinant human granulocyte colony-stimulating factor (rhG-CSF) is widely used as treatment for granulocytopaenia during cytotoxic chemotherapy; however, optimal scheduling of this pharmaceutical is unknown. Biomathematical models can help to pre-select optimal application schedules but precise pharmacokinetic properties of the pharmaceuticals are required at first. In this study, we have aimed to construct a pharmacokinetic model of G-CSF derivatives filgrastim and pegfilgrastim in mice.
Methods: Healthy CD-1 mice and those with cyclophosphamide-induced granulocytopaenia were studied after administration of filgrastim and pegfilgrastim in different dosing and timing schedules. Close meshed time series of granulocytes and G-CSF plasma concentrations were determined. An ordinary differential equations model of pharmacokinetics was constructed on the basis of known mechanisms of drug distribution and degradation.
Results: Predictions of the model fit well with all experimental data for both filgrastim and pegfilgrastim. We obtained a unique parameter setting for all experimental scenarios. Differences in pharmacokinetics between filgrastim and pegfilgrastim can be explained by different estimates of model parameters rather than by different model mechanisms. Parameter estimates with respect to distribution and clearance of the drug derivatives are in agreement with qualitative experimental results.
Conclusion: Dynamics of filgrastim and pegfilgrastim plasma levels can be explained by the same pharmacokinetic model but different model parameters. Beause of a strong clearance mechanism mediated by granulocytes, granulocytotic and granulocytopaenic conditions must be studied simultaneously to construct a reliable model. The pharmacokinetic model will be extended to a murine model of granulopoiesis under chemotherapy and G-CSF application. 相似文献
Methods: Healthy CD-1 mice and those with cyclophosphamide-induced granulocytopaenia were studied after administration of filgrastim and pegfilgrastim in different dosing and timing schedules. Close meshed time series of granulocytes and G-CSF plasma concentrations were determined. An ordinary differential equations model of pharmacokinetics was constructed on the basis of known mechanisms of drug distribution and degradation.
Results: Predictions of the model fit well with all experimental data for both filgrastim and pegfilgrastim. We obtained a unique parameter setting for all experimental scenarios. Differences in pharmacokinetics between filgrastim and pegfilgrastim can be explained by different estimates of model parameters rather than by different model mechanisms. Parameter estimates with respect to distribution and clearance of the drug derivatives are in agreement with qualitative experimental results.
Conclusion: Dynamics of filgrastim and pegfilgrastim plasma levels can be explained by the same pharmacokinetic model but different model parameters. Beause of a strong clearance mechanism mediated by granulocytes, granulocytotic and granulocytopaenic conditions must be studied simultaneously to construct a reliable model. The pharmacokinetic model will be extended to a murine model of granulopoiesis under chemotherapy and G-CSF application. 相似文献
220.
Steven Arcidiacono Jason W. Soares Alexa M. Meehan Patrick Marek Romy Kirby 《Journal of peptide science》2009,15(6):398-403
The interaction of cecropin P1 (CP1) with Escherichiacoli was investigated to gain insight into the time‐dependent antimicrobial action. Biophysical characterizations of CP1 with whole bacterial cells were performed using both fluorescent and colorimetric assays to investigate the role of membrane permeability and lipopolysaccharide (LPS) binding in lytic behavior. The kinetics of CP1 growth inhibition assays indicated a minimal inhibitory concentration (MIC) of 3 µM . Bactericidal kinetics at the MIC indicated rapid killing of E.coli (<30 min). Membrane permeability studies illustrated permeation as a time‐dependent event. Maximum permeability at the MIC occurred within 30 min, which correlates to the bactericidal action. Further investigation showed that the immediate permeabilizing action of CP1 is concentration‐dependent, which correlates to the concentration‐dependent nature of the inhibition assays. At the MIC and above, the immediate permeability was significant enough that the cells could not recover and exhibit growth. Below the MIC, immediate permeability was evident, but the level was insufficient to inhibit growth. Dansyl polymyxin B displacement studies showed LPS binding is essentially the same at all concentrations investigated. However, it does appear that only the immediate interaction is important, because binding continued to increase over time beyond cell viability. Our studies correlated CP1 bactericidal kinetics to membrane permeability suggesting CP1 concentration‐dependent killing is driven by the extent of the immediate permeabilizing action of the peptide. Copyright © 2009 European Peptide Society and John Wiley & Sons, Ltd. 相似文献