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41.
Isolation and preliminary characterization of temperature-sensitive mutants of measles virus. 总被引:7,自引:4,他引:7
Twenty-four genetically stable temperature-sensitive mutants of measles virus were isolated after mutangenesis by 5-azacytidine, 5 fluorouracil, or proflavine. The restricted replication of all mutants at 39 C was blocked subsequent to cell penetration and could not be attributed to heat inactivation of virus infectivity. Complementation analysis was made possible through the use of poly-L-ornithine. The members of one complementation group exhibited wild-type RNA synthesis at the nonpermissive temperature and induced the synthesis of virus antigens. These mutants were found defective in both hemolysin antigen synthesis and cell fusion "from within," supporting the unitary hypothesis for these functions. The members of the other two complementation groups synthesized neither virion RNA nor detectable virus antigens at the nonpermissive temperature. 相似文献
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Guo J Zhan S Somers J Westenbroek RE Catterall WA Roach DE Sheldon RS Lees-Miller JP Li P Shimoni Y Duff HJ 《American journal of physiology. Heart and circulatory physiology》2006,291(6):H2669-H2679
Overexpression of calcineurin in transgenic mouse heart results in massive cardiac hypertrophy followed by sudden death. Sudden deaths are caused by abrupt transitions from sinus rhythm to heart block (asystole) in calcineurin-overexpressing (CN) mice. Preliminary studies showed decreased maximum change in potential over time (dV/dt(max)) of phase 0 of the action potential. Accordingly, the hypothesis was tested that decreased activity of the sodium channel contributes to heart block. Profound decreases in activity of sodium currents (I(Na)) paralleled the changes in action potential characteristics. Progressive age-dependent decreases were observed such that at 42-50 days of life little sodium channel function existed. However, this was not paralleled by decreased protein expression as assessed by immunocytochemistry or by Western blot. Since calcineurin can interact with the ryanodine receptor, we assessed whether chronic in vitro treatment with BAPTA-AM, thapsigargin, and ryanodine could rescue the decrease of I(Na). All of these treatments rescued I(Na) to levels indistinguishable from wild type. The nonspecific PKC inhibitor bisindolylmaleimide I also rescued the decrease of I(Na). To assess whether decreased sodium channel activity contributes to sudden death in vivo, the response to encainide (20 mg/kg) was assessed: 6 of 10 young CN mice died because of asystole, whereas 0 of 10 wild-type mice died (P < 0.01). Moreover, encainide produced exaggerated prolongation of the QRS width in sinus beats before the heart block. Catecholamine tone appears necessary to support life in older CN mice because propranolol (1 mg/kg) triggered asystolic death in five of six CN mice. We conclude that decrease in sodium channel activity is in the common final pathway to asystole in CN mice. 相似文献
45.
Olson KR Healy MJ Qin Z Skovgaard N Vulesevic B Duff DW Whitfield NL Yang G Wang R Perry SF 《American journal of physiology. Regulatory, integrative and comparative physiology》2008,295(2):R669-R680
O2 chemoreceptors elicit cardiorespiratory reflexes in all vertebrates, but consensus on O2-sensing signal transduction mechanism(s) is lacking. We recently proposed that hydrogen sulfide (H2S) metabolism is involved in O2 sensing in vascular smooth muscle. Here, we examined the possibility that H2S is an O2 sensor in trout chemoreceptors where the first pair of gills is a primary site of aquatic O2 sensing and the homolog of the mammalian carotid body. Intrabuccal injection of H2S in unanesthetized trout produced a dose-dependent bradycardia and increased ventilatory frequency and amplitude similar to the hypoxic response. Removal of the first, but not second, pair of gills significantly inhibited H2S-mediated bradycardia, consistent with the loss of aquatic chemoreceptors. mRNA for H2S-synthesizing enzymes, cystathionine beta-synthase and cystathionine gamma-lyase, was present in branchial tissue. Homogenized gills produced H2S enzymatically, and H2S production was inhibited by O2, whereas mitochondrial H2S consumption was O2 dependent. Ambient hypoxia did not affect plasma H2S in unanesthetized trout, but produced a PO2-dependent increase in a sulfide moiety suggestive of increased H2S production. In isolated zebrafish neuroepithelial cells, the putative chemoreceptive cells of fish, both hypoxia and H2S, produced a similar approximately 10-mV depolarization. These studies are consistent with H2S involvement in O2 sensing/signal transduction pathway(s) in chemoreceptive cells, as previously demonstrated in vascular smooth muscle. This novel mechanism, whereby H2S concentration ([H2S]) is governed by the balance between constitutive production and oxidation, tightly couples tissue [H2S] to PO2 and may provide an exquisitely sensitive, yet simple, O2 sensor in a variety of tissues. 相似文献
46.
