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排序方式: 共有198条查询结果,搜索用时 15 毫秒
41.
Jan Milichovsky Franti?ek Bárta Heinz H. Schmeiser Volker M. Arlt Eva Frei Marie Stiborová Václav Martínek 《International journal of molecular sciences》2016,17(2)
Aristolochic acid I (AAI) is a plant drug found in Aristolochia species that causes aristolochic acid nephropathy, Balkan endemic nephropathy and their associated urothelial malignancies. AAI is activated via nitroreduction producing genotoxic N-hydroxyaristolactam, which forms DNA adducts. The major enzymes responsible for the reductive bioactivation of AAI are NAD(P)H:quinone oxidoreductase and cytochromes P450 (CYP) 1A1 and 1A2. Using site-directed mutagenesis we investigated the possible mechanisms of CYP1A1/1A2/1B1-catalyzed AAI nitroreduction. Molecular modelling predicted that the hydroxyl groups of serine122/threonine124 (Ser122/Thr124) amino acids in the CYP1A1/1A2-AAI binary complexes located near to the nitro group of AAI, are mechanistically important as they provide the proton required for the stepwise reduction reaction. In contrast, the closely related CYP1B1 with no hydroxyl group containing residues in its active site is ineffective in catalyzing AAI nitroreduction. In order to construct an experimental model, mutant forms of CYP1A1 and 1A2 were prepared, where Ser122 and Thr124 were replaced by Ala (CYP1A1-S122A) and Val (CYP1A2-T124V), respectively. Similarly, a CYP1B1 mutant was prepared in which Ala133 was replaced by Ser (CYP1B1-A133S). Site-directed mutagenesis was performed using a quickchange approach. Wild and mutated forms of these enzymes were heterologously expressed in Escherichia coli and isolated enzymes characterized using UV-vis spectroscopy to verify correct protein folding. Their catalytic activity was confirmed with CYP1A1, 1A2 and 1B1 marker substrates. Using 32P-postlabelling we determined the efficiency of wild-type and mutant forms of CYP1A1, 1A2, and 1B1 reconstituted with NADPH:CYP oxidoreductase to bioactivate AAI to reactive intermediates forming covalent DNA adducts. The S122A and T124V mutations in CYP1A1 and 1A2, respectively, abolished the efficiency of CYP1A1 and 1A2 enzymes to generate AAI-DNA adducts. In contrast, the formation of AAI-DNA adducts was catalyzed by CYP1B1 with the A133S mutation. Our experimental model confirms the importance of the hydroxyl group possessing amino acids in the active center of CYP1A1 and 1A2 for AAI nitroreduction. 相似文献
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43.
Dr. Angelo Frei Soumya Ramu Gabrielle J. Lowe Dr. Hue Dinh Dr. Lucie Semenec Dr. Alysha G. Elliott Johannes Zuegg Dr. Anke Deckers Prof. Nicole Jung Prof. Stefan Bräse Dr. Amy K. Cain Prof. Mark A. T. Blaskovich 《ChemMedChem》2021,16(20):3165-3171
Antimicrobial resistance is a looming health crisis, and it is becoming increasingly clear that organic chemistry alone is not sufficient to continue to provide the world with novel and effective antibiotics. Recently there has been an increased number of reports describing promising antimicrobial properties of metal-containing compounds. Platinum complexes are well known in the field of inorganic medicinal chemistry for their tremendous success as anticancer agents. Here we report on the promising antibacterial properties of platinum cyclooctadiene (COD) complexes. Amongst the 15 compounds studied, the simplest compounds Pt(COD)X2 (X=Cl, I, Pt1 and Pt2 ) showed excellent activity against a panel of Gram-positive bacteria including vancomycin and methicillin resistant Staphylococcus aureus. Additionally, the lead compounds show no toxicity against mammalian cells or haemolytic properties at the highest tested concentrations, indicating that the observed activity is specific against bacteria. Finally, these compounds showed no toxicity against Galleria mellonella at the highest measured concentrations. However, preliminary efficacy studies in the same animal model found no decrease in bacterial load upon treatment with Pt1 and Pt2 . Serum exchange studies suggest that these compounds exhibit high serum binding which reduces their bioavailability in vivo, mandating alternative administration routes such as e. g. topical application. 相似文献
44.
A set of 54 rice landrace samples was compiled from various Asian countries, including six red/brownish and eight black/purple varieties. Brown rice samples were analyzed for lipid content and fatty acid profile, as well as all‐trans‐β‐carotene content. Black/purple varieties were found to be higher in crude lipid content than the red/brownish and colorless varieties. They also had a higher β‐carotene content than the other two color classes. The highest β‐carotene content determined was 0.22 mg kg−1. Black/purple varieties tended to have a higher proportion of saturated fatty acids in their lipid fraction and a lower proportion of unsaturated fatty acids. The differences were statistically significant (P < 0.05) for oleic acid, which accounted for 42.1% of the lipid fraction in black/purple varieties and for 45.3% and 46.3% in red/brownish and colorless varieties, respectively. β‐Carotene content showed a significantly positive correlation with the crude lipid content (P < 0.001) and the content of saturated fatty acids (P < 0.001) on a dry matter basis. However, it was not correlated with the unsaturated fatty acids content on a dry matter basis. Within the total lipid extract, β‐carotene showed a significantly positive correlation with the proportion of saturated fatty acids (P < 0.01), especially palmitic acid (P < 0.01), and a significantly negative correlation with unsaturated fatty acids (P < 0.001), especially oleic acid (P < 0.01). Copyright © 2005 Society of Chemical Industry 相似文献
45.
