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1.
Accumulation of nuclear and mitochondrial DNA damage is thought to be particularly deleterious in post-mitotic cells, which cannot be replaced through cell division. Recent experimental evidence demonstrates the importance of DNA damage responses for neuronal survival. Here, we summarize current literature on DNA damage responses in the mammalian CNS in aging and neurodegeneration. Base excision repair (BER) is the main pathway for the removal of small DNA base modifications, such as alkylation, deamination and oxidation, which are generated as by-products of normal metabolism and accumulate with age in various experimental models. Using neuronal cell cultures, human brain tissue and animal models, we and others have shown an active BER pathway functioning in the brain, both in the mitochondrial and nuclear compartments. Mitochondrial DNA repair may play a more essential role in neuronal cells because these cells depend largely on intact mitochondrial function for energy metabolism. We have characterized several BER enzymes in mammalian mitochondria and have shown that BER activities change with age in mitochondria from different brain regions. Together, the results reviewed here advocate that mitochondrial DNA damage response plays an important role in aging and in the pathogenesis of neurodegenerative diseases. 相似文献
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Stevnsner T Thorslund T de Souza-Pinto NC Bohr VA 《Experimental gerontology》2002,37(10-11):1189-1196
Reactive oxygen species (ROS) are formed in all living organisms as a by-product of normal metabolism (endogenous sources) and as a consequence of exposure to environmental compounds (exogenous sources). Endogenous ROS are largely formed during oxidative phosphorylation in the mitochondria and, therefore, mitochondrial DNA (mtDNA) is at particularly high risk of ROS-induced damage. Mitochondria are essential for cell viability, and oxidative damage to mtDNA has been implicated as a causative factor in a wide variety of degenerative diseases, and in cancer and aging. One of the most common oxidative DNA lesions is 7,8-dihydro-8-oxoguanine (8-oxoG), which can introduce G/C to T/A transversions after DNA replication. Oxidative DNA base lesions, including 8-oxoG, are repaired primarily by the base excision repair (BER) pathway. While we know much about how this pathway functions in processing the nuclear DNA lesions, little is yet known about BER in mitochondria. We have used a number of different approaches to explore the mechanisms of DNA damage processing in the mtDNA. We have been able to demonstrate that mammalian mitochondria efficiently remove 8-oxoG from their genome, and that the efficiency of 8-oxoG incision increases with age in rats and mice. Yet 8-oxoG accumulates in mtDNA during aging. Changes in mitochondrial function with age have been observed in several organisms and accumulation of DNA lesions in mtDNA with age may be an underlying cause for numerous age-associated diseases including cancer. 相似文献
3.
Mitochondrial DNA is constantly exposed to oxidative injury. Due to its location close to the main site of reactive oxygen species, the inner mitochondrial membrane, mtDNA is more susceptible than nuclear DNA to oxidative damage. The accumulation of DNA damage is thought to play a critical role in the aging process and to be particularly deleterious in post-mitotic cells. Thus, DNA repair is an important mechanism for maintenance of genomic integrity. Despite the importance of mitochondria in the aging process, it was thought for many years that mitochondria lacked an enzymatic DNA repair system comparable to that in the nuclear compartment. However, it is now well established that DNA repair actively takes place in mitochondria. Oxidative DNA damage processing, base excision repair mechanisms were the first to be described in these organelles, and consequently the best understood. However, new proteins and novel DNA repair pathways, thought to be exclusively present in the nucleus, have recently been described also to be present in mitochondria. Here we review the main mitochondrial DNA repair pathways and their association with the aging process. 相似文献
4.
Previous studies have shown that human topoisomerase I interacts directly with the tumor-suppressor protein p53. In the past few years it has repeatedly been suggested that topoisomerase I and p53 may play a joint role in the response to genotoxic stress. This led to the suggestion that p53 and human topoisomerase I may cooperate in the process of DNA repair and/or apoptosis. Recently we have demonstrated that a human topoisomerase I cleavage complex can be recognized by an additional topoisomerase I molecule and thereby form a so-called double cleavage complex. The double cleavage complex creates an about 13 nucleotides long single-stranded gap that may provide an entry site for recombinational repair events. Here we demonstrate that p53 stimulates both the DNA relaxation activity as well as the formation of the human topoisomerase I double cleavage complex by at least a factor of six. Stimulation of topoisomerase I activity by p53 is mediated via the central part of topoisomerase I. We also show that human, bovine, and murine p53 stimulate human topoisomerase I relaxation activity equally well. From these results it is conceivable that p53's stimulatory activity on topoisomerase I may play a role in DNA recombination and repair as well as in apoptosis. 相似文献
5.
Tinna Laufey Asgeirsdottir Kerry Anne McGeary 《The European journal of health economics》2009,10(4):455-465
At a time when the government of Iceland is considering privatization of alcohol sales and a reduction of its governmental
fees, it is timely to estimate the potential effects of this policy change. Given that the privatization of sales coupled
with a tax reduction should lead to a decrease in the unit price of alcohol, one would expect the quantity consumed to increase.
While it is of interest to project the impact of the proposed bill on the market for alcohol, another important consideration
is the impact that increased alcohol consumption and, more specifically, probable alcohol misuse would have on other markets
in Iceland. The only available study on this subject using Icelandic data yields surprising results. Tómasson et al. (Scand
J Public Health 32:47–52, 2004) unexpectedly found no effect of probable alcohol abuse on sick leave. A logical next step
would be to examine the effect of probable alcohol abuse on other important labor-market outcomes. Nationally representative
survey data from 2002 allow for an analysis of probable misuse of alcohol and labor-supply choices. Labor-supply choices are
considered with reference to possible effects of policies already in force, as well as proposed changes to current policies.
Contrary to intuition, but in agreement with the previously mentioned Icelandic study, the adverse effects of probable misuse
of alcohol on employment status or hours worked are not confirmed within this sample. The reasons for the results are unclear,
although some suggestions are hypothesized. Currently, data to test those theories convincingly are not available.
相似文献
Kerry Anne McGearyEmail: |
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Mette Soerensen Serena Dato Qihua Tan Mikael Thinggaard Rabea Kleindorp Marian Beekman H. Eka D. Suchiman Rune Jacobsen Matt McGue Tinna Stevnsner Vilhelm A. Bohr Anton J. M. de Craen Rudi G. J. Westendorp Stefan Schreiber P. Eline Slagboom Almut Nebel James W. Vaupel Kaare Christensen Lene Christiansen 《Age (Dordrecht, Netherlands)》2013,35(2):487-500
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