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601.
Brain glycogen metabolism was investigated by employing isofagomine, an inhibitor of glycogen phosphorylase. Cultured cerebellar
and neocortical astrocytes were incubated in medium containing [U-13C]glucose in the absence or presence of isofagomine and the amounts and percent labeling of intra- and extracellular metabolites
were determined by mass spectrometry (MS). The percent labeling in glycogen was markedly decreased in the presence of isofagomine.
Surprisingly, the percent labeling of intracellular lactate was also decreased demonstrating the importance of glycogen turnover.
The decrease was limited to the percent labeling in the intracellular pool of lactate, which was considerably lower compared
to that observed in the medium in which it was close to 100%. These findings indicate compartmentation of lactate derived
from glycogenolysis and that derived from glycolysis. Inhibiting glycogen degradation had no effect on the percent labeling
in citrate. However, the percent labeling of extracellular glutamine was slightly decreased in neocortical astrocytes exposed
to isofagomine, indicating an importance of glycogen turnover in the synthesis of releasable glutamine. In conclusion, the
results demonstrate that glycogen in cultured astrocytes is continuously synthesized and degraded. Moreover, it was found
that lactate originating from glycogen is compartmentalized from that derived from glucose, which lends further support to
a compartmentalized metabolism in astrocytes.
Special issue dedicated to Dr. Bernd Hamprecht. 相似文献
602.
Ulrich HD 《Current biology : CB》2005,15(7):R257-R259
SUMO modification of human thymine-DNA glycosylase facilitates the processing of base excision repair substrates by an unusual mechanism: while leaving the catalytic center unaffected, it induces product release by eliciting a conformational change in the enzyme. 相似文献
603.
Hansen M Wind T Blouse GE Christensen A Petersen HH Kjelgaard S Mathiasen L Holtet TL Andreasen PA 《The Journal of biological chemistry》2005,280(46):38424-38437
To find new principles for inhibiting serine proteases, we screened phage-displayed random peptide repertoires with urokinase-type plasminogen activator (uPA) as the target. The most frequent of the isolated phage clones contained the disulfide bridge-constrained sequence CSWRGLENHRMC, which we designated upain-1. When expressed recombinantly with a protein fusion partner, upain-1 inhibited the enzymatic activity of uPA competitively with a temperature and pH-dependent K(i), which at 25 degrees C and pH 7.4 was approximately 500 nm. At the same conditions, the equilibrium dissociation constant K(D), monitored by displacement of p-aminobenzamidine from the specificity pocket of uPA, was approximately 400 nm. By an inhibitory screen against other serine proteases, including trypsin, upain-1 was found to be highly selective for uPA. The cyclical structure of upain-1 was indispensable for uPA binding. Alanine-scanning mutagenesis identified Arg(4) of upain-1 as the P(1) residue and indicated an extended binding interaction including the specificity pocket and the 37-, 60-, and 97-loops of uPA and the P(1), P(2), P(3)', P(4)', and the P(5)' residues of upain-1. Substitution with alanine of the P(2) residue, Trp(3), converted upain-1 into a distinct, although poor, uPA substrate. Upain-1 represents a new type of uPA inhibitor that achieves selectivity by targeting uPA-specific surface loops. Most likely, the inhibitory activity depends on its cyclical structure and the unusual P(2) residue preventing the scissile bond from assuming a tetrahedral geometry and thus from undergoing hydrolysis. Peptide-derived inhibitors such as upain-1 may provide novel mechanistic information about enzyme-inhibitor interactions and alternative methodologies for designing effective protease inhibitors. 相似文献
604.
