全文获取类型
收费全文 | 1627篇 |
免费 | 140篇 |
国内免费 | 2篇 |
出版年
2022年 | 10篇 |
2021年 | 35篇 |
2020年 | 15篇 |
2019年 | 22篇 |
2018年 | 34篇 |
2017年 | 29篇 |
2016年 | 41篇 |
2015年 | 69篇 |
2014年 | 80篇 |
2013年 | 99篇 |
2012年 | 121篇 |
2011年 | 113篇 |
2010年 | 69篇 |
2009年 | 63篇 |
2008年 | 86篇 |
2007年 | 90篇 |
2006年 | 81篇 |
2005年 | 70篇 |
2004年 | 75篇 |
2003年 | 72篇 |
2002年 | 71篇 |
2001年 | 11篇 |
2000年 | 13篇 |
1999年 | 18篇 |
1998年 | 23篇 |
1997年 | 12篇 |
1996年 | 11篇 |
1995年 | 14篇 |
1994年 | 10篇 |
1993年 | 16篇 |
1992年 | 14篇 |
1991年 | 11篇 |
1990年 | 12篇 |
1989年 | 8篇 |
1988年 | 9篇 |
1987年 | 9篇 |
1986年 | 8篇 |
1985年 | 11篇 |
1984年 | 15篇 |
1983年 | 18篇 |
1982年 | 13篇 |
1981年 | 12篇 |
1980年 | 17篇 |
1979年 | 6篇 |
1978年 | 8篇 |
1977年 | 10篇 |
1976年 | 10篇 |
1974年 | 7篇 |
1964年 | 6篇 |
1960年 | 5篇 |
排序方式: 共有1769条查询结果,搜索用时 46 毫秒
81.
Marian M. Bindoli A. Callegarin F. Rigobello M. P. Vincenti E. Bragadin M. Scutari G. 《Neurochemical research》1999,24(7):875-881
The effect of 2,6-diisopropylphenol (propofol) in comparison to that of the halogenated anesthetics enflurane, isoflurane, and halothane on tetrapenylphosphonium uptake by rat brain synaptosomes was studied. A direct method to separately measure the synaptosomal and the mitochondrial transmembrane potential by using the tetraphenylphosphonium cation (TPP+) was utilized. The latter is a lipophylic charged molecule which distributes between two compartments according to the transmembrane electrical potential in the presence or absence of 60 mM KCl as a synaptosomal membrane depolarizing agent. After previously reporting the damages induced by general anesthetics on isolated mitochondria, the aim of this paper was to study their possible action on the synaptosomal membrane potential and whether or not drugs concentrations damaging isolated mitochondria are also effective on synaptosomal mitochondria. The results indicated that, in the presence of glucose, mitochondria included in synaptosomes were able to maintain a transmembrane potential of 202 ± 8 mV (mean ± SD) while the synaptosomal membrane showed a potential of 78 ± 8 mV (mean ± SD). When anesthetic concentrations (0.6–1 mM propofol, 10–40 M enflurane, 30–50 M isoflurane, 8–15 M halothane) that impair mitochondrial energy metabolism were used, the synaptosomal transmembrane potential was maintained and, in addition, a slight increase of the TPP+ taken up was observed as the anesthetic concentration was increased. 相似文献
82.
Zimecki M Chodaczek G Kocieba M Kruzel ML 《FEMS immunology and medical microbiology》2004,42(2):167-172
C3H/HeCr mice are more susceptible to infection compared with other strains. Lactoferrin (LF), a protein involved in innate defense, was shown to protect mice against lethal endotoxemia. In this investigation we attempt to explain the cause of increased susceptibility of C3H/HeCr mice to LPS and lack of protective LF action in these mice. We found that C3H/HeCr mice produced up to 5-fold more serum TNFalpha and 66% higher IFNgamma levels in response to i.v. LPS injection than the control, CBA strain. 24 h pretreatment of C3H/HeCr mice with LF did not cause inhibition of the LPS-induced TNFalpha serum levels, whereas in CBA mice LF significantly decreased TNFalpha level. IL-6 serum levels, in turn, were lowered in C3H/HeCr mice but elevated in CBA mice. That differential regulation of cytokine production by LF in C3H/HeCr mice paralleled a decreased survival after lethal LPS injection - 10% vs. 60% in control, PBS treated mice. In addition, determination of colony forming units (CFU) in livers and spleens after administration of 10(8) Escherichia coli revealed that pretreatment of CBA mice with LF caused a marked reduction of CFU in these organs, whereas in C3H/HeCr mice the changes were insignificant. These results indicate that the altered TNFalpha/IL-6 ratio in C3H/HeCr mice, as compared to control CBA mice, as well as the increased IFNgamma level, may be responsible for the increased susceptibility to endotoxemia in that substrain. We also suggest that an association exists between the LF protective effect against endotoxic sequelae and the insult-induced systemic immune response. 相似文献
83.
