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71.
Prakash Peddi Charles W. Loftin Jennifer S. Dickey Jessica M. Hair Kara J. Burns Khaled Aziz Dave C. Francisco Mihalis I. Panayiotidis Olga A. Sedelnikova William M. Bonner Thomas A. Winters Alexandros G. Georgakilas 《Free radical biology & medicine》2010,48(10):1435-1443
DNA-dependent protein kinase (DNA-PK) is a key non-homologous-end-joining (NHEJ) nuclear serine/threonine protein kinase involved in various DNA metabolic and damage signaling pathways contributing to the maintenance of genomic stability and prevention of cancer. To examine the role of DNA-PK in processing of non-DSB clustered DNA damage, we have used three models of DNA-PK deficiency, i.e., chemical inactivation of its kinase activity by the novel inhibitors IC86621 and NU7026, knockdown and complete absence of the protein in human breast cancer (MCF-7) and glioblastoma cell lines (MO59-J/K). A compromised DNA-PK repair pathway led to the accumulation of clustered DNA lesions induced by γ-rays. Tumor cells lacking protein expression or with inhibited kinase activity showed a marked decrease in their ability to process oxidatively induced non-DSB clustered DNA lesions measured using a modified version of pulsed-field gel electrophoresis or single-cell gel electrophoresis (comet assay). In all cases, DNA-PK inactivation led to a higher level of lesion persistence even after 24–72 h of repair. We suggest a model in which DNA-PK deficiency affects the processing of these clusters first by compromising base excision repair and second by the presence of catalytically inactive DNA-PK inhibiting the efficient processing of these lesions owing to the failure of DNA-PK to disassociate from the DNA ends. The information rendered will be important for understanding not only cancer etiology in the presence of an NHEJ deficiency but also cancer treatments based on the induction of oxidative stress and inhibition of cluster repair. 相似文献
72.
Kara L. Vine Julie M. Locke John B. Bremner Stephen G. Pyne Marie Ranson 《Bioorganic & medicinal chemistry letters》2010,20(9):2908-2911
A urokinase targeting conjugate of 2′-deoxy-5-fluorouridine (5-FUdr) was synthesized and tested for tumor-cell selective cytotoxicity in vitro. The 5-FUdr prodrug 2′-deoxy-5-fluoro-3′-O-(3-carboxypropanoyl)uridine (5-FUdrsuccOH) containing an ester-labile succinate linker was attached to the specific urokinase inhibitor plasminogen activator inhibitor type II (PAI-2) and was found to preferentially kill urokinase-over expressing cancer cells. Up to 7 molecules of 5-FUdr were incorporated per PAI-2 molecule without affecting protein activity. This is the first time a small organic cytotoxin has been conjugated to PAI-2. 相似文献
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The protective effects of melatonin, vitamin E, and selenium alone or in combination were tested against cadmium-induced oxidative
damage in rat testes. A total of 60 male rats were equally divided into five study groups, one of which acted as control receiving
subcutaneous injections of physiological saline. The remaining four groups were treated with subcutaneous injections of cadmium
chloride at a dose of 1 mg/kg weight. The first study group received no treatment. The second group was treated with a combination
of 60 mg/kg vitamin E and 1 mg/kg sodium selenite. Group 3 was treated with 10 mg/kg melatonin, and the fourth group received
a combination of vitamin E, sodium selenite, and melatonin at the doses mentioned above. After 1 month, the animals were killed,
and the testes were excised for histological inspection and determination of tissue malondialdehyde and the activity of superoxide
dismutase. The animals receiving no treatment showed significantly higher malondialdehyde levels and reduced activity of the
enzyme (p < 0.05). Treatment with antioxidants resulted in a significant reduction in malondialdehyde when compared to the nontreated
animals (p < 0.05) and an increase in the superoxide dismutase activity that was almost the same as the controls. The combination of
melatonin, vitamin E, and selenium appears to have the more profound effect against cadmium-induced testicular injury. 相似文献
76.
