全文获取类型
收费全文 | 370篇 |
免费 | 32篇 |
出版年
2020年 | 5篇 |
2016年 | 8篇 |
2015年 | 9篇 |
2014年 | 4篇 |
2013年 | 6篇 |
2012年 | 12篇 |
2011年 | 7篇 |
2010年 | 5篇 |
2009年 | 11篇 |
2007年 | 9篇 |
2006年 | 12篇 |
2005年 | 8篇 |
2004年 | 8篇 |
2003年 | 6篇 |
2002年 | 6篇 |
2001年 | 11篇 |
2000年 | 11篇 |
1999年 | 6篇 |
1998年 | 9篇 |
1997年 | 4篇 |
1994年 | 5篇 |
1992年 | 7篇 |
1991年 | 7篇 |
1990年 | 8篇 |
1989年 | 12篇 |
1988年 | 10篇 |
1986年 | 5篇 |
1985年 | 9篇 |
1983年 | 6篇 |
1982年 | 6篇 |
1981年 | 4篇 |
1980年 | 4篇 |
1978年 | 5篇 |
1977年 | 4篇 |
1976年 | 5篇 |
1968年 | 6篇 |
1960年 | 4篇 |
1959年 | 3篇 |
1957年 | 3篇 |
1955年 | 3篇 |
1953年 | 3篇 |
1938年 | 4篇 |
1936年 | 9篇 |
1935年 | 5篇 |
1933年 | 8篇 |
1932年 | 9篇 |
1931年 | 9篇 |
1929年 | 7篇 |
1923年 | 3篇 |
1918年 | 3篇 |
排序方式: 共有402条查询结果,搜索用时 171 毫秒
61.
Ferreira VF Jorqueira A Souza AM da Silva MN de Souza MC Gouvêa RM Rodrigues CR Pinto AV Castro HC Santos DO Araújo HP Bourguignon SC 《Bioorganic & medicinal chemistry》2006,14(16):5459-5466
Starting from alpha- and beta-lapachones, in this work we compared the biological and theoretical profile of several oxyran derivatives of lapachone as potential trypanocidal agents. Our biological results showed that the oxyrans tested act as trypanocidal agents against Trypanosoma cruzi with minimal cytotoxicity in the VERO cell line compared to naphthoquinones. The oxyran derivative of alpha-lapachone (7a) showed to be one of the most potent compounds. In our molecular modeling study, we analyzed the C-ring moiety and the redox center of beta-lapachone molecule as the moieties responsible for the trypanocidal and cytotoxic effects on mammalian cell line. The computational methods used to delineate the structural requirements for the trypanocidal profile pointed out that the transposition of the C-ring moiety of beta-lapachone, combined with its oxyran ring, introduced important molecular requirements for trypanocidal activity in the HOMO energy, HOMO orbital coefficient, LUMO density, electrostatic potential map, dipole moment vector, and calculated logP (clogP) parameter. This study could lead to the development of new antichagasic medicines based on alpha-lapachone analogs. 相似文献
62.
Differentiation of micronuclei (MN) caused by ionizing radiation from those caused by chemicals is a crucial step for managing treatment of individuals exposed to radiation. MN in binucleated lymphocytes in peripheral blood are widely used as biomarkers for estimating dose of radiation, but they are not specific for ionizing radiation. MN induced by ionizing radiation originate predominantly as a result of chromosome breaks (clastogenic action), whereas MN caused by chemical agents are derived from the loss of entire chromosomes (aneugenic action). C-banding highlights centromeres, which might make it possible to distinguish radiation induced MN, i.e., as a byproduct of acentric fragments, from those caused by the loss of entire chromosomes. To test the use of C-banding for identifying radiation induced MN, a blood sample from a healthy donor was irradiated with 3 Gy of Co-60 gamma rays and cultured. Cells were harvested and dropped onto slides, divided into a group stained directly with Giemsa and another processed for C banding, then stained with Giemsa. The frequency of MN in 500 binucleated cells was scored for each method. In preparations stained with Giemsa directly, the MN appeared as uniformly stained structures, whereas after C banding, some MN exhibited darker regions corresponding to centromeres that indicated that they were not derived from acentric fragments. The C-banding technique enables differentiation of MN from acentric chromosomal material. This distinction is useful for improving the specificity of the MN assay as a biomarker for ionizing radiation. 相似文献
63.
