全文获取类型
收费全文 | 1356篇 |
免费 | 71篇 |
国内免费 | 67篇 |
出版年
2024年 | 5篇 |
2023年 | 27篇 |
2022年 | 39篇 |
2021年 | 66篇 |
2020年 | 58篇 |
2019年 | 70篇 |
2018年 | 66篇 |
2017年 | 36篇 |
2016年 | 51篇 |
2015年 | 48篇 |
2014年 | 75篇 |
2013年 | 126篇 |
2012年 | 43篇 |
2011年 | 60篇 |
2010年 | 45篇 |
2009年 | 56篇 |
2008年 | 58篇 |
2007年 | 61篇 |
2006年 | 55篇 |
2005年 | 47篇 |
2004年 | 56篇 |
2003年 | 35篇 |
2002年 | 36篇 |
2001年 | 17篇 |
2000年 | 22篇 |
1999年 | 24篇 |
1998年 | 15篇 |
1997年 | 25篇 |
1996年 | 13篇 |
1995年 | 19篇 |
1994年 | 10篇 |
1993年 | 18篇 |
1992年 | 19篇 |
1991年 | 8篇 |
1990年 | 5篇 |
1989年 | 14篇 |
1988年 | 3篇 |
1987年 | 4篇 |
1986年 | 14篇 |
1985年 | 7篇 |
1984年 | 11篇 |
1983年 | 4篇 |
1982年 | 4篇 |
1981年 | 5篇 |
1980年 | 4篇 |
1979年 | 2篇 |
1977年 | 1篇 |
1976年 | 3篇 |
1974年 | 2篇 |
1972年 | 1篇 |
排序方式: 共有1494条查询结果,搜索用时 171 毫秒
131.
132.
133.
Cytotoxic drugs administered in polychemotherapy cause a characteristic neutropenic period depending on the schedule of the drugs, which can partly be prevented by G-CSF growth factor support. To quantify these effects and to gain a deeper insight into the dynamics of bone marrow recovery after such suppressing and stimulating disturbances, we construct a biomathematical compartment model of human granulopoiesis under polychemotherapy with G-CSF support. The underlying assumptions and mathematical techniques used to obtain the model are explained in detail. A large variety of biological and clinical data as well as knowledge from a model of murine haematopoiesis are evaluated to construct a physiological model for humans.Particular emphasis is placed on estimating the influence of chemotherapeutic drugs on the granulopoietic system. As a result, we present an innovative method to estimate the bone marrow damage caused by cytotoxic drugs with respect to single identifiable cell stages only on the basis of measured peripheral blood leukocyte dynamics. Conversely, our model can be used in a planning phase of a clinical trial to estimate the haematotoxicity of regimens based on new combinations of drugs already considered and with or without growth factor support.Acknowledgement This paper was supported by the DFG (Deutsche Forschungsgemeinschaft) in the framework of the project Aufbau von Simulationsmodellen der h{\a}matopoetischen Dynamik nach konventioneller und hochdosierter Chemotherapie und Zytokingabe beim Menschen (Nr. LO 342/8-2). We would like to thank the German High Grade Non-Hodgkins-Lymphoma Study Group and the German Hodgkins Lymphoma Study Group for the kind provision of data. 相似文献
134.
Tesco G Ginestroni A Hiltunen M Kim M Dolios G Hyman BT Wang R Berezovska O Tanzi RE 《Journal of neurochemistry》2005,95(2):446-456
The 37-43 amino acid Abeta peptide is the principal component of beta-amyloid deposits in Alzheimer's disease (AD) brain, and is derived by serial proteolysis of the amyloid precursor protein (APP) by beta- and gamma-secretase. gamma-Secretase also cleaves APP at Val50 in the Abeta numbering (epsilon cleavage), resulting in the release of a fragment called APP intracellular domain (AICD). The aim of this study was to determine whether amino acid substitutions in the APP transmembrane domain differentially affect Abeta and AICD generation. We found that the APPV715F substitution, which has been previously shown to dramatically decrease Abeta40 and Abeta42 while increasing Abeta38 levels, does not affect in vitro generation of AICD. Furthermore, we found that the APPL720P substitution, which has been previously shown to prevent in vitro generation of AICD, completely prevents Abeta generation. Using a fluorescence resonance energy transfer (FRET) method, we next found that both the APPV715F and APPL720P substitutions significantly increase the distance between the N- and C-terminus of presenilin 1 (PS1), which has been proposed to contain the catalytic site of gamma-secretase. In conclusion, both APPV715F and APPL720P change PS1 conformation with differential effects on Abeta and AICD production. 相似文献
135.
Moreau E Fortin S Desjardins M Rousseau JL Petitclerc E C-Gaudreault R 《Bioorganic & medicinal chemistry》2005,13(24):1430-6712
In our ongoing research program aimed at the optimization of microtubule-self-assembly disrupting agents, we have prepared three series of phenylurea analogues (CEU), derived from N-(3-ω-hydroxyalkyl or 4-ω-hydroxyalkyl or 3-ω-hydroxyalkynyl)-phenyl-N′-(2-chloroethyl)ureas. Most compounds exhibit potent growth inhibitory activity on human colon carcinoma HT-29, human skin melanoma M21, and human breast carcinoma MCF-7 tumor cell lines, with a GI50 ranging from 250 nM to 8 μM. Among these new molecules, three CEUs exhibit GI50 in the nanomolar range. They are more potent by approximately an order of magnitude than previously described CEU analogues. As such, they are attractive hit compounds for the development of potent new alkylating antitubulin drugs. 相似文献
136.
