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971.
PF Augustijns 《Canadian Metallurgical Quarterly》1996,48(3):277-280
The transepithelial transport and uptake of chloroquine were studied in cultured human intestinal Caco-2 cell layers, to investigate whether a specific mechanism facilitates the flux of chloroquine. Due to ionization of chloroquine at the pH of the intestinal lumen, the fraction of the neutral form, which is required for partitioning into biological membranes, is very low, while oral bioavailability has been reported to be nearly complete. Several observations, such as concentration-dependent uptake and temperature-dependent transepithelial flux, suggest the presence of carrier mediated transport. However, alternative mechanisms may be invoked to explain these observations. It is suggested that concentration dependence can originate from ion-trapping in acidic compartments of the cell or non-specific binding to cell components, while temperature-dependent transport can, at least partly, be explained by the temperature dependence of the acid dissociation constants of chloroquine. No differences were observed in the transepithelial flux of the enantiomers of chloroquine. pH-dependent uptake as well as pH-dependent transepithelial transport suggest that the translocation of chloroquine occurs according to the fraction of neutral molecules. From the data obtained in this study, it is concluded that chloroquine crosses the gastrointestinal barrier by passive diffusion. The extensive area of the gastrointestinal tract probably compensates for the low fraction of the neutral molecule. An interesting finding of this study was the concentration-dependent increase in transepithelial electrical resistance across monolayers incubated with chloroquine at the apical side. 相似文献
972.
H Mizuguchi PF Cook CH Tai CA Hasemann K Uyeda 《Canadian Metallurgical Quarterly》1999,274(4):2166-2175
A bifunctional enzyme, fructose-6-phosphate,2-kinase/fructose 2, 6-bisphosphatase (Fru-6-P,2-kinase/Fru-2,6-Pase), catalyzes synthesis and degradation of fructose 2,6-bisphosphate (Fru-2,6-P2). Previously, the rat liver Fru-2,6-Pase reaction (Fru-2,6-P2 --> Fru-6-P + Pi) has been shown to proceed via a phosphoenzyme intermediate with His258 phosphorylated, and mutation of the histidine to alanine resulted in complete loss of activity (Tauler, A., Lin, K., and Pilkis, S. J. (1990) J. Biol. Chem. 265, 15617-15622). In the present study, it is shown that mutation of the corresponding histidine (His256) of the rat testis enzyme decreases activity by less than a factor of 10 with a kcat of 17% compared with the wild type enzyme. Mutation of His390 (in close proximity to His256) to Ala results in a kcat of 12.5% compared with the wild type enzyme. Attempts to detect a phosphohistidine intermediate with the H256A mutant enzyme were unsuccessful, but the phosphoenzyme is detected in the wild type, H390A, R255A, R305S, and E325A mutant enzymes. Data demonstrate that the mutation of His256 induces a change in the phosphatase hydrolytic reaction mechanism. Elimination of the nucleophilic catalyst, H256A, results in a change in mechanism. In the H256A mutant enzyme, His390 likely acts as a general base to activate water for direct hydrolysis of the 2-phosphate of Fru-2,6-P2. Mutation of Arg255 and Arg305 suggests that the arginines probably have a role in neutralizing excess charge on the 2-phosphate and polarizing the phosphoryl for subsequent transfer to either His256 or water. The role of Glu325 is less certain, but it may serve as a general acid, protonating the leaving 2-hydroxyl of Fru-2,6-P2. 相似文献
973.
PF Van Look 《Canadian Metallurgical Quarterly》1996,313(7062):893-894
974.
P Burkhard GS Rao E Hohenester KD Schnackerz PF Cook JN Jansonius 《Canadian Metallurgical Quarterly》1998,283(1):121-133
The dependence of hormonal responses to exercise on sexual maturation was tested in three-year longitudinal experiment on 34 girls (11-12 years old at the beginning of the study). Sexual maturation of the girls was evaluated using Tanner scale. Girls were divided into three groups: maturation stages 1-2, 2-4 and 4-5. Children performed a 20-min cycle exercise at 60% of maximal oxygen uptake (VO max) once a year. Cortisol, insulin, somatotropin, beta-estradiol, progesterone and testosterone were determined in venous blood by RIA procedures. High basal levels of beta-estradiol and somatotropin appeared in stages 2-4 (387 +/- 92 pmol.l-1) and 12.9 +/- 2.85 ng.ml-1, respectively) and 4-5 (358 +/- 54 pmol.l-1) and 14.3 +/- 1.53 ng.ml-1, respectively). The basal progesterone level increased with maturation, testosterone appeared in the blood in stages 2-4 and 4-5. The exercise resulted in increased levels of cortisol and somatotropin, and a drop in insulin in all girls. The cortisol response was most pronounced in stage 1-2. Postexercise insulin concentration was the highest in stage 4-5. beta-estradiol level increased by 23% in stages 1-2 and 4-5, while the response was insignificant in stages 2-4. Exercise-induced progesterone increase was significant in stage 4-5. In conclusion, sexual maturation associates with several quantitative changes in exercise-induced hormonal responses. 相似文献
975.