Goutelle S Bourguignon L Jelliffe RW Conte JE Maire P 《Journal of theoretical biology》2011,282(1):80-92
There is a critical need for improved and shorter tuberculosis (TB) treatment. Current in vitro models of TB, while valuable, are poor predictors of the antibacterial effect of drugs in vivo. Mathematical models may be useful to overcome the limitations of traditional approaches in TB research. The objective of this study was to set up a prototype mathematical model of TB treatment by rifampin, based on pharmacokinetic, pharmacodynamic and disease submodels.The full mathematical model can simulate the time-course of tuberculous disease from the first day of infection to the last day of therapy. Therapeutic simulations were performed with the full model to study the antibacterial effect of various dosage regimens of rifampin in lungs.The model reproduced some qualitative and quantitative properties of the bactericidal activity of rifampin observed in clinical data. The kill curves simulated with the model showed a typical biphasic decline in the number of extracellular bacteria consistent with observations in TB patients. Simulations performed with more simple pharmacokinetic/pharmacodynamic models indicated a possible role of a protected intracellular bacterial compartment in such a biphasic decline.This modeling effort strongly suggests that current dosage regimens of RIF may be further optimized. In addition, it suggests a new hypothesis for bacterial persistence during TB treatment. 相似文献
64.
65.
M Neuburger A M Polidori E Piètre M Faure A Jourdain J Bourguignon B Pucci R Douce 《European journal of biochemistry》2000,267(10):2882-2889
Lipoamide dehydrogenase or dihydrolipoamide dehydrogenase (EC 1.8.1. 4) is the E3-protein component of the mitochondrial 2-oxoacid dehydrogenase multienzyme complexes. It is also the L-protein component of the glycine decarboxylase system. Although the enzymology of this enzyme has been studied exhaustively using free lipoamide as substrate, no data are available concerning the kinetic parameters of this enzyme with its physiological substrates, the dihydrolipoyl domain of the E2 component (dihydrolipoyl acyltransferase) of the 2-oxoacid dehydrogenase multienzyme complexes or the dihydrolipoyl H-protein of the mitochondrial glycine decarboxylase. In this paper, we demonstrate that Tris(2-carboxyethyl)phosphine, a specific disulfide reducing agent, allows a continuous reduction of the lipoyl group associated with the H-protein during the course of the reaction catalysed by the L-protein. This provided a valuable new tool with which to study the catalytic properties of the lipoamide dehydrogenase. The L-protein displayed a much higher affinity for the dihydrolipoyl H-protein than for free dihydrolipoamide. The oxidation of the dihydrolipoyl H-protein was not affected by the presence of structurally related analogues (apoH-protein or octanoylated H-protein). In marked contrast, these analogues strongly and competitively inhibited the decarboxylation of the glycine molecule catalysed by the P-protein component of the glycine decarboxylase system. Small unfolded proteolytic fragments of the H-protein, containing the lipoamide moiety, displayed Km values for the L-protein close to that found for the H-protein. On the other hand, these fragments were not able to promote the decarboxylation of the glycine in the presence of the P-protein. New highly hydrophilic lipoate analogues were synthesized. All of them showed Km and kcat/Km values very close to that found for the H-protein. From our results we concluded that no structural interaction is required for the L-protein to catalyse the oxidation of the dihydrolipoyl H-protein. We discuss the possibility that one function of the H-protein is to maintain a high concentration of the hydrophobic lipoate molecules in a nonmicellar state which would be accessible to the catalytic site of the lipoamide dehydrogenase. 相似文献
66.