Convit J Ulrich M Polegre MA Avila A Rodríguez N Mazzedo MI Blanco B 《Memórias do Instituto Oswaldo Cruz》2004,99(1):57-62
Severe mucocutaneous (MCL) and diffuse (DCL) forms of American cutaneous leishmaniasis (ACL) are infrequent in Venezuela. Chemotherapy produces only transitory remission in DCL, and occasional treatment failures are observed in MCL. We have evaluated therapy with an experimental vaccine in patients with severe leishmaniasis. Four patients with MCL and 3 with early DCL were treated with monthly intradermal injections of a vaccine containing promastigotes of Leishmania (Viannia) braziliensis killed by pasteurization and viable Bacillus Calmette- Guerin. Clinical and immunological responses were evaluated. Integrity of protein constituents in extracts of pasteurized promastigotes was evaluated by gel electrophoresis. Complete remission of lesions occurred after 5-9 injections in patients with MCL or 7-10 injections in patients with early DCL. DCL patients developed positive skin reactions, average size 18.7 mm. All have been free of active lesions for at least 10 months. Adverse effects of the vaccine were limited to local reactivity to BCG at the injection sites and fever in 2 patients. Extracts of pasteurized and fresh promastigotes did not reveal differences in the integrity of protein components detectable by gel electrophoresis. Immunotherapy with this modified vaccine offers an effective, safe option for the treatment of patients who do not respond to immunotherapy with vaccine containing autoclaved parasites or to chemotherapy. 相似文献
84.
Background
Involvement of conservative molecular modules and cellular mechanisms in the widely diversified processes of eukaryotic cell morphogenesis leads to the intriguing question: how do similar proteins contribute to dissimilar morphogenetic outputs. Formins (FH2 proteins) play a central part in the control of actin organization and dynamics, providing a good example of evolutionarily versatile use of a conserved protein domain in the context of a variety of lineage-specific structural and signalling interactions. 相似文献85.
86.
Alterations in brain metabolism induced by chronic morphine treatment: NMR studies in rat CNS 总被引:2,自引:0,他引:2
Sharma SK Yashpal K Fundytus ME Sauriol F Henry JL Coderre TJ 《Neurochemical research》2003,28(9):1369-1373
High-resolution (500 MHz) multiresonance/multinuclear proton (1H) nuclear magnetic resonance (NMR) spectroscopy was used to detect metabolic changes and cellular injury in the rat brain stem and spinal cord following chronic morphine treatment. Compensatory changes were observed in glycine, glutamate, and inositols in the brain stem, but not the spinal cord, of chronic morphine-treated rats. In spinal cord, increases were detected in lactate and N-acetyl-aspartate (NAA), suggesting that there is anaerobic glycolysis, plasma membrane damage, and altered pH preferentially in the spinal cord of chronic morphine-treated rats. 相似文献
87.
HDL subspecies Lp(A-I) and Lp(A-I,A-II) have different anti-atherogenic potentials. To determine the role of lipoprotein lipase (LPL) and hepatic lipase (HL) in regulating these particles, we measured these enzyme activities in 28 healthy subjects with well-controlled Type 1 diabetes, and studied their relationship with Lp(A-I) and Lp(A-I,A-II). LPL was positively correlated with the apolipoprotein A-I (apoA-I), cholesterol, and phospholipid mass in total Lp(A-I), and with the apoA-I in large Lp(A-I) (r >or= 0.58, P >or= 0.001). HL was negatively correlated with all the above Lp(A-I) parameters plus Lp(A-I) triglyceride (r >or= -0.53, P or= 0.50, P 相似文献
88.