SH Hu M Loughnan R Miller CM Weeks RH Blessing PF Alewood RJ Lewis JL Martin 《Canadian Metallurgical Quarterly》1998,37(33):11425-11433
Conotoxins are valuable probes of receptors and ion channels because of their small size and highly selective activity. alpha-Conotoxin EpI, a 16-residue peptide from the mollusk-hunting Conus episcopatus, has the amino acid sequence GCCSDPRCNMNNPDY(SO3H)C-NH2 and appears to be an extremely potent and selective inhibitor of the alpha3beta2 and alpha3beta4 neuronal subtypes of the nicotinic acetylcholine receptor (nAChR). The desulfated form of EpI ([Tyr15]EpI) has a potency and selectivity for the nAChR receptor similar to those of EpI. Here we describe the crystal structure of [Tyr15]EpI solved at a resolution of 1.1 A using SnB. The asymmetric unit has a total of 284 non-hydrogen atoms, making this one of the largest structures solved de novo by direct methods. The [Tyr15]EpI structure brings to six the number of alpha-conotoxin structures that have been determined to date. Four of these, [Tyr15]EpI, PnIA, PnIB, and MII, have an alpha4/7 cysteine framework and are selective for the neuronal subtype of the nAChR. The structure of [Tyr15]EpI has the same backbone fold as the other alpha4/7-conotoxin structures, supporting the notion that this conotoxin cysteine framework and spacing give rise to a conserved fold. The surface charge distribution of [Tyr15]EpI is similar to that of PnIA and PnIB but is likely to be different from that of MII, suggesting that [Tyr15]EpI and MII may have different binding modes for the same receptor subtype. 相似文献
976.
PF González-Daz 《Canadian Metallurgical Quarterly》1988,38(10):2951-2957
977.
DG Tubergen GS Gilchrist RT O'Brien PF Coccia HN Sather MJ Waskerwitz GD Hammond 《Canadian Metallurgical Quarterly》1993,11(3):520-526
PURPOSE: This study (Childrens Cancer Group [CCG]-105) was designed in part to determine in a prospective randomized trial whether intrathecal methotrexate (IT MTX) administered during induction, consolidation, and maintenance could provide protection from CNS relapse equivalent to that provided by cranial radiation (CXRT) in children with acute lymphoblastic leukemia (ALL) and intermediate-risk features. PATIENTS AND METHODS: We randomized 1,388 children with intermediate-risk ALL to the two CNS regimens. They received either IT MTX at intervals throughout their course of therapy or CXRT (18 Gy) during consolidation with IT MTX during induction, consolidation, and delayed intensification. Systemic therapy was randomized to one of four treatment regimens derived from a regimen used by CCG in recent studies for this patient population and three more intensive regimens based on the Berlin-Frankfurt-Munster trials. RESULTS: Life-table estimates at 7 years show a 93% and 91% CNS relapse-free survival rate for the CXRT and IT MTX groups, respectively. The corresponding event-free survival (EFS) rates are 68% and 64%. The differences are not significant. Patients who received more intensive systemic therapy had a 94% CNS relapse-free survival rate on either CXRT or IT MTX, while patients who received standard systemic therapy had 90% and 80% rates for CXRT and IT MTX, respectively (P < .0001). Patients less than 10 years of age who received CXRT or IT MTX had 72% and 71% EFS rates if they received more intensive systemic therapy. Patients 10 years or older who received CXRT had an improved EFS (61% v 53%) with a more intensive systemic program. This was primarily due to fewer bone marrow relapses (P = .04). CONCLUSIONS: IT MTX during induction, consolidation, and maintenance provides protection from CNS relapse in patients with intermediate-risk ALL equivalent to that provided by CXRT if more intensive systemic therapy is given. The CNS relapse rate with either CXRT or IT MTX is in part dependent on the associated systemic therapy. For intermediate-risk patients less than 10 years of age, IT MTX with an intensified systemic regimen provided CNS prophylaxis comparable to that provided by CXRT, whereas older patients had fewer systemic relapses if they received CXRT. 相似文献
978.