M Faure J Bourguignon M Neuburger D MacHerel L Sieker R Ober R Kahn C Cohen-Addad R Douce 《European journal of biochemistry》2000,267(10):2890-2898
The glycine decarboxylase complex consists of four different component enzymes (P-, H-, T- and L-proteins). The 14-kDa lipoamide-containing H-protein plays a pivotal role in the complete sequence of reactions as its prosthetic group (lipoic acid) interacts successively with the three other components of the complex and undergoes a cycle of reductive methylamination, methylamine transfer and electron transfer. With the aim to understand the interaction between the H-protein and its different partners, we have previously determined the crystal structure of the oxidized and methylaminated forms of the H-protein. In the present study, we have crystallized the H-protein in its reduced state and the L-protein (lipoamide dehydrogenase or dihydrolipoamide dehydrogenase). The L-protein has been overexpressed in Escherichia coli and refolded from inclusion bodies in an active form. Crystals were obtained from the refolded L-protein and the structure has been determined by X-ray crystallography. This first crystal structure of a plant dihydrolipoamide dehydrogenase is similar to other known dihydrolipoamide dehydrogenase structures. The crystal structure of the H-protein in its reduced form has been determined and compared to the structure of the other forms of the protein. It is isomorphous to the structure of the oxidized form. In contrast with methylaminated H-protein where the loaded lipoamide arm was locked into a cavity of the protein, the reduced lipoamide arm appeared freely exposed to the solvent. Such a freedom is required to allow its targeting inside the hollow active site of L-protein. Our results strongly suggest that a direct interaction between the H- and L-proteins is not necessary for the reoxidation of the reduced lipoamide arm bound to the H-protein. This hypothesis is supported by biochemical data [Neuburger, M., Polidori, A.M., Piètre, E., Faure, M., Jourdain, A., Bourguignon, J., Pucci, B. & Douce, R. (2000) Eur. J. Biochem. 267, 2882-2889] and by small angle X-ray scattering experiments reported herein. 相似文献
67.
Immunohistochemical distribution of inter-alpha-trypsin inhibitor chains in normal and malignant human lung tissue. 总被引:2,自引:0,他引:2
J Bourguignon H Borghi R Sesboüé M Diarra-Mehrpour J F Bernaudin J Métayer J P Martin L Thiberville 《The journal of histochemistry and cytochemistry》1999,47(12):1625-1632
The inter-alpha-trypsin inhibitor (ITI) family is a group of plasma proteins built up from heavy (HC1, HC2, HC3) and light (bikunin) chains synthesized in the liver. In this study we determined the distribution of ITI constitutive chains in normal and cancerous lung tissues using polyclonal antibodies. In normal lung tissue, H2, H3, and bikunin chains were found in polymorphonuclear cells, whereas H1 and bikunin proteins were found in mast cells. Bikunin was further observed in bronchoepithelial mucous cells. In lung carcinoma, similar findings were obtained on infiltrating polymorphonuclear and mast cells surrounding the tumor islets. Highly differentiated cancerous cells displayed strong intracytoplasmic staining with H1 and bikunin antiserum in both adenocarcinoma and squamous cell carcinoma. Moreover, weak but frequent H2 expression was observed in adenocarcinoma cells, whereas no H3-related protein could be detected in cancer cells. Local lung ITI expression was confirmed by RT-PCR. Although the respective role of inflammatory and tumor cells in ITI chain synthesis cannot be presently clarified, these results show that heavy chains as well as bikunin are involved in malignant transformation of lung tissue.(J Histochem Cytochem 47:1625-1632, 1999) 相似文献
68.
69.
70.
Interaction between the Component Enzymes of the Glycine Decarboxylase Multienzyme Complex 总被引:14,自引:6,他引:8 下载免费PDF全文
The glycine decarboxylase multienzyme complex comprises about one-third of the soluble protein of the matrix of pea (Pisum sativum) leaf mitochondria where it exists at a concentration of approximately 130 milligrams protein/milliliter. Under these conditions the complex is stable with an approximate subunit ratio of 2 P-protein dimers:27 H-protein monomers:9 T-protein monomers:1 L-protein dimer. When the complex is diluted it tends to dissociate into its component enzymes. This prevents the purification of the intact complex by gel filtration or ultracentrifugation. In the dissociated state the H-protein acts as a mobile cosubstrate that commutes between the other three enzymes and shows typical substrate kinetics. When the complex is reformed, the H-protein no longer acts as a substrate but as an integrated part of the enzyme complex. 相似文献