JR Jauchem MR Frei KL Ryan JH Merritt MR Murphy 《Canadian Metallurgical Quarterly》1999,46(1):117-120
OBJECTIVE: This report describes the radiologic findings and discusses the clinical consequences of acute traumatic aortic tear occurring with an aberrant right subclavian artery. CONCLUSION: Identification of an aberrant right subclavian artery with acute traumatic aortic tear must be emphasized to reduce iatrogenic morbidity and mortality. 相似文献
46.
R Schiffmann NK Dwyer IA Lubensky M Tsokos VE Sutliff JS Latimer KP Frei RO Brady NW Barton EJ Blanchette-Mackie E Goldin 《Canadian Metallurgical Quarterly》1998,95(3):1207-1212
Mucolipidosis type IV is an autosomal recessive lysosomal storage disease of unknown etiology that causes severe neurological and ophthalmological abnormalities. In an attempt to obtain insight into the nature of the metabolic abnormality in this disorder, we prospectively evaluated 15 consecutive patients, aged 2 to 23 years, over a period of 22 months. The finding of iron deficiency in some of the patients led us to the discovery that all patients but one had markedly elevated blood gastrin levels. None had vitamin B12 deficiency. Gastroscopy in three patients showed normal gross appearance of the mucosa in two patients, 4 and 7 years old, and mucosal atrophy in a 22-year-old. Parietal cells were present in normal numbers and contained large cytoplasmic inclusions that were confirmed immunohistochemically to be lysosomal in nature. Other gastric epithelial cells appeared normal. Parietal cells contained very few tubulovesicular membranes, suggesting cellular activation, whereas apical canaliculi appeared relatively nonactivated. Both subunits of the parietal cell H+/K+-ATPase were present, and both partially colocalized with f-actin at the apical membrane. We conclude that patients with mucolipidosis type IV are constitutively achlorhydric and have partially activated parietal cells. We hypothesize that the defective protein in this disease is closely associated with the final stages of parietal cell activation and is critical for a specific type of cellular vacuolar trafficking between the cytoplasm and the apical membrane domain. 相似文献
47.
MP Zanni D Mauri-Hellweg C Brander T Wendland B Schnyder E Frei S von Greyerz A Bircher WJ Pichler 《Canadian Metallurgical Quarterly》1997,158(3):1139-1148
To investigate the cellular immune response to the drug lidocaine, we generated T cell lines and clones from the peripheral blood of four patients with proven allergy to lidocaine. The patients had contact dermatitis after topical application of lidocaine, and local swelling or generalized erythema exudativum multiforme after submucosal/subcutaneous injection of lidocaine. Two of three lidocaine-specific T cell lines were oligoclonal and one even became monoclonal, while the simultaneously analyzed immune response to tetanus toxoid was polyclonal. The lidocaine-specific T cell lines cross-reacted to mepivacaine, but not to other local anesthetics (bupivacaine, procaine, oxybuprocaine, and tetracaine). The majority of reactive T cells belonged to the CD4 cell lineage and were MHC class II restricted, but cloning also revealed some MHC class I-restricted CD8+ clones. A total of 2 of 56 lidocaine-specific T cell clones were CD4-CD8- and expressed TCR-gammadelta. The majority of 13 analyzed CD4 clones produced a rather polarized cytokine pattern, with a dominance of Th2-like cytokines showing a high IL-5 production. In addition, three CD4+ and all CD8+ (n = 7) clones secreted high IFN-gamma and low levels of IL-5/IL-4 (Th1-like). The data illustrate that a drug that sensitizes via the skin elicits a heterogeneous T cell response. The high IL-5 production and the participation of specific CD4+CD8+ and even gammadelta+ T cells appear to be distinguishing features of this hapten-specific immune response. 相似文献
48.
A temperature-sensitive mutant of Moloney murine leukemia virus defective in an early function and injected into newborn mice produced lower limb paralysis. Susceptible mice were inbred strains CFW/D, CBA/H, C3H/Bi/Ka, and outbred NIH Swiss stock. Inbred W/Fu rats and C57BL/Ka mice did not develop the paralysis, though the latter were infected with virus; the sera from these mice produced paralysis in susceptible CFW mice. 相似文献
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50.
M. Balz H.A. Therese J. Li J.S. Gutmann M. Kappl L. Nasdala W. Hofmeister H.‐J. Butt W. Tremel 《Advanced functional materials》2005,15(4):683-688
The concepts of template‐induced crystallization on self‐assembled monolayers (SAMs) and the use of polymer additives are combined into a new strategy, where, through the cooperative interaction of a SAM matrix involved in the nucleation process, poly(acrylic acid), a dissolved polyelectrolyte, and the dissolved ions, hierarchically ordered mineral structures are formed. The adsorption of poly(acrylic acid) to the SAM is monitored using a quartz microbalance. Transmission electron microscopy measurements on samples that are taken from polyacrylate solution in short intervals after the start of the reaction reveals that nanometer‐sized particles pre‐formed in solution are being attached to the polymer template. These CaCO3 nanoparticles are still amorphous 20 min after the start of the mineralization process; the transformation from the amorphous to the crystalline phase takes place within the first 60 min of the reaction. The morphologies of the crystalline products exhibit characteristic differences from those that are obtained in crystallization experiments on self‐assembled monolayers without the polyelectrolyte. This model of cooperative formation of vaterite nanowires represents an alternative to current models of structure formation, where two‐phase systems (e.g., microemulsions or foams) act as a structure‐directing interface, or the mineralization process is caused by the diffusion of a hydrolyzable component from a non‐aqueous into an aqueous phase. 相似文献