全文获取类型
收费全文 | 714篇 |
免费 | 52篇 |
专业分类
766篇 |
出版年
2021年 | 6篇 |
2020年 | 11篇 |
2018年 | 11篇 |
2017年 | 9篇 |
2016年 | 13篇 |
2015年 | 22篇 |
2014年 | 18篇 |
2013年 | 27篇 |
2012年 | 39篇 |
2011年 | 41篇 |
2010年 | 15篇 |
2009年 | 16篇 |
2008年 | 35篇 |
2007年 | 34篇 |
2006年 | 16篇 |
2005年 | 19篇 |
2004年 | 27篇 |
2003年 | 31篇 |
2002年 | 16篇 |
2001年 | 16篇 |
2000年 | 20篇 |
1999年 | 20篇 |
1997年 | 6篇 |
1994年 | 8篇 |
1993年 | 6篇 |
1992年 | 11篇 |
1991年 | 8篇 |
1990年 | 6篇 |
1989年 | 17篇 |
1988年 | 17篇 |
1987年 | 11篇 |
1986年 | 7篇 |
1985年 | 11篇 |
1984年 | 9篇 |
1983年 | 5篇 |
1982年 | 11篇 |
1981年 | 11篇 |
1980年 | 8篇 |
1979年 | 14篇 |
1978年 | 7篇 |
1976年 | 12篇 |
1974年 | 7篇 |
1973年 | 8篇 |
1972年 | 12篇 |
1971年 | 12篇 |
1970年 | 10篇 |
1969年 | 6篇 |
1968年 | 7篇 |
1967年 | 5篇 |
1966年 | 6篇 |
排序方式: 共有766条查询结果,搜索用时 15 毫秒
41.
Etelka?Farkas Yiffat?Katz Sudhakar?Bhusare Reuven?Reich Gerd-Volker?R?schenthaler Martin?K?nigsmann Eli?BreuerEmail author 《Journal of biological inorganic chemistry》2004,9(3):307-315
Overactive matrix metalloproteinases (MMPs) are associated with a variety of disease states. Therefore, their inhibition is a highly desirable goal. Yet, more than a decade of worldwide activity has not produced even one clinically useful inhibitor. Because of the crucial role of zinc in the activity of the enzyme, the design of inhibitors is usually based upon a so-called zinc binding group (ZBG). Yet, many of the hitherto synthesized potent inhibitors failed clinically, presumably because they bind stronger to metals other than zinc. We have developed in vivo potent inhibitors based on the carbamoylphosphonic group as a putative ZBG. In this paper we report stability constants for Ca(II), Mg(II), Zn(II) and Cu(II) complexes of two potent, in vivo active, MMP inhibitors, cyclopentylcarbamoylphosphonic acid (1) and 2-(N,N-dimethylamino)ethylcarbamoylphosphonic acid (2). Precipitation prevented the determination of stability constants for iron(III) complexes of 1 and 2. For comparison with carbamoylphosphonates 1 and 2, we synthesized 2-cyclohexyl-1,1-difluoroethylphosphonic acid (3), which does not inhibit MMP, and determined the stability constants of its complexes with Mg(II), Ca(II) and Zn(II). Comparison with the values obtained from the complexes of 1 and 2 with those from 3 indicates participation of the C=O group in the metal binding of the former compounds. The complex stability orders for both 1 and 2 are Ca(II)<Mg(II)<Zn(II)<Cu(II). In addition, the results indicate that at pH>8 the dimethylamino group of compound 2 can also participate in the binding of the transition metals Cu and Zn. On the other hand, the amino group in carbamoylphosphonic acid 2 lowers the stability of the complexes with metals favoring oxygen ligands (Ca, Mg and Fe) and increases the selectivity towards Zn. These results are helpful for rationalizing the results observed on our MMP inhibitors hitherto examined, and are expected to be useful for the design of new selective inhibitors.Electronic Supplementary Material Supplementary material is available in the online version of this article at http://dx.doi.org/10.1007/s00775-004-0524-5 相似文献
42.