J Zguricas PF Dijkstra ES Gelsema PJ Snijders HP Wüstefeld HW Venema SE Hovius D Lindhout 《Canadian Metallurgical Quarterly》1997,34(1):55-62
A new two-step high-performance liquid chromatography (HPLC) procedure has been developed to separate modified histone H1 subtypes. Reversed-phase (RP) HPLC followed by hydrophilic-interaction liquid chromatography (HILIC) was used for analytical and semi-preparative scale fractionation of multi-phosphorylated H1 histone subtypes into their non-phosphorylated and distinct phosphorylated forms. The HILIC system utilizes the weak cation-exchange column PolyCAT A and an increasing sodium perchlorate gradient in a methanephosphonic acid-triethylamine buffer (pH 3.0) in the presence of 70% (v/v) acetonitrile. The identity and purity of the individual histone subfractions obtained was assayed by capillary electrophoretic analysis. The results demonstrate that application of the combined RP-HPLC-HILIC procedure to the analysis and isolation of modified H1 histone subtypes provides an innovative and important alternative to traditional separation techniques that will be extremely useful in studying the biological function of histone phosphorylation. 相似文献
979.
We have characterized the changes in intrinsic fluorescence that the insulin receptor undergoes upon ligand binding and autophosphorylation. The binding of insulin to its receptor results in an increase in the receptor's fluorescence intensity, emission energy and anisotropy. We monitored the time course of the anisotropy change, and these data, coupled with studies monitoring the energy transfer from insulin receptor tryptophan donors to a fluorescent-labeled insulin, allowed us to conclude that the change in anisotropy is due to a conformational change in the receptor induced by hormone binding. Since insulin association is very fast, the time course also allowed us to estimate the slower rate of formation of this conformationally-altered state. The time course of receptor autophosphorylation was measured under similar conditions and was found to be similar to the ligand-induced anisotropy time course. The simultaneous use of two fluorescent-labeled insulin analogs also allowed us to assess the maximum distance between the two hormones bound to the receptor. Addition of ATP produces a large, seemingly instantaneous increase in anisotropy. Our observation that ATP binds to the insulin receptor in the presence and absence of insulin supports the idea that the conformational change produced by insulin binding increases the rate of autophosphorylation rather than increases ATP affinity. A suggested model for these changes is presented. 相似文献
980.
Selective inhibition of mutant human mitochondrial DNA replication in vitro by peptide nucleic acids
RW Taylor PF Chinnery DM Turnbull RN Lightowlers 《Canadian Metallurgical Quarterly》1997,15(2):212-215
Mitochondrila DNA (mtDNA) is the only extrachromosomal DNA in humans. It is a small (16.5 kb) genome which encodes 13 essential peptides of the respiratory chain, two rRNAs and 22 tRNAs. Defects of this genome are now recognized as important causes of disease and may take the form of point mutations or rearrangements. There is no effective treatment for patients with mtDNA mutations. In the majority of patients with mtDNA defects, both mutant and wild-type molecules are present in the same cell-a phenomenon known as intracellular heteroplasmy. In addition, in the presence of heteroplasmy there is a threshold whereby a certain level of mutant mtDNA is necessary before the disease becomes biochemically and clinically apparent. Based on the presence of heteroplasmy and the recessive nature of these mutations, we believe it will be possible to treat patients by selectively inhibiting the replication of the mutant mtDNA, thereby allowing propagation of only the wild-type molecule. To confirm the validity of such an approach we synthesised peptide nucleic acids (PNAs) complementary to human mtDNA templates containing a deletion breakpoint or single base mutation, both mutations well documented to cause disease. Using an in vitro replication run-off assay under physiological conditions, the antigenomic PNAs specifically inhibited replication of mutant but not wild-type mtDNA templates. Furthermore, we have shown uptake of these PNAs into cultured human myoblasts. We believe that we have therefore established the potential value of antigenomic PNA therapy for patients with heteroplasmic mtDNA disorders. 相似文献