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31.
The 18S ribosomal RNAs of 21 tetrapods were sequenced and aligned with five
published tetrapod sequences. When the coelacanth was used as an outgroup,
Lissamphibia (living amphibians) and Amniota (amniotes) were found to be
statistically significant monophyletic groups. Although little resolution
was obtained among the lissamphibian taxa, the amniote sequences support a
sister-group relationship between birds and mammals. Portions of the 28S
ribosomal RNA (rRNA) molecule in 11 tetrapods also were sequenced, although
the phylogenetic results were inconclusive. In contrast to previous
studies, deletion or down- weighting of base-paired sites were found to
have little effect on phylogenetic relationships. Molecular evidence for
amniote relationships is reviewed, showing that three genes
(beta-hemoglobin, myoglobin, and 18S rRNA) unambiguously support a
bird-mammal relationship, compared with one gene (histone H2B) that favors
a bird- crocodilian clade. Separate analyses of four other genes (alpha-
crystallin A, alpha-hemoglobin, insulin, and 28S rRNA) and a combined
analysis of all sequence data are inconclusive, in that different groups
are defined in different analyses and none are strongly supported. It is
suggested that until sequences become available from a broader array of
taxa, the molecular evidence is best evaluated at the level of individual
genes, with emphasis placed on those studies with the greatest number of
taxa and sites. When this is done, a bird-mammal relationship is most
strongly supported. When regarded in combination with the morphological
evidence for this association, it must be considered at least as plausible
as a bird-crocodilian relationship.
相似文献
32.
Six trained males [mean maximal O2 uptake (VO2max) = 66 ml X kg-1 X min-1] performed 30 min of cycling (mean = 76.8% VO2max) during normoxia (21.35 +/- 0.16% O2) and hyperoxia (61.34 +/- 1.0% O2). Values for VO2, CO2 output (VCO2), minute ventilation (VE), respiratory exchange ratio (RER), venous lactate, glycerol, free fatty acids, glucose, and alanine were obtained before, during, and after the exercise bout to investigate the possibility that a substrate shift is responsible for the previously observed enhanced performance and decreased RER during exercise with hyperoxia. VO2, free fatty acids, glucose, and alanine values were not significantly different in hyperoxia compared with normoxia. VCO2, RER, VE, and glycerol and lactate levels were all lower during hyperoxia. These results are interpreted to support the possibility of a substrate shift during hyperoxia. 相似文献
33.
John R. Cashman Ketankumar K. Parikh George J. Traiger Robert P. Hanzlik 《Chemico-biological interactions》1983,45(3):341-347
Thiobenzamide is known to be hepatotoxic in the rat and the relative hepatotoxicity of para-substituted thiobenzamides has previously been shown to depend strictly on the electronic character of the para substituent. We have now extended this study to include ortho and meta monosubstituted thiobenzamides. Among the meta-substituted compounds, hepatotoxicity varies in strict accordance with the electronic character of the substituent, whereas the ortho-substituted compounds show no toxicity at comparable doses regardless of the nature of the substituent. Explanations for these substituent effects are provided in terms of the chemical reactivity of the compounds and their corresponding S-oxide and S,S-dioxide metabolites. 相似文献
34.
John R. Cashman Robert P. Hanzlik 《Biochemical and biophysical research communications》1981,98(1):147-153
The hepatotoxin thiobenzamide is S-oxidized by the microsomal flavin-containing monooxygenase (MFMO)1 in liver, lung, and kidney of rabbit, mouse and rat. Its oxidation is accompanied by a large spectral shift which can be used as the basis of a simple convenient photometric assay for the MFMO system. 相似文献
35.
J P Antel M B Bania A Reder N Cashman 《Journal of immunology (Baltimore, Md. : 1950)》1986,137(1):137-141
Concanavalin A (Con A)-induced suppressor activity has previously been shown to be reduced in multiple sclerosis (MS) patients with active clinical disease. In this study, we demonstrate that OKT3, as well as Con A induced suppressor activity mediated by unfractionated peripheral blood mononuclear cells is reduced in patients with the progressive form of MS. By performing reconstitution experiments involving E+, T4+, or T8+ cells derived from either MS patients or controls, and normal allogeneic macrophages or E- cells, we sought to define the cellular basis for this suppressor defect. In both MS and control groups, E+ cells were required to obtain measurable levels of suppression. Suppressor levels induced by Con A-activated cultures containing E+ cells from MS patients were lower than those induced by those containing control donor E+ cells. Suppression mediated by T8+ cells from MS patients was also lower than for controls. In the control group, suppression mediated by T8+ cells exceeded that mediated by T4+ cells; such differences were not apparent in the MS group. These results suggest that although Con A-induced suppression can be mediated by a number of T and non-T cell subsets, the functional suppressor defect measured in the MS population does involve the T8+ cell subset. 相似文献
36.
37.
