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91.
92.
Alexander Riechers Andreas Grauer Stefan Ritter Bianca Sperl Thorsten Berg Burkhard König 《Journal of molecular recognition : JMR》2010,23(3):329-334
The modulation of biological signal transduction pathways by masking phosphorylated amino acid residues represents a viable route toward pharmacologic protein regulation. Binding of phosphorylated amino acid residues has been achieved with synthetic metal‐chelate receptors. The affinity and selectivity of such receptors can be enhanced if combined with a second binding site. We demonstrate this principle with a series of synthetic ditopic metal‐chelate receptors, which were synthesized and investigated for their binding affinity to phosphorylated short peptides under conditions of physiological pH. The compounds showing highest affinity were subsequently used to inhibit the interaction of the human STAT1 protein to a peptide derived from the interferon‐γ receptor, and between the checkpoint kinase Chk2 and its preferred binding motif. Two of the investigated ditopic synthetic receptors show a significant increase in inhibition activity. The results show that regulation of protein function by binding to phosphorylated amino acids is possible. The introduction of additional binding sites into the synthetic receptors increases their affinity, but the flexibility of the structures investigated so far prohibited stringent amino acid sequence selectivity in peptide binding. Copyright © 2009 John Wiley & Sons, Ltd. 相似文献
93.
Sapone A Gustavino B Monfrinotti M Canistro D Broccoli M Pozzetti L Affatato A Valgimigli L Forti GC Pedulli GF Biagi GL Abdel-Rahman SZ Paolini M 《Mutation research》2007,626(1-2):143-154
Epidemiological evidence suggests a link between consumption of chlorinated drinking water and various cancers. Chlorination of water rich in organic chemicals produces carcinogenic organochlorine by-products (OBPs) such as trihalomethanes and haloacetic acids. Since the discovery of the first OBP in the 1970s, there have been several investigations designed to determine the biological effects of single chemicals or small artificial OBP combinations. However, there is still insufficient information regarding the general biological response to these compounds, and further studies are still needed to evaluate their potential genotoxic effects. In the current study, we evaluated the effect of three drinking water disinfectants on the activity of cytochrome P450 (CYP)-linked metabolizing enzymes and on the generation of oxidative stress in the livers of male and female Cyprinus carpio fish (carp). The fish were exposed in situ for up 20 days to surface water obtained from the Trasmene lake in Italy. The water was treated with 1-2 mg/L of either sodium hypochlorite (NaClO) or chlorine dioxide (ClO2) as traditional disinfectants or with a relatively new disinfectant product, peracetic acid (PAA). Micronucleus (MN) frequencies in circulating erythrocytes from the fish were also analysed as a biomarker of genotoxic effect. In the CYP-linked enzyme assays, a significant induction (up to a 57-fold increase in the deethylation of ethoxyresorufin with PAA treatment) and a notable inactivation (up to almost a 90% loss in hydroxylation of p-nitrophenol with all disinfectants, and of testosterone 2beta-hydroxylation with NaClO) was observed in subcellular liver preparations from exposed fish. Using the electron paramagnetic resonance (EPR) spectroscopy radical-probe technique, we also observed that CYP-modulation was associated with the production of reactive oxygen species (ROS). In addition, we found a significant increase in MN frequency in circulating erythrocytes after 10 days of exposure of fish to water treated with ClO2, while a non-significant six-fold increase in MN frequency was observed with NaClO, but not with PAA. Our data suggest that the use of ClO2 and NaClO to disinfect drinking water could generate harmful OBP mixtures that are able to perturb CYP-mediated reactions, generate oxidative stress and induce genetic damage. These data may provide a mechanistic explanation for epidemiological studies linking consumption of chlorinated drinking water to increased risk of urinary, gastrointestinal and bladder cancers. 相似文献
94.
95.
Gamrekelashvili J Krüger C von Wasielewski R Hoffmann M Huster KM Busch DH Manns MP Korangy F Greten TF 《Journal of immunology (Baltimore, Md. : 1950)》2007,178(3):1573-1580
The manner in which cells die is believed to have a major impact on the nature of immune responses to their released Ags. In this study, we present the first direct analysis of tumor-specific immune responses to in vivo occurring tumor cell death through apoptosis or necrosis. Mice bearing thymidine kinase-transfected tumors were treated either with ganciclovir to induce tumor cell apoptosis in vivo or a vascular targeting agent, ZD6126, to induce tumor cell necrosis in vivo. In contrast to tumor apoptosis, induction of necrosis reduced the frequency and impaired the function of tumor-specific CD8(+) T cells. Adoptive transfer of lymphocytes from mice with apoptotic tumors into tumor-challenged mice resulted in a significant tumor protection, which was absent when splenocytes were transferred from mice with necrotic tumors. Anti-CD40 treatment reversed impaired Ag-specific CD8(+) T cell responses in these mice. These observations have not only fundamental importance for the development of immunotherapy protocols but also help to understand the underlying mechanism of in vivo immune responses to tumor cell death. 相似文献
96.