Schaeferhenrich A Beyer-Sehlmeyer G Festag G Kuechler A Haag N Weise A Liehr T Claussen U Marian B Sendt W Scheele J Pool-Zobel BL 《Mutation research》2003,526(1-2):19-32
Oxidative stress and resulting lipid peroxidation are important risk factors for dietary-associated colon cancer. To get a better understanding of the underlying molecular mechanisms, we need to characterise the risk potential of the key compounds, which cause DNA damage in cancer-relevant genes and especially in human target cells. Here, we investigated the genotoxic effects of 4-hydroxy-2-nonenal (HNE) and hydrogen peroxide (H(2)O(2)) in human colon cells (LT97). LT97 is a recently established cell line from a differentiated microadenoma and represents cells from frequent preneoplastic lesions of the colon. The genomic characterisation of LT97 was performed with 24-colour FISH. Genotoxicity was determined with single cell microgelelectrophoresis (Comet assay). Comet FISH was used to study the sensitivity of TP53-a crucial target gene for the transition of adenoma to carcinoma-towards HNE. Expression of glutathione S-transferases (GST), which deactivates HNE, was determined as GST activity and GSTP1 protein levels. LT97 cells were compared to primary human colon cells and to a differentiated clone of HT29. Karyotyping revealed that the LT97 cell line had a stable karyotype with only two clones, each containing a translocation t(7;17) and one aberrant chromosome 1. The Comet assay experiments showed that both HNE and H(2)O(2) were clearly genotoxic in the different human colon cells. HNE was more genotoxic in LT97 than in HT29clone19A and primary human colon cells. After HNE incubation, TP53 migrated more efficiently into the comet tail than the global DNA, which suggests a higher susceptibility of the TP53 gene to HNE. GST expression was significantly lower in LT97 than in HT29clone19A cells, which could explain the higher genotoxicity of HNE in the colon adenoma cells. In conclusion, the LT97 is a relevant model for studying genotoxicity of colon cancer risk factors since colon adenoma are common preneoplastic lesions occurring in advanced age. 相似文献
89.
Mislow JM Holaska JM Kim MS Lee KK Segura-Totten M Wilson KL McNally EM 《FEBS letters》2002,519(1-3):135-140
The mitogen-stimulated protein kinase p70(s6k)/p85(s6k) (S6K) plays an essential role in cell proliferation and growth, with inhibitors of the S6K signalling pathway showing promise as anti-tumour therapeutics. Here, we report that the bisindolylmaleimide derivative Ro 31-6045, previously reported to be inactive as a kinase inhibitor, inhibited S6K activity in vivo with an IC50=8 microM. Structure/function analysis using mutant forms of S6K indicates that Ro 31-6045 inhibition is independent of the upstream activator mTOR. Ro 31-6045 will prove useful in elucidating the complex activation mechanism of S6K and its independence from mTOR will allow confirmation of functional data obtained using the mTOR inhibitor rapamycin. 相似文献
90.
Effects of cytotoxic T lymphocytes (CTL) directed against a single simian immunodeficiency virus (SIV) Gag CTL epitope on the course of SIVmac239 infection 下载免费PDF全文
Allen TM Jing P Calore B Horton H O'Connor DH Hanke T Piekarczyk M Ruddersdorf R Mothé BR Emerson C Wilson N Lifson JD Belyakov IM Berzofsky JA Wang C Allison DB Montefiori DC Desrosiers RC Wolinsky S Kunstman KJ Altman JD Sette A McMichael AJ Watkins DI 《Journal of virology》2002,76(20):10507-10511
Vaccine-induced cytotoxic T lymphocytes (CTL) have been implicated in the control of virus replication in simian immunodeficiency virus (SIV)-challenged and simian-human immunodeficiency virus-challenged macaques. Therefore, we wanted to test the impact that vaccine-induced CTL responses against an immunodominant Gag epitope might have in the absence of other immune responses. By themselves, these strong CTL responses failed to control SIVmac239 replication. 相似文献