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11.
Iron porphyrin treatment extends survival in a transgenic animal model of amyotrophic lateral sclerosis 总被引:2,自引:0,他引:2
Wu AS Kiaei M Aguirre N Crow JP Calingasan NY Browne SE Beal MF 《Journal of neurochemistry》2003,85(1):142-150
Oxidative damage, produced by mutant Cu/Zn superoxide dismutase (SOD1), may play a role in the pathogenesis of amyotrophic lateral sclerosis (ALS), a devastating motor neuron degenerative disease. A novel approach to antioxidant therapy is the use of metalloporphyrins that catalytically scavenge a wide range of reactive oxygen and reactive nitrogen species. In this study, we examined the therapeutic potential of iron porphyrin (FeTCPP) in the G93A mutant SOD1 transgenic mouse model of ALS. We found that intraperitoneal injection of FeTCPP significantly improved motor function and extended survival in G93A mice. Similar results were seen with a second group of mice wherein treatment with FeTCPP was initiated at the onset of hindlimb weakness-roughly equivalent to the time at which treatment would begin in human patients. FeTCPP-treated mice also showed a significant reduction in levels of malondialdehyde (a marker of lipid peroxidation), in total content of protein carbonyls (a marker of protein oxidation), and increased neuronal survival in the spinal cord. These results therefore provide further evidence of oxidative damage in a mouse model of ALS, and suggest that FeTCPP could be beneficial for the treatment of ALS patients. 相似文献
12.
Beal MF 《Nature reviews. Neuroscience》2001,2(5):325-334
Research into the pathogenesis of Parkinson's disease has been rapidly advanced by the development of animal models. Initial models were developed by using toxins that specifically targeted dopamine neurons, the most successful of which used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, a toxin that causes parkinsonism in man. More recently, the identification of alpha-synuclein mutations as a rare cause of Parkinson's disease has led to the development of alpha-synuclein transgenic mice and Drosophila. Here, I discuss the merits and limitations of these different animal models in our attempts to understand the physiology of Parkinson's disease and to develop new therapies. 相似文献
13.
Beal MF 《Free radical research》2002,36(4):455-460
Coenzyme Q 10 (CoQ 10 ) is an essential cofactor of the electron transport gene as well as an important antioxidant, which is particularly effective within mitochondria. A number of prior studies have shown that it can exert efficacy in treating patients with known mitochondrial disorders. We investigated the potential usefulness of coenzyme Q 10 in animal models of Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and Huntington's disease (HD). It has been demonstrated that CoQ 10 can protect against striatal lesions produced by the mitochondrial toxins malonate and 3-nitropropionic acid. These toxins have been utilized to model the striatal pathology, which occurs in HD. It also protects against 1-methyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity in mice. CoQ 10 significantly extended survival in a transgenic mouse model of ALS. CoQ 10 can significantly extend survival, delay motor deficits and delay weight loss and attenuate the development of striatal atrophy in a transgenic mouse model of HD. In this mouse model, it showed additive efficacy when combined with the N -methyl- d -aspartate (NMDA) receptor antagonist, remacemide. CoQ 10 is presently being studied as a potential treatment for early PD as well as in combination with remacemide as a potential treatment for HD. 相似文献
14.
Role of rhamnolipid biosurfactants in the uptake and mineralization of hexadecane in Pseudomonas aeruginosa 总被引:3,自引:0,他引:3
A study was undertaken to investigate the mechanisms for biosurfactant-enhanced hexadecane uptake into Pseudomonas aeruginosa. Two strains of Ps. aeruginosa were studied, one producing rhamnolipids (PG201) and the other rhamnolipid deficient (UO299). Rhamnolipids produced by PG201 acted to increase the solubility of n-hexadecane in the culture medium (from 1.84 to 22.76 microg l(-1). Rates of(l4)C-n-hexadecane uptake and mineralization were higher in PG201 than in UO299. However, the degree of difference was lower than expected. Additional studies were carried out on the cell surface properties of the two strains. During growth on n-hexadecane, the cell surface hydrophobicity of both PG201 (50.5%) and UO299 (33.7%) increased compared with that observed in water-soluble growth substrates (7-8%). Studies were also carried out to ascertain any energy requirements for the transport of n-hexadecane into Ps. aeruginosa cells. The addition of CCCP (an inhibitor of cytochrome oxidase which thereby blocks oxidative phosphorylation) at a range of concentrations caused a marked decrease in n-hexadecane uptake, indicating that n-hexadecane uptake in Ps. aeruginosa is an energy-dependent process. These studies support the hypothesis of alkane transport into microbial cells by direct contact with larger alkane droplets and by pseudosolubilization. Also, it appears that both mechanisms occur simultaneously. 相似文献
15.