Schueller C Schneider B Kempf VA Haas A 《Microbes and infection / Institut Pasteur》2007,9(3):355-363
Afipia felis is a Gram-negative alpha-proteobacterium, a rare cause of human cat scratch disease (CSD), and likely a pathogen of amoeba. Here, we show that various members of the genus Afipia attach to and are taken up by various non-professional phagocytic mammalian cells (epithelial CHO, endothelial EA.hy926, epithelial HeLa, epithelial INT407 cells, endothelial HMEC-1, endothelial HUVEC, and fibroblast L929 cells). However, only A. felis was able to do this efficiently. Invasion depended on a functional actin cytoskeleton and much less on microtubule dynamics. Bacteria were slowly taken up into HMEC-1 (and HUVEC) via pocket-like structures and they resided within membrane-surrounded phagosomes. While A. felis was found in a non-canonical endocytic compartment in macrophage cells, Afipia-containing phagosomes in HMEC-1 were transiently positive for early endosomal EEA1 and then became and remained positive for lysosome-associated membrane protein-1 (LAMP1) and the proton-pumping ATPase, suggesting undisturbed, albeit slowed, phagosome biogenesis in these cells. Similarly, at 24h of infection, most phagosomes in HeLa, INT407, HUVEC and in EA.hy926 cells were positive for LAMP1. In summary, A. felis enters various non-professional phagocytes and its compartmentation differs between macrophages and non-professional phagocytes. 相似文献
97.
Costa BB Corrêa R De Souza MM Pretto JB Ardenghi JV De Campos-Buzzi F Cechinel Filho V 《Zeitschrift für Naturforschung. C, Journal of biosciences》2007,62(3-4):201-206
This paper describes the antinociceptive effects of tetrahydrophthalimides and related compounds in mice. Twenty compounds were obtained by the reaction of cis-1,2,3,6-tetrahydrophthalic anhydride with appropriate amines, dehydration, and addition to the imidic double bond. They were analyzed in the writhing test at 10 mg/kg given intraperitoneally. The most active compound 2-benzyl-5-morpholin-4-yl-hexahydroisoindole-1,3-dione (19) was studied on formalin, capsaicin, glutamate and hot plate models. The antinociceptive activity demonstrated by some studied compounds is promising, and some of them were more active than acetylsalicylic acid and paracetamol used as reference drugs in writhing tests in mice. Compound 19 was about 5-fold more potent than the reference drugs, being also effective by oral route and against the inflammatory response in the formalin test. The results suggest that compound 19 could be used as a model to obtain new and more potent antinociceptive agents. It exhibits an interesting antinociceptive profile, and does not interact with opioid systems. 相似文献
98.
The actute phase reaction mediated by the proinflammatory cytokine IL6 initiates a number of metabolic changes in the liver,
which may contribute to the pathogenesis of the septic shock during prolonged exposition. Here, the impact of IL6 on the hepatic
glucose providing capacity was studied by monitoring glycogen degradation and the expression of the gluconeogenic phosphoenolpyruvate
carboxykinase (PCK1) in rat livers during the daily feeding rhythm. Eight hours after i.p. injection of IL6, mRNA levels of
α2-macroglobulin, a prominent acute phase reactant in rat liver, were elevated as shown by Northern blot analysis and in situ
hybridization (ISH). PCK1 mRNA levels were decreased by IL6 to 50% of levels in untreated animals due to the reduction of
PCK1 mRNA in the periportal zone of the liver as shown by ISH. PCK1 enzyme activity was not affected by IL6. Glycogen degradation
was accelerated by IL6, which led to nearly complete depletion of glycogen pools in periportal areas 8 h after IL6 injection.
This was very likely due to inhibition of glycogen pool replenishment. Thus, the depletion of glycogen stores in the liver
might contribute to the impairment of hepatic glucose production during prolonged acute phase challenge. 相似文献
99.
100.
Rainer Voisard Tanja Krügers Barbara Reinhardt Bianca Vaida Regine Baur Tina Herter Anke Lüske Dorothea Weckermann Karl Weingärtner Wolfgang Rössler Vinzenz Hombach Thomas Mertens 《BMC microbiology》2007,7(1):1-6