Petersen G Moesgaard B Schmid PC Schmid HH Broholm H Kosteljanetz M Hansen HS 《Journal of neurochemistry》2005,93(2):299-309
The endogenous levels of the two cannabinoid receptor ligands 2-arachidonoyl glycerol and anandamide, and their respective congeners, monoacyl glycerols and N-acylethanolamines, as well as the phospholipid precursors of N-acylethanolamines, were measured by gas chromatography-mass spectrometry in glioblastoma (WHO grade IV) tissue and meningioma (WHO grade I) tissue and compared with human non-tumour brain tissue. Furthermore, the metabolic turnover of N-acylethanolamines was compared by measurements of the enzymatic activity of N-acyltransferase, N-acylphosphatidylethanolamine-hydrolysing phospholipase D and fatty acid amide hydrolase in the same three types of tissue. Glioblastomas were characterized by enhanced levels of N-acylethanolamines (eightfold, 128 +/- 59 pmol/micromol lipid phosphorus) including anandamide (17-fold, 4.6 +/- 3.1 pmol/micromol lipid phosphorus) and several species of N-acylphosphatidylethanolamines (three to eightfold). This was accompanied by a more than 60% reduction in the enzyme activities of N-acylphosphatidylethanolamine-hydrolysing phospholipase D and fatty acid amide hydrolase. By contrast, meningiomas were characterized by a massively enhanced level of 2-monoacyl glycerols (20-fold, 2293 +/- 361 pmol/micromol lipid phosphorus) including 2-arachidonoyl glycerol (20-fold, 1524 +/- 361 pmol/micromol lipid phosphorus). This was accompanied by an enhanced in vitro conversion of phosphatidylcholine to monoacyl glycerol (fivefold). The enhanced level of the 2-arachidonoyl glycerol, anandamide and other N-acylethanolamines detected in the two types of tumour tissue may possibly act as endogenous anti-tumour mediators by stimulation of both cannabinoid and non-cannabinoid receptor-mediated mechanisms. 相似文献
605.
Meltzer HM Maage A Ydersbond TA Haug E Glattre E Holm H 《Biological trace element research》2002,90(1-3):83-98
The effects of an arsenic-rich fish diet and selenium (Se) supplementation on blood arsenic (As), Se, and thyroid hormones
were studied in 32 women divided into four equal groups. Groups 1 and 4 received 400 μg Se-methionine daily, group 2 received
400 μg selenite daily, and group 3 received placebo tablets for 15 wk. In addition, groups 1–3 increased their fish intake,
eating at least three fish dinners weekly. Mean blood Se concentrations (initially 1.68 ± 0.24 μmol/L) increased twofold in
the Se-methionine groups (p < 0.0001) and by 32% in the selenite group (p < 0.01). Group means of blood As concentrations increased by 63% (p < 0.01), 50% (p < 0.01), 106% (p < 0.01), and 29% (p < 0.05) in the four groups, respectively. Analyzed As intake from duplicate portions of consumed fish correlated with final
blood As concentrations (r=0.85, p < 0.001, n=32). In the group not receiving Se, there was a positive correlation between final blood As concentrations and plasma T4
: T3 ratio (r=0.80, p < 0.02, n=8). Initially, blood As concentrations correlated negatively with both T3 and T4 in plasma, but this correlation disappeared
upon Se supplementation. The results demonstrate that increased intake of fish may influence blood As concentrations and that
circulating thyroid hormones may be influenced by Se-As interactions. 相似文献
606.
Helle SI Ekse D Holly JM Lønning PE 《The Journal of steroid biochemistry and molecular biology》2002,81(1):95-102
Plasma insulin-like growth factor (IGF)-I, free IGF-I and -II, IGF-binding protein (IGFBP)-1, -2, and -3 together with IGFBP-3 protease activity were measured in 114 postmenopausal and 39 premenopausal healthy women. For each parameter, the mathematical distribution was characterised, and the normal range for pre- and postmenopausal women described, together with correlations to demographic variables and sex-steroids (postmenopausal women).Postmenopausal women had lower levels of plasma IGF-I (P<0.001) and free IGF-I (P<0.001) compared to premenopausal women, while plasma IGFBP-2 (P<0.05) and immunoreactive IGFBP-3 (P<0.001) were higher in postmenopausal women. Free IGF-I (but none of the other parameters) was significantly lower in postmenopausal smokers compared to non-smokers (P<0.05).IGF-I and -II both correlated positively to height (r=0.203, P<0.05 and r=0.198, P<0.05, respectively), while IGF-II correlated positively to weight (r=0.250, P<0.01). Plasma IGF-I correlated positively to androstenedione (r=0.292, P<0.01) and dehydroepiandrosterone sulphate (DHEAS, r=0.202, P<0.05), while a significant positive correlation was observed between IGF-II on the one side and oestradiol (E(2), r=0.227), oestrone sulphate (E(1)S, r=0.238) and androstenedione (r=0.213) on the other side (P<0.05 for all).Our results support a relation between sex-steroids and IGF-I and -II in healthy postmenopausal women. The lower levels of total and free IGF-I in postmenopausal compared to premenopausal women indicate lower bioavailability of this growth factor in elderly females. 相似文献
607.