Troy Voelker Haiji Xia Keith Fandrick Robert Johnson Aaron Janowsky John R. Cashman 《Bioorganic & medicinal chemistry》2009,17(5):2047-2068
Enhancement of 5-hydroxytryptamine (5-HT, serotonin) neurotransmission is a viable means of treating depression. On the basis of this observation, agents that inhibit re-uptake of 5-HT were prepared based on (?)-cocaine and aryltropanes as lead compounds because they are reasonably potent 5-HT re-uptake inhibitors. Molecular dissection of an aryltropane provided a series of 5- and 6-membered ring compounds. From among this library of compounds a series of disubstituted tetrahydrofurans bearing 2-alkyl aryl and 5-alkyl amino groups were identified as having highly potent and selective 5-HT re-uptake inhibition. The compounds were evaluated for their ability to compete with radiolabeled RTI-55 binding and to inhibit re-uptake of neurotransmitters at the human dopamine, serotonin and norepinephrine transporters. Based on potency (e.g., Ki = 800 pM) and significant functional selectivity (e.g., IC50 ratios for human dopamine:serotonin or norepinephrine:serotonin, ?1397) highly potent and selective serotonin re-uptake inhibitors were identified. Optimal features playing a dominant role in binding affinity and re-uptake inhibition included lipophilic substitution on the aromatic moiety, trans relative stereochemistry of the 2,5-disubstituted tetrahydrofuran ring, and a total of four or five methylene groups between the alkyl amine and the alkyl aryl moiety and the tetrahydrofuran group. A number of the most potent serotonin re-uptake inhibitors were tested in Balb/c mice in the forced-swim test (FST), a behavioral test used to measure the effects of antidepressant agents. Acute administration of 32c (10 mg/kg), or 32d (10 mg/kg) ip tended to decrease the duration of mouse immobility in the FST although the effect was not statistically significant. 相似文献
38.
Eileen F. Murphy Guido J. Hooiveld Michael Müller Raffaelle A. Calogero Kevin D. Cashman 《Genes & nutrition》2009,4(2):103-112
We conducted an in-depth investigation of the effects of conjugated linoleic acid (CLA) on the expression of key metabolic genes and genes of known importance in intestinal lipid metabolism using the Caco-2 cell model. Cells were treated with 80 μmol/L of linoleic acid (control), trans-10, cis-12 CLA or cis-9, trans-11 CLA. RNA was isolated from the cells, labelled and hybridized to the Affymetrix U133 2.0 Plus arrays (n = 3). Data and functional analysis were preformed using Bioconductor. Gene ontology analysis (GO) revealed a significant enrichment (P < 0.0001) for the GO term lipid metabolism with genes up-regulated by trans-10, cis-12 CLA. Trans-10, cis-12 CLA, but not cis-9, trans-11 CLA, altered the expression of a number of genes involved in lipid transport, fatty acid metabolism, lipolysis, β-oxidation, steroid metabolism, cholesterol biosynthesis, membrane lipid metabolism, gluconeogenesis and the citrate cycle. These observations warrant further investigation to understand their potential role in the metabolic syndrome. 相似文献
39.
Karl J. Okolotowicz Ranxin Shi Xueying Zheng Mary MacDonald John C. Reed John R. Cashman 《Bioorganic & medicinal chemistry》2010,18(5):1918-1924
Dysregulated antigen receptor-mediated NF-κB activation can contribute to development of autoimmunity, chronic inflammation, and malignancy. A chemical biology screening strategy has identified a substituted benzimidazole that selectively inhibits antigen receptor-mediated NF-κB activation without blocking other NF-κB activation pathways. A library of analogs was synthesized and the structure–activity relationship and metabolic stability for the series is presented. 相似文献
40.
Paramithiotis E Pinard M Lawton T LaBoissiere S Leathers VL Zou WQ Estey LA Lamontagne J Lehto MT Kondejewski LH Francoeur GP Papadopoulos M Haghighat A Spatz SJ Head M Will R Ironside J O'Rourke K Tonelli Q Ledebur HC Chakrabartty A Cashman NR 《Nature medicine》2003,9(7):893-899
Conformational conversion of proteins in disease is likely to be accompanied by molecular surface exposure of previously sequestered amino-acid side chains. We found that induction of beta-sheet structures in recombinant prion proteins is associated with increased solvent accessibility of tyrosine. Antibodies directed against the prion protein repeat motif, tyrosine-tyrosine-arginine, recognize the pathological isoform of the prion protein but not the normal cellular isoform, as assessed by immunoprecipitation, plate capture immunoassay and flow cytometry. Antibody binding to the pathological epitope is saturable and specific, and can be created in vitro by partial denaturation of normal brain prion protein. Conformation-selective exposure of Tyr-Tyr-Arg provides a probe for the distribution and structure of pathologically misfolded prion protein, and may lead to new diagnostics and therapeutics for prion diseases. 相似文献