Beal AM 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2000,125(2):189-196
Selective and non-selective beta-adrenoceptor antagonists were used to block the increases in fluid, protein and amylase secretion caused by sympathomimetic stimulation of the parotid gland of red kangaroos during intracarotid infusion of isoprenaline. ICI118551 at antagonist/agonist ratios up to 300:1 caused increasing but incomplete blockade of fluid secretion, and protein/amylase release. Atenolol at antagonist/agonist ratios up to 300:1 was only marginally more potent than ICI118551 at blocking the fluid, protein and amylase responses. Propranolol at antagonist/agonist ratios of 30:1 was as effective at blocking fluid and protein secretion as the highest ratios of either atenolol or ICI118551. Simultaneous administration of atenolol (30:1) with ICI118551 (30:1) was not as potent as propranolol (30:1). Thus, the beta-adrenoceptor/s in the acini of the kangaroo parotid gland appear to have antagonist-binding affinities atypical of those found for eutherian tissues. The data are consistent with the gland possessing either a single anomalous beta-adrenoceptor or functional beta(2)-receptors in addition to the beta(1)-receptors which are characteristic of eutherian salivary glands. 相似文献
16.
Metabolic Dysfunction in Familial, but Not Sporadic, Amyotrophic Lateral Sclerosis 总被引:12,自引:2,他引:12
Susan E. Browne †Allen C. Bowling M. Jay Baik ‡Mark Gurney †Robert H. Brown Jr. M. Flint Beal 《Journal of neurochemistry》1998,71(1):281-287
Abstract: Autosomal dominant familial amyotrophic lateral sclerosis (FALS) is associated with mutations in the gene encoding Cu/Zn superoxide dismutase (SOD1). Previous studies have implicated the involvement of metabolic dysfunction in ALS pathogenesis. To further investigate the biochemical features of FALS and sporadic ALS (SALS), we examined SOD activity and mitochondrial oxidative phosphorylation enzyme activities in motor cortex (Brodmann area 4), parietal cortex (Brodmann area 40), and cerebellum from control subjects, FALS patients with and without known SOD mutations, SALS patients, and disease controls (Pick's disease, progressive supranuclear palsy, diffuse Lewy body disease). Cytosolic SOD activity, predominantly Cu/Zn SOD, was decreased ∼50% in all regions in FALS patients with SOD mutations but was not significantly altered in other patient groups. Marked increases in complex I and II–III activities were seen in FALS patients with SOD mutations but not in SALS patients. We also measured electron transport chain enzyme activities in a transgenic mouse model of FALS. Complex I activity was significantly increased in the forebrain of 60-day-old G93A transgenic mice overexpressing human mutant SOD1, relative to levels in transgenic wild-type animals, supporting the hypothesis that the motor neuron disorder associated with SOD1 mutations involves a defect in mitochondrial energy metabolism. 相似文献
17.
M Fields C G Lewis T Beal D Scholfield K Patterson J C Smith S Reiser 《Proceedings of the Society for Experimental Biology and Medicine. Society for Experimental Biology and Medicine (New York, N.Y.)》1987,186(2):183-187
The present investigation was undertaken to establish whether the severity of copper deficiency in rats fed diets containing fructose is affected by the presence and type of endogenous sex hormones. Intact and castrated male rats and intact and ovariectomized females were fed from weaning a copper-deficient diet (0.6 ppm) containing 62% fructose for 8 weeks. Regardless of castration, male rats were anemic, exhibited heart hypertrophy, and died of the deficiency. However, castration ameliorated the anemia and delayed the mortality. In contrast, none of the females died of the deficiency. It is suggested that in addition to the sex of the animal, levels of testosterone in the male may also play a role in the severity of copper deficiency. 相似文献
18.