608.
Structural signatures of the complex formed between 3-nitro-4-hydroxybenzoate and the Zn(II)-substituted R(6) insulin hexamer
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Olsen HB Leuenberger-Fisher MR Kadima W Borchardt D Kaarsholm NC Dunn MF 《Protein science : a publication of the Protein Society》2003,12(9):1902-1913
3-Nitro-4-hydroxybenzoate (3N4H) is a probe of the structure and dynamics of the metal-centered His B10 assembly sites of the insulin hexamer. Each His B10 site consists of a approximately 12 A-long cavity situated on the threefold symmetry axis. These sites play an important role in the storage and release of insulin in vivo. The allosteric behavior of the insulin hexamer is modulated by ligand binding to the His B10 zinc sites and to the phenolic pockets. Binding to these sites drives transitions among three allosteric states, designated T(6), T(3)R(3), and R(6). Although a wide variety of mono anions bind to the His B10 zinc sites of R(3), X-ray structures of ligands complexed to this site exist only for H(2)O, Cl(-), and SCN(-). This work combines one- and two-dimensional (1)H NMR and UV-Vis absorbance studies of the structure and dynamics of the 3N4H complex, which establish the following: (1). relative to the NMR time scale, 3N4H exchange between free and bound states is slow, while flipping among three equivalent orientations about the site threefold axis is fast; (2). binding of 3N4H perturbs resonances within the His B10 zinc site and generates NOEs between ligand resonances and the insulin C-alpha and side chain resonances of ValB2, AsnB3, LeuB6, and CysB7; and (3).3N4H exchange for other ligands is limited by a protein conformational transition. These results are consistent with coordination of the 3N4H carboxylate to the His B10 zinc ion and van der Waals interactions with Val B2, Asn B3, Leu B6, and Cys A7. 相似文献
609.
Forest management is associated with physiological stress in an old-growth forest passerine 总被引:4,自引:0,他引:4
Suorsa P Huhta E Nikula A Nikinmaa M Jäntti A Helle H Hakkarainen H 《Proceedings. Biological sciences / The Royal Society》2003,270(1518):963-969
We investigated how physiological stress in an area-sensitive old-growth forest passerine, the Eurasian treecreeper (Certhia familiaris), is associated with forest fragmentation and forest structure. We found evidence that the concentrations of plasma corticosterone in chicks were higher under poor food supply in dense, young forests than in sparse, old forests. In addition, nestlings in large forest patches had lower corticosterone levels and a better body condition than in small forest patches. In general, corticosterone levels were negatively related to body condition and survival. We also found a decrease in corticosterone levels within the breeding season, which may have been a result of an increase in food supply from the first to the second broods. Our results suggest that forest fragmentation may decrease the fitness of free-living individual treecreepers. 相似文献
610.
Tota B Mazza R Angelone T Nullans G Metz-Boutigue MH Aunis D Helle KB 《Regulatory peptides》2003,114(2-3):123-130
The negative inotropic effects of synthetic peptides derived from the N-terminus of chromogranin A (CgA) were studied in an avascular model of the vertebrate myocardium, the isolated working frog heart (Rana esculenta). The peptides were frog and bovine CgA(4-16) and CgA(47-66), and bovine CgA(1-40) with (CgA(1-40SS)) and without an intact disulfide bridge (CgA(1-40SH)). Under basal cardiac conditions, four of the peptides caused a concentration-dependent negative inotropism that was comparable to the negative inotropy reported for human recombinant vasostatin I (CgA(1-78)) and bovine CgA(7-57). By comparison of the structural characteristics of the bovine and frog sequences with their minimally effective concentrations ranging from 68 to 125 nM of peptide, the results were consistent with the natural structure (CgA(17-38SS)) being essential for the negative inotropism. In addition, the partial sequences of the frog and bovine vasostatin I were effective in counteracting the characteristic positive inotropism exerted by isoproterenol (1 nM) at minimally effective concentrations ranging from 45 to 272 nM. Taken together, these results extend the first evidence for a cardiosuppressive role of the N-terminal domain of chromogranin A known for its co-storage with catecholamines in the sympathoadrenal system of vertebrates. 相似文献