Complexes of the natural siderophore, desferricoprogen (DFC), with several trivalent and divalent metal ions in aqueous solution were studied by pH-potentiometry, UV-Vis spectrophotometry and cyclic voltammetry. DFC was found to be an effective metal binding ligand, which, in addition to Fe(III), forms complexes of high stability with Ga(III), Al(III), In(III), Cu(II), Ni(II) and Zn(II). Fe(II), however, is oxidized by DFC under anaerobic conditions and Fe(III) complexes are formed. By comparing the results with those of desferrioxamine B (DFB), it can be concluded that the conjugated beta-double bond slightly increases the stability of the hydroxamate chelates, consequently increases the stability of mono-chelated complexes of DFC. Any steric effect by the connecting chains arises only in the bis- and tris-chelated complexes. With metal ions possessing a relatively big ionic radius (Cu(II), Ni(II), Zn(II), In(III)) DFC, containing a bit longer chains than DFB, forms slightly more stable complexes. With smaller metal ions the trend is the opposite. Also a notable difference is that stable trinuclear complex, [Cu(3)L(2)], is formed with DFC but not with DFB. Possible bio-relevance of the Fe(II)/Fe(III) results is also discussed in the paper. 相似文献
43.
Tóth F Horváth G Szikszay M Farkas J Tóth G Borsodi A Benyhe S 《Regulatory peptides》2004,122(2):139-146
Tyr-D-Ala-Gly-Phe-D-Nle-Arg-Phe (DADN) a synthetic analogue of the endogenous Met-enkephalin-Arg-Phe (Tyr-Gly-Gly-Phe-Met-Arg-Phe; MERF), was investigated in radioligand binding assays, [(35)S]GTPgammaS stimulation experiments as well as in in vivo algesiometric tests. Binding properties of [(3)H]DADN were measured in crude membrane fractions of rat spinal cord tissues and in homogenates of Chinese hamster ovary (CHO) cells selectively expressing delta-, kappa-or micro-opioid receptors. The highest affinity for [(3)H]DADN binding was observed in membranes from CHO cells transfected with micro-opioid receptors confirming the micro-selectivity of the peptide. Unlabeled DADN was also investigated in functional biochemical experiments by measuring opioid receptor-mediated G-protein activation in rat brain membrane fractions. The peptide stimulated the activity of the regulatory G-proteins in a concentration dependent manner, and the stimulation was efficiently inhibited in the presence of micro-receptor specific antagonist ligands further supporting the selectivity profile of DADN. Intrathecally administered DADN produced a dose-related, naloxone-reversible antinociception in rat hot water tail-flick tests. Among the selective opioid antagonists tested, the delta-selective naltrindole (NTI) and the kappa-specific norbinaltorphimine (norBNI) showed only slight blocking effects compared with naloxone. The results obtained in the in vitro agonist-stimulated [(35)S]GTPgammaS binding assays are in good agreement with the opioid agonist effect seen in the in vivo pain test. 相似文献
44.
Zega A Mlinsek G Solmajer T Trampus-Bakija A Stegnar M Urleb U 《Bioorganic & medicinal chemistry letters》2004,14(6):1563-1567
A series of azaphenylalanine derivatives were investigated as novel thrombin inhibitors based on the prodrug principle. By systematic structural modifications we have identified optimal groups for this series that led us to potent inhibitors of thrombin incorporating the benzamidine fragment at the P1 position, and their potentially orally active benzamidoxime prodrugs. The binding modes in the thrombin active site of two representative compounds were identified by X-ray crystallographic analysis. 相似文献
45.
Bálint E Bakay M Onody K Farkas F Horváth G Tolvaj G Dávid K Horányi M Béládi I 《Acta microbiologica et immunologica Hungarica》2004,51(3):359-369
Sera from 86 patients with chronic hepatitis C virus (HCV) infection treated with recombinant interferons-alpha (rIFN-alpha) were screened for IFN-binding and antiviral effect-neutralizing antibodies. Out of the 61 patients treated with rIFN-alpha2b, 46% had binding and 28% had neutralizing antibodies. 44% of the 25 patients treated with rIFN-alpha2a developed binding antibodies and 24% had neutralizing antibodies. Contradictory data were observed concerning the appearance of anti-IFN antibodies and the outcome of IFN therapy. A significantly higher number of the patients with a sustained response to rIFN-alpha2b therapy formed antibodies than the number among the non-responder patients. At the same time, in the patients treated with rIFN-alpha2a, opposite data were found. The activity of the antibodies in some sera was studied against the antiproliferative effect of IFNs on Daudi cells by measuring the [3H]thymidine incorporation. The binding antibodies without neutralization of the antiviral effect of the IFNs inhibited the antiproliferative activity of the rIFNs, similarly to antibodies having both IFN-binding and antiviral effect-neutralizing capacities. At the same time, the antiproliferative effect of the natural IFN was less affected. It is suggested that the antiproliferative assay is more sensitive than the antiviral method for demonstration of the presence of antibodies exerting an inhibitory effect on the biological activities of IFN. 相似文献
46.
