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Klinman JP 《Biochimica et biophysica acta》2006,1757(8):981-987
Recent data from studies of enzyme catalyzed hydrogen transfer reactions implicate a new theoretical context in which to understand C-H activation. This is much closer to the Marcus theory of electron transfer, in that environmental factors influence the probability of effective wave function overlap from donor to acceptor atoms. The larger size of hydrogen and the availability of three isotopes (H, D and T) introduce a dimension to the kinetic analysis that is not available for electron transfer. This concerns the role of gating between donor and acceptor atoms, in particular whether the system in question is able to tune distance between reactants to achieve maximal tunneling efficiency. Analysis of enzyme systems is providing increasing evidence of a role for active site residues in optimizing the inter-nuclear distance for nuclear tunneling. The ease with which this optimization can be perturbed, through site-specific mutagenesis or an alteration in reaction conditions, is also readily apparent from an analysis of the changes in the temperature dependence of hydrogen isotope effects. 相似文献
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The behavior of three cyclic and three acyclic analogues of 1-aminocyclopropane-1-carboxylic acid (ACC) with ACC oxidase has been analyzed with regard to turnover rates, product distribution, and O(2) uncoupling. The cyclic analogues all form ethylene, and the acyclic analogues all undergo decarboxylation. The degree of uncoupling varies from almost none (ACC) to 21-fold (glycine), while turnover rates (k(cat)) are all within a factor of 4-fold of that of ACC. The aggregate data point toward a rate-determining formation of an activated iron-oxo intermediate, which partitions between amine oxidation and reductive uncoupling in a manner that is dependent on substrate structure. 相似文献
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AOC3 is highly expressed in adipocytes and smooth muscle cells, but its function in these cells is currently unknown. The in vivo substrate(s) of AOC3 is/are also unknown, but could provide an invaluable clue to the enzyme's function. Expression of untagged, soluble human AOC3 in insect cells provides a relatively simple means of obtaining pure enzyme. Characterization of enzyme indicates a 6% titer for the active site 2,4,5-trihydroxyphenylalanine quinone (TPQ) cofactor and corrected k(cat) values as high as 7 s(-1). Substrate kinetic profiling shows that the enzyme accepts a variety of primary amines with different chemical features, including nonphysiological branched-chain and aliphatic amines, with measured k(cat)/K(m) values between 10(2) and 10(4) M(-1) s(-1). K(m)(O(2)) approximates the partial pressure of oxygen found in the interstitial space. Comparison of the properties of purified murine to human enzyme indicates k(cat)/K(m) values that are within 3 to 4-fold, with the exception of methylamine and aminoacetone that are ca. 10-fold more active with human AOC3. With drug development efforts investigating AOC3 as an anti-inflammatory target, these studies suggest that caution is called for when screening the efficacy of inhibitors designed against human enzymes in non-transgenic mouse models. Differentiated murine 3T3-L1 adipocytes show a uniform distribution of AOC3 on the cell surface and whole cell K(m) values that are reasonably close to values measured using purified enzymes. The latter studies support a relevance of the kinetic parameters measured with isolated AOC3 variants to adipocyte function. From our studies, a number of possible substrates with relatively high k(cat)/K(m) have been discovered, including dopamine and cysteamine, which may implicate a role for adipocyte AOC3 in insulin-signaling and fatty acid metabolism, respectively. Finally, the demonstrated AOC3 turnover of primary amines that are non-native to human tissue suggests possible roles for the adipocyte enzyme in subcutaneous bacterial infiltration and obesity. 相似文献
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Bleomycin (BLM) induces life-threatening pneumonitis and pulmonary fibrosis in 20% of patients, limiting its use as a chemotherapeutic agent. Oligonucleotides expressing immunostimulatory CpG motifs (CpG ODN) stimulate cells that express Toll-like receptor 9 to initiate an inflammatory response. This short-lived inflammation is physiologically suppressed by a counter-regulatory process that peaks five days later. Using a murine model of BLM-induced lung injury, the effect of CpG ODN treatment on pulmonary inflammation, fibrosis and mortality was examined. Administering CpG ODN 5 days before BLM (so that the peak of the counter-regulatory process induced by CpG ODN coincided with BLM delivery) resulted in a dose-dependent reduction in pulmonary toxicity (p < 0.005). Delaying the initiation of therapy until the day of or after BLM administration worsened the inflammatory process, consistent with the counter-regulatory process rather than initial pro-inflammatory response being critical to CpG induced protection. The protection afforded by CpG ODN correlated with reduced leukocyte accumulation and inflammatory cytokine/chemokine production in the lungs. These changes were associated with the increased production of IL-10, a critical element of the counter-regulatory process triggered by CpG ODN, and the concomitant down-regulation of BLM-induced IL-17A and TGF-β1 (which promote pulmonary toxicity). This work represents the first example of the physiologic counter-regulation of TLR induced immune activation being harnessed to block an unrelated inflammatory response. 相似文献
26.