Brett M. Macey Matthew J. Jenny Heidi R. Williams Lindy K. Thibodeaux Marion Beal Jonas S. Almeida Charles Cunningham Annalaura Mancia Gregory W. Warr Erin J. Burge A. Fred Holland Paul S. Gross Sonomi Hikima Karen G. Burnett Louis Burnett Robert W. Chapman 《Comparative biochemistry and physiology. Part A, Molecular & integrative physiology》2010,155(3):341-349
Heavy metals, such as copper, zinc and cadmium, represent some of the most common and serious pollutants in coastal estuaries. In the present study, we used a combination of linear and artificial neural network (ANN) modelling to detect and explore interactions among low-dose mixtures of these heavy metals and their impacts on fundamental physiological processes in tissues of the Eastern oyster, Crassostrea virginica. Animals were exposed to Cd (0.001–0.400 μM), Zn (0.001–3.059 μM) or Cu (0.002–0.787 μM), either alone or in combination for 1 to 27 days. We measured indicators of acid–base balance (hemolymph pH and total CO2), gas exchange (Po2), immunocompetence (total hemocyte counts, numbers of invasive bacteria), antioxidant status (glutathione, GSH), oxidative damage (lipid peroxidation; LPx), and metal accumulation in the gill and the hepatopancreas. Linear analysis showed that oxidative membrane damage from tissue accumulation of environmental metals was correlated with impaired acid–base balance in oysters. ANN analysis revealed interactions of metals with hemolymph acid–base chemistry in predicting oxidative damage that were not evident from linear analyses. These results highlight the usefulness of machine learning approaches, such as ANNs, for improving our ability to recognize and understand the effects of sub-acute exposure to contaminant mixtures. 相似文献
19.
Beal MF 《Amino acids》2011,40(5):1305-1313
There is a substantial body of literature, which has demonstrated that creatine has neuroprotective effects both in vitro
and in vivo. Creatine can protect against excitotoxicity as well as against β-amyloid toxicity in vitro. We carried out studies
examining the efficacy of creatine as a neuroprotective agent in vivo. We demonstrated that creatine can protect against excitotoxic
lesions produced by N-methyl-d-aspartate. We also showed that creatine is neuroprotective against lesions produced by the toxins malonate and 3-nitropropionic
acid (3-NP) which are reversible and irreversible inhibitors of succinate dehydrogenase, respectively. Creatine produced dose-dependent
neuroprotective effects against MPTP toxicity reducing the loss of dopamine within the striatum and the loss of dopaminergic
neurons in the substantia nigra. We carried out a number of studies of the neuroprotective effects of creatine in transgenic
mouse models of neurodegenerative diseases. We demonstrated that creatine produced an extension of survival, improved motor
performance, and a reduction in loss of motor neurons in a transgenic mouse model of amyotrophic lateral sclerosis (ALS).
Creatine produced an extension of survival, as well as improved motor function, and a reduction in striatal atrophy in the
R6/2 and the N-171-82Q transgenic mouse models of Huntington’s disease (HD), even when its administration was delayed until
the onset of disease symptoms. We recently examined the neuroprotective effects of a combination of coenzyme Q10 (CoQ10) with
creatine against both MPTP and 3-NP toxicity. We found that the combination of CoQ and creatine together produced additive
neuroprotective effects in a chronic MPTP model, and it blocked the development of alpha-synuclein aggregates. In the 3-NP
model of HD, CoQ and creatine produced additive neuroprotective effects against the size of the striatal lesions. In the R6/2
transgenic mouse model of HD, the combination of CoQ and creatine produced additive effects on improving survival. Creatine
may stabilize mitochondrial creatine kinase, and prevent activation of the mitochondrial permeability transition. Creatine,
however, was still neuroprotective in mice, which were deficient in mitochondrial creatine kinase. Administration of creatine
increases the brain levels of creatine and phosphocreatine. Due to its neuroprotective effects, creatine is now in clinical
trials for the treatment of Parkinson’s disease (PD) and HD. A phase 2 futility trial in PD showed approximately a 50% improvement
in Unified Parkinson’s Disease Rating Scale at one year, and the compound was judged to be non futile. Creatine is now in
a phase III clinical trial being carried out by the NET PD consortium. Creatine reduced plasma levels of 8-hydroxy-2-deoxyguanosine
in HD patients phase II trial and was well-tolerated. Creatine is now being studied in a phase III clinical trial in HD, the
CREST trial. Creatine, therefore, shows great promise in the treatment of a variety of neurodegenerative diseases. 相似文献
20.
Cleland , R. E. (Indiana U., Bloomington), and B. B. Hyde . Evidence of relationship between extra diminutive chromosomes in geographically remote races of Oenothera. Amer. Jour. Bot. 50(2): 179–185. Illus. 1963.—Two California races of O. hookeri, Mono (from Mono Co.) and Mataguey (from San Diego Co.), have extra diminutive chromosomes. These diminutives do not associate with any of the normal chromosomes present. The extras from the 2 races, however, are able to synapse with each other and to form chiasmata, although the extras in Mono are distinctly larger than these in Mataguey. This suggests that they are at least partially homologous and that they have come from a common source. Two alternative hypotheses for their origin are suggested: (1) they have resulted from the loss of pairing ends through deletion, having descended from the same chromosome; (2) they represent normal chromosomes derived from another subgenus, through an inter-subgeneric cross followed by a backcross to hookeri. The facts tend to favor the latter hypothesis. 相似文献