Gélinas R Labarthe F Bouchard B Mc Duff J Charron G Young ME Des Rosiers C 《American journal of physiology. Heart and circulatory physiology》2008,294(4):H1571-H1580
Although a shift from fatty acids (FAs) to carbohydrates (CHOs) is considered beneficial for the diseased heart, it is unclear why subjects with FA beta-oxidation defects are prone to cardiac decompensation under stress conditions. The present study investigated potential alterations in the myocardial utilization of CHOs for energy production and anaplerosis in 12-wk-old peroxisome proliferator-activating receptor-alpha (PPARalpha) null mice (a model of FA beta-oxidation defects). Carbon-13 methodology was used to assess substrate flux through energy-yielding pathways in hearts perfused ex vivo at two workloads with a physiological substrate mixture mimicking the fed state, and real-time RT-quantitative polymerase chain reaction was used to document the expression of selected metabolic genes. When compared with that from control C57BL/6 mice, isolated working hearts from PPARalpha null mice displayed an impaired capacity to withstand a rise in preload (mimicking an increased venous return as it occurs during exercise) as reflected by a 20% decline in the aortic flow rate. At the metabolic level, beyond the expected shift from FA (5-fold down) to CHO (1.5-fold up; P < 0.001) at both preloads, PPARalpha null hearts also displayed 1) a significantly greater contribution of exogenous lactate and glucose and/or glycogen (2-fold up) to endogenous pyruvate formation, whereas that of exogenous pyruvate remained unchanged and 2) marginal alterations in citric acid cycle-related parameters. The lactate production rate was the only measured parameter that was affected differently by preloads in control and PPARalpha null mouse hearts, suggesting a restricted reserve for the latter hearts to enhance glycolysis when the energy demand is increased. Alterations in the expression of some glycolysis-related genes suggest potential mechanisms involved in this defective CHO metabolism. Collectively, our data highlight the importance of metabolic alterations in CHO metabolism associated with FA oxidation defects as a factor that may predispose the heart to decompensation under stress conditions even in the fed state. 相似文献
47.
Yu WH Matsuoka Y Sziráki I Hashim A Lafrancois J Sershen H Duff KE 《Neurochemical research》2008,33(5):902-911
Familial Parkinson’s disease (PD) has been linked to point mutations and duplication of the α-synuclein gene and mutant α-synuclein
expression increases the vulnerability of neurons to exogenous insults. In this study, we analyzed the levels of dopamine
and its metabolites in the olfactory bulb (OB), and nigrostriatal regions of transgenic mice expressing human, mutant A53T
α-synuclein (α-syn tg) and their non-transgenic (ntg) littermates using a sub-toxic, moderate dose of MPTP to determine if
mutant human α-synuclein sensitizes the central dopaminergic systems to oxidative stress. We observed that after a single,
sub-lethal MPTP injection, dopamine levels were reduced in striatum and SN in both the α-syn tg and ntg mice. In the olfactory
bulb, a region usually resistant to MPTP toxicity, levels were reduced only in the α-syn tg mice. In addition, we identified
a significant increase in dopamine metabolism in the α-syn transgenic, but not ntg mice. Finally, MPTP treatment of α-syn
tg mice was associated with a marked elevation in the oxidative product, 3-nitrotyrosine that co-migrated with α-synuclein.
Cumulatively, the data support the hypothesis that mutant α-synuclein sensitizes dopaminergic neurons to neurotoxic insults
and is associated with greater oxidative stress. The α-syn tg line is therefore useful to study the genetic and environmental
inter-relationship in PD. 相似文献
48.
Egg parasitoids of the diamondback moth, Plutella xylostella (L.) (Lepidoptera: Plutellidae), from south-east Queensland 总被引:1,自引:0,他引:1
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A covalent cross-linking technique was used to bind iodinated interleukin-1 (IL1) alpha and beta to plasma proteins. One specific IL1 beta binding protein was observed, that when cross-linked to 125I-ILl beta migrated to approximately 60 kDa on SDS-PAGE. The protein did not bind IL1 alpha. The 43 -kDa protein was partially purified using a wheat germ agglutinin affinity column. The isolated factor again specifically bound IL1 beta, and appeared to consist of single chain glycoprotein. The protein was heat stable and had a rapid association time with IL1 beta. This protein may be an important carrier molecule for IL1 beta in vivo. 相似文献