McLachlan A Kekre N McNulty J Pandey S 《Apoptosis : an international journal on programmed cell death》2005,10(3):619-630
The major hurdle in the fight against cancer is the non-specific nature of current treatments. The search for specific drugs that are non-cytotoxic to normal cells and can effectively target cancer cells has lead some researchers to investigate the potential anti-cancer activity of natural compounds. Some natural compounds, such as Taxol, have been shown to posses some anti-cancer potential. Pancratistatin (PST) is a natural compound that was isolated from the spider lily Pancratium littorale and shown to exhibit antineoplastic activity. The specificity of PST to cancer cells and the mechanism of PSTs action remain unknown. This study provides a detailed look at the effect of PST treatment on cancerous and normal cells. Our results indicate that PST induced apoptosis selectively in cancer cells and that the mitochondria may be the site of action of PST in cancer cells. A biochemical target available specifically in cancer cells may lead to the development of new and more effective cancer fighting agents. 相似文献
137.
Sultana H Rivero F Blau-Wasser R Schwager S Balbo A Bozzaro S Schleicher M Noegel AA 《Traffic (Copenhagen, Denmark)》2005,6(10):930-946
Data from mutant analysis in yeast and Dictyostelium indicate a role for the cyclase-associated protein (CAP) in endocytosis and vesicle transport. We have used genetic and biochemical approaches to identify novel interacting partners of Dictyostelium CAP to help explain its molecular interactions in these processes. Cyclase-associated protein associates and interacts with subunits of the highly conserved vacuolar H(+)-ATPase (V-ATPase) and co-localizes to some extent with the V-ATPase. Furthermore, CAP is essential for maintaining the structural organization, integrity and functioning of the endo-lysosomal system, as distribution and morphology of V-ATPase- and Nramp1-decorated membranes were disturbed in a CAP mutant (CAP bsr) accompanied by an increased endosomal pH. Moreover, concanamycin A (CMA), a specific inhibitor of the V-ATPase, had a more severe effect on CAP bsr than on wild-type cells, and the mutant did not show adaptation to the drug. Also, the distribution of green fluorescent protein-CAP was affected upon CMA treatment in the wildtype and recovered after adaptation. Distribution of the V-ATPase in CAP bsr was drastically altered upon hypo-osmotic shock, and growth was slower and reached lower saturation densities in the mutant under hyper-osmotic conditions. Taken together, our data unravel a link of CAP with the actin cytoskeleton and endocytosis and suggest that CAP is an essential component of the endo-lysosomal system in Dictyostelium. 相似文献
138.
Sunlight-mediated photooxygenation of 3-O-acetyl and 3-O-methyl derivatives of 1,2-O-alkylidene-5(E)-eno-5,6,8-trideoxy-α-d-xylo-oct-1,4-furano-7-uloses (1a-e) in carbon tetrachloride solution gave stable 4,7-epidioxy derivatives in 4R (2a-e) and 4S (3a-e) configurations. The presence of an endo alkyl, on the 1,2-O-alkylidene group and its size, resulted in an increase of the yield of the 4S isomers. 3-O-Acetyl derivatives yielded products as a mixture of C-7 anomers, whereas 3-O-methyl derivatives gave pure single stereoisomers. 相似文献
139.
140.
Dopamine and cyclic AMP-regulated phosphoprotein-32 phosphorylation pattern in cocaine and morphine-sensitized rats 总被引:4,自引:0,他引:4
Scheggi S Rauggi R Gambarana C Tagliamonte A De Montis MG 《Journal of neurochemistry》2004,90(4):792-799
This study reports some of the modifications in dopaminergic signalling that accompany cocaine and morphine behavioural sensitization. Cocaine-sensitized rats showed increased phosphorylation of dopamine- and cyclic AMP-regulated phosphoprotein Mr 32 kDa (DARPP-32) at threonine-75 (Thr75) and decreased DARPP-32 phosphorylation at Thr34, in the caudate-putamen (CPu) and nucleus accumbens (NAc) 7 days after sensitization assessment. Conversely, in morphine-sensitized rats, no apparent modifications in DARPP-32 phosphorylation pattern were observed. Morphine-sensitized rats have increased binding and coupling of micro -opioid receptors and increased dopaminergic transmission in striatal areas and, upon morphine challenge, exhibit dopamine D1 receptor-dependent stereotypies. Thus, the DARPP-32 phosphorylation pattern was studied in morphine-sensitized rats at different times after morphine challenge. Morphine challenge increased levels of phospho-Thr75 DARPP-32 and decreased levels of phospho-Thr34 DARPP-32 in a time-dependent manner in the CPu and NAc. In order to assess whether these modifications were related to modified cyclic AMP-dependent protein kinase (PKA) activity, the phosphorylation levels of two other PKA substrates were examined, the GluR1 and NR1 subunits of alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate and NMDA receptors respectively. The phosphorylation levels of GluR1 and NR1 subunits decreased in parallel with those of phospho-Thr-34 DARPP-32, supporting the hypothesis that morphine challenge elicited a decrease in PKA activity in morphine-sensitized rats. 相似文献