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991.
SM Wahl T Greenwell-Wild G Peng H Hale-Donze TM Doherty D Mizel JM Orenstein 《Canadian Metallurgical Quarterly》1998,95(21):12574-12579
Infection with HIV-1 results in pronounced immune suppression and susceptibility to opportunistic infections (OI). Reciprocally, OI augment HIV-1 replication. As we have shown for Mycobacterium avium complex (MAC) and Pneumocystis carinii, macrophages infected with opportunistic pathogens and within lymphoid tissues containing OI, exhibit striking levels of viral replication. To explore potential underlying mechanisms for increased HIV-1 replication associated with coinfection, blood monocytes were exposed to MAC antigens (MAg) or viable MAC and their levels of tumor necrosis factor alpha (TNFalpha) and HIV-1 coreceptors monitored. MAC enhanced TNFalpha production in vitro, consistent with its expression in coinfected lymph nodes. Using a polyclonal antibody to the CCR5 coreceptor that mediates viral entry of macrophage tropic HIV-1, a subset of unstimulated monocytes was shown to be CCR5-positive by fluorescence-activated cell sorter analysis. After stimulation with MAg or infection with MAC, CCR5 expression was increased at both the mRNA level and on the cell surface. Up-regulation of CCR5 by MAC was not paralleled by an increase in the T cell tropic coreceptor, CXCR4. Increases in NF-kappaB, TNFalpha, and CCR5 were consistent with the enhanced production of HIV-1 in MAg-treated adherent macrophage cultures as measured by HIV-1 p24 levels. Increased CCR5 was also detected in coinfected lymph nodes as compared with tissues with only HIV-1. The increased production of TNFalpha, together with elevated expression of CCR5, provide potential mechanisms for enhanced infection and replication of HIV-1 by macrophages in OI-infected cells and tissues. Consequently, treating OI may inhibit not only the OI-induced pathology, but also limit the viral burden. 相似文献
992.
993.
Delta 4-3-Ketosteroid-5 beta-reductase (5 beta-reductase) precedes 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) in steroid hormone metabolism. Both enzymes are members of the aldo-keto reductase (AKR) superfamily and possess catalytic tetrads differing by a single amino acid. In 3 alpha-HSD, the tetrad consists of Tyr55, Lys84, Asp50, and His117, but a glutamic acid replaces His117 in 5 beta-reductase. By introducing the H117E point mutation into 3 alpha-HSD, we engineered 5 beta-reductase activity into the dehydrogenase. Homogeneous H117E 3 alpha-HSD reduced the double bond in testosterone to form 5 beta-dihydrotestosterone with kcat = 0.25 min-1 and Km = 19.0 microM and reduced the double bond in progesterone to generate 5 beta-dihydroprogesterone with kcat = 0.97 min-1 and Km = 33.0 microM. These kinetic parameters were similar to those reported for homogeneous rat liver 5 beta-reductase [Okuda, A., and Okuda, R. (1984) J. Biol. Chem. 259, 7519-7524]. The H117E mutant also reduced 5beta-dihydrosteroids to 5 beta, 3 alpha-tetrahydrosteroids with a 600-1000-fold decrease in kcat/Km versus wild-type 3 alpha-HSD. The ratio of 5 beta-reductase:3 alpha-HSD activity in the H117E mutant was approximately 1:1. Although the H117A mutant reduced Delta 4-3-ketosteroids, the 3 alpha-HSD activity predominated because the 5 beta-dihydrosteroids were rapidly converted to the 5 beta,3 alpha-tetrahydrosteroids. The pH-rate profiles for carbon-carbon double-bond and ketone reduction catalyzed by the H117E mutant were superimposable, suggesting a common titratable group (pKb = 6.3) for both reactions. In wild-type 3 alpha-HSD, the titratable group responsible for 3-ketosteroid reduction has a pKb = 6.9 and is assignable to Tyr55. The pH-rate profiles for 3-ketosteroid reduction by the H117A mutant were pH-independent. Our data indicate that Tyr55 functions as a general acid for both 3 alpha-HSD and 5 beta-reductase activities. We suggest that a protonated Glu117 increases the acidity of Tyr55 to promote acid-catalyzed enolization of the Delta 4-3-ketosteroid substrate. Further, the identity of amino acid 117 determines whether an AKR can function as a 5 beta-reductase by reorienting the substrate relative to the nicotinamide cofactor. This study provides functional evidence that utilization of modified catalytic residues on an identical protein scaffold is important for evolution of enzymatic activities within the same metabolic pathway. 相似文献
994.
995.