Sato T Shimosato T Alvord WG Klinman DM 《Journal of immunology (Baltimore, Md. : 1950)》2008,180(11):7648-7654
Inhalation of silica-containing dust particles induces silicosis, an inflammatory disease of the lungs characterized by the infiltration of macrophages and neutrophils into the lungs and the production of proinflammatory cytokines, chemokines, and reactive oxygen species (ROS). Synthetic oligodeoxynucleotides (ODN) expressing "immunosuppressive motifs" were recently shown to block pathologic inflammatory reactions in murine models of autoimmune disease. Based on those findings, the potential of suppressive ODN to prevent acute murine silicosis was examined. In vitro studies indicate that suppressive ODN blunt silica-induced macrophage toxicity. This effect was associated with a reduction in ROS production and p47phox expression (a subunit of NADPH oxidase key to ROS generation). In vivo studies show that pretreatment with suppressive (but not control) ODN reduces silica-dependent pulmonary inflammation, as manifest by fewer infiltrating cells, less cytokine/chemokine production, and lower levels of ROS (p < 0.01 for all parameters). Treatment with suppressive ODN also reduced disease severity and improved the survival (p < 0.05) of mice exposed to silica. 相似文献
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The role of intra- and extravesicular ascorbate has been investigated in dopamine beta-monooxygenase (D beta M) turnover using adrenal medulla chromaffin granule ghosts. Resealing of vesicle ghosts with high levels of intravesicular ascorbate leads to viable vesicles, as evidenced from the high rates of the ATP-dependent accumulation of tyramine, Vmax = 14 +/- 1 nmol/min.mg and Km = 20 +/- 6 microM. However, the D beta M-catalyzed conversion of tyramine to octopamine occurs slowly, Vmax = 0.50 +/- 0.13 nmol/min.mg and Km = 29 +/- 18 mM. When ascorbate is present instead in the external buffer, the D beta M rate increases 3.6-fold for a final Vmax = 1.8 +/- 0.2 and Km = 1.2 +/- 0.3 mM. This relatively high rate of enzyme turnover is retained in ghosts resealed with a large excess of ascorbate oxidase, ruling out contamination by intravesicular ascorbate as the source of enzyme activity. The synergistic effect of intravesicular ascorbate was examined under conditions of 2 mM external ascorbate, showing that the enzymatic rate increases 2.7-fold, from 1.2 (0 internal ascorbate) to 3.2 +/- 0.4 nmol/min.mg (saturating internal ascorbate). This result confirms that high levels of internal ascorbate are not damaging to intravesicular D beta M. These studies demonstrate very clearly that external ascorbate is the preferred reductant for the membranous form of D beta M in chromaffin granule ghosts. 相似文献
29.
The stimulation of splenic foci in vitro 总被引:8,自引:0,他引:8
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