47.
Barceló-Coblijn G Kitajka K Puskás LG Hogyes E Zvara A Hackler L Farkas T 《Biochimica et biophysica acta》2003,1632(1-3):72-79
Rats were fed from conception till adulthood either with normal rat chow with a linoleic (LA) to linolenic acid (LNA) ratio of 8.2:1 or a rat chow supplemented with a mixture of perilla and soy bean oil giving a ratio of LA to LNA of 4.7:1. Fat content of the feed was 5%. Fatty acid and molecular species composition of ethanolamine phosphoglyceride was determined. Effect of this diet on gene expression was also studied. There was an accumulation of docosahexaenoic (DHA) and arachidonic acids (AA) in brains of the experimental animals. Changes in the ratio sn-1 saturated, sn-2 docosahexaenoic to sn-1 monounsaturated, sn-2 docosahexaenoic were observed. Twenty genes were found overexpressed in response to the 4.7:1 mixture diet and four were found down-regulated compared to normal rat chow. Among them were the genes related to energy household, lipid metabolism and respiration. The degree of up-regulation exceeded that observed with perilla with a ratio of LA to LNA 8.2:1 [Proc. Natl. Acad. Sci. U. S. A. 99 (2002) 2619]. It was concluded that brain sensitively reacts to the fatty acid composition of the diet. It was suggested that alteration in membrane architecture and function coupled with alterations in gene expression profiles may contribute to the observed beneficial impact of n-3 type polyunsaturated fatty acids on cognitive functions. 相似文献
48.
Farkas DL Becker D 《Pigment cell research / sponsored by the European Society for Pigment Cell Research and the International Pigment Cell Society》2001,14(1):2-8
Light-based imaging has extensive applications for medicine and biology, and recent advances in optical imaging modalities, such as confocal and multi-photon scanning fluorescence microscopy, bioluminescence, optical coherence tomography, and spectral imaging, have opened new avenues for visualizing and recording over time dynamic changes in genetic, developmental, and disease mechanisms that cannot be captured by conventional light microscopy. In the present article, we focus on spectral imaging, and using human melanoma and its precursor lesions as an example, we describe the ability of spectral imaging to detect early-stage disease, capture gene expression profiles in tissue specimens, and visualize gene functions in tumors growing in living animals. 相似文献
49.
The suprachiasmatic nuclei (SCN) constitute the principal pacemaker of the circadian timing system in mammals. The generated rhythm is forwarded mostly through projections to various hypothalamic nuclei. On the other hand, the regulated processes feedback to the SCN. One of the possible feedback pathways is the orexinergic projection from the lateral hypothalamus. Orexins are recently identified neuropeptides with an overall facilitatory effect on waking behaviors. Orexinergic fibers are widely distributed throughout the brain and are also present in the SCN. In this study we examined the effect of orexin-A on the spontaneous activity of rat SCN cell in vitro. Neurons showed 2 different firing pattern (continuous-regular, intermittent-irregular). Orexin-A increased firing rate in both cell types at 10(-8) M concentration, but caused a clear suppression of neuronal activity at 10(-7) M. Continuously firing neurons were less responsive than those firing intermittently. These results show that orexin-A may play a role in the modulation of the circadian pacemaker function. The neuropeptide might exert both direct, postsynaptic effects on SCN neurons and indirect, presynaptic effects on excitatory and inhibitory terminals. The dose-dependent modification of the firing rate indicate that the weight of these factors changes with the concentration of orexin-A. 相似文献
50.
In laboratory studies performed in the United States and Hungary, the dump fly Hydrotaea aenescens (Wiedemann) was reared successfully in manure of 1- to 8-wk-old dairy calves, and in manure from adult lactating dairy cows. Survival in manure collected from 1-wk-old calves was poor (7.2%), better in manure collected from 2- and 3-wk-old calves (53.5%), and best in manure collected from 4- to 8-wk-old calves (71.4%). Survival in cow manure was slightly lower (47.4%) than that in calf manure. Reasons for different rates of development in the United States and in Hungary, and by calf age are discussed as are implications for biological control. 相似文献