We measured whether males of five species of poeciliid fish made detours to the right or left of a vertical-bar obstacle in order to approach a group of females. Three of these species, Gambusia holbrookiGambusia nicaraguensis and Poecilia reticulata showed a significant bias to the left, whereas Brachyrhaphis roseni and Girardinus falcatus showed a significant bias to the right. When tested for direction of turning in front of an opaque barrier, or when a dummy predator was used as a target in a detour test, G. holbrooki and G. falcatus showed similar biases to the right (opaque barrier) and left (predator), thus suggesting that the difference observed when females were used as a target could arise from species differences in the degree of sexual motivation in a novel environment. The two species that showed bias to the right with the females were less likely to exhibit sexual behaviour when placed in a novel environment. Moreover, manipulation of the factors affecting the relative strength of sexual motivation and of fear of a novel environment, such as how long fish were maintained in captivity or in the test apparatus before being tested, caused shifts in the direction of the lateral asymmetries. These results suggest that the presence of functional asymmetries in behaviour could be widespread among vertebrates and that the direction of such asymmetries tends to be strikingly similar in closely related species, thus supporting the hypothesis of an early evolution of laterality in brain and behaviour.Copyright 1997 The Association for the Study of Animal Behaviour1997The Association for the Study of Animal Behaviour 相似文献
996.
We consider counting process methods for analysing time-to-event data with multiple or recurrent outcomes, using the models developed by Anderson and Gill, Wei, Lin and Weissfeld and Prentice, Williams and Peterson. We compare the methods, and show how to implement them using popular statistical software programs. By analysing three data sets, we illustrate the strengths and pitfalls of each method. The first example is simulated and involves the effect of a hidden covariate. The second is based on a trial of gamma interferon, and behaves remarkably like the first. The third and most interesting example involves both multiple events and discontinuous intervals at risk, and the three approaches give dissimilar answers. We recommend the AG and marginal models for the analysis of this type of data. 相似文献
997.
AG McNees M O'Donnell PH Horton HY Kim SJ Kim CM Harris TM Harris RS Lloyd 《Canadian Metallurgical Quarterly》1997,272(52):33211-33219
Like other polycyclic aromatic hydrocarbons, certain metabolites of benz[a]anthracene have been implicated as potent carcinogens. These effects are thought to be caused by the covalent binding of these species to nucleophilic groups on the bases of DNA. To address the molecular mechanisms by which these molecules induce mutations, this study employed oligonucleotides containing four site-specific N6 adenine-benz[a]anthracene diol epoxide adducts. Using a prokaryotic in vivo replication system, we have shown that both non-bay region anti-trans-benz[a]anthracene adducts are essentially nonmutagenic. In contrast, the bay region anti-trans-benz[a]anthracene lesions do induce point mutations at the adduct site. The mutagenic frequency of these bay region lesions is dependent on the stereochemistry about the adduct-forming bond, as well as the strain of Escherichia coli in which they are replicated. The ability of the bacterial replication machinery to bypass the lesions does not correlate with the differences observed in their mutagenesis. While both non-bay region adducts are readily bypassed in vivo, the bay region adducts are both blocking to approximately the same degree. In vitro studies of the interactions of E. coli DNA polymerase III with these adducts have also been undertaken to further dissect the relationship between adduct structure and biological activity. 相似文献
998.
999.
1000.
I Pulay TM Konkoly M Arkosy M Tarjányi L Flautner 《Canadian Metallurgical Quarterly》1997,138(18):1113-1117
Acute pancreatitis is associated with greater and smaller necrosis in 20% of the cases. The lethality rate of sterile and infected necrosis is 10 and 15-40%, respectively. The results of a retrospective and a prospective study in acute pancreatitis have been analyzed in this study. Twenty patients suffering from infected necrosis due to acute necrotising pancreatitis were selected into the retrospective study. They were divided into two groups: Group 1 (N = 10) survivors, Group 2 (N = 10) those who died. The fate of patients was determined by their age, the severity of pancreatitis, and the effectiveness of the operation. In a prospective study 63 patients were operated due to benign pancreatic disease with fluid collection. Microbiological samples were taken during surgery in every case. It could be stated that the Enterobacteriaceae spp. play the principal role in the infection, and the anaerobic bacteria occur sporadically. The omission of bacteriological sample taking during surgery frustrates the targeted antibiotic treatment. The blood culturing may have useful contribution. The targeted antibiotic therapy based on relevant microbiological sample taking is substantial complementary of the surgical intervention in the treatment of the inflammatory pancreatic diseases. 相似文献