The present study was carried to evaluate the protective effects of melatonin alone and vitamin E with selenium combination
against high dose cadmium-induced oxidative stress in rats. The control group received subcutanous physiological saline. The
first study group administered cadmium chloride (CdCl2) by subcutaneous injection of dose of 1 mg/kg. The second study group administered cadmium plus vitamin E with selenium (1 mg/kg
sodium selenite with 60 mg/kg vitamin E); the third study group administered cadmium plus 10 mg/kg melatonin (MLT); the fourth
study group administered CdCl2 plus a combination of melatonin in addition to vitamin E and selenium for a month. Determination levels of plasma malondialdehyde
(MDA), glutathione peroxidase (GSH-Px), blood superoxide dismutase (SOD), creatinine alanine transaminase (ALT), aspartate
aminotransferase (AST), alkaline phosphatase (ALP), blood urea nitrogen (BUN), and urea were measured in serum. In only CdCl2 administered group, the MDA, creatinine, ALT, AST, ALP, and urea levels in the serum were significantly higher than the control
group (p < 0.05). Whereas in all other groups, this values were significantly lower than the only CdCl2 administered group (p < 0.05). Erythrocytes GSH-Px, serum SOD activities of only CdCl2 received group were significantly lower than the control group (p < 0.05). In conclusion, vitamin E + Se, melatonin and vitamin E, and Se, in addition to MLT combinations, had protective
effects against high dose cadmium-induced oxidative damage. 相似文献
77.
Ultrastructural changes in the kidneys of rats after acute cadmium exposure and the effects of exogenous metallothionein (MT)
were studied by transmission electron microscopy. Thirty-six adult Wistar rats were divided into three groups. Cadmium chloride
(CdCl2) (3.5 mg/kg/day) was injected subcutaneously in the first group. In the second group, 30 μmol/kg MT was administered in addition
to CdCl2. Control rats received 0.5 ml subcutaneous saline solution. Four rats from each group were killed on days 1, 3, 5, and 7
after administration of the compounds. Kidney tissues were taken and fixed in 2.5% glutaraldehyde solution for electron microscopic
observations. Tissue damage in kidney increased as time passed since the administration of CdCl2 in the first group. Degeneration in the proximal and distal tubules was observed. Increased apoptosis was seen in the proximal
tubules epithelium, especially on day 7. Peritubular capillaries became dilated, there was degeneration of the endothelial
cells, and the amount of intertubular collagen fibers was increased. On day 1, irregular microvilli in the proximal tubules,
deepening of the basal striations, and myelin figures; on day 3, multiple vesicular mitochondria and regions of edema around
tubules; on days 5 and 7, increased apoptotic cell in the proximal tubules and widened rough endoplasmic reticulum of the
endothelial cells of glomerular capillaries were observed. We observed that the structural alterations that increased depending
on the day of Cd administration decreased after exogenous MT administration, the dilation of the peritubular capillaries persisted,
and there were degenerated proximal tubules. It was established that cadmium chloride was toxic for kidney cortex and caused
structural damage. Exogenous MT partly prevents CdCl2-induced damage. 相似文献
78.
Hypoxia-ischemia with reperfusion is known to cause reactive oxygen species-related damage in mammalian systems, yet, the anoxia tolerant freshwater turtle is able to survive repeated bouts of anoxia/reoxygenation without apparent damage. Although the physiology of anoxia tolerance has been much studied, the adaptations that permit survival of reoxygenation stress have been largely ignored. In this study, we examine ROS production in the turtle striatum and in primary neuronal cultures, and examine the effects of adenosine (AD) on cell survival and ROS. Hydroxyl radical formation was measured by the conversion of salicylate to 2,3-dihydroxybenzoic acid (2,3-DHBA) using microdialysis; reoxygenation after 1 or 4 h anoxia did not result in increased ROS production compared with basal normoxic levels, nor did H2 O2 increase after anoxia/reoxygenation in neuronally enriched cell cultures. Blockade of AD receptors increased both ROS production and cell death in vitro , while AD agonists decreased cell death and ROS. As turtle neurons proved surprisingly susceptible to externally imposed ROS stress (H2 O2 ), we propose that the suppression of ROS formation, coupled to high antioxidant levels, is necessary for reoxygenation survival. As an evolutionarily selected adaptation, the ability to suppress ROS formation could prove an interesting path to investigate new therapeutic targets in mammals. 相似文献
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80.
Isolation and characterization of replication-competent human immunodeficiency virus type 1 from a subset of elite suppressors
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Blankson JN Bailey JR Thayil S Yang HC Lassen K Lai J Gandhi SK Siliciano JD Williams TM Siliciano RF 《Journal of virology》2007,81(5):2508-2518
Elite suppressors (ES) are untreated human immunodeficiency virus type 1 (HIV-1)-infected individuals who control viremia to levels below the limit of detection of current assays. The mechanisms involved in this control have not been fully elucidated. Several studies have demonstrated that some ES are infected with defective viruses, but it remains unclear whether others are infected with replication-competent HIV-1. To answer this question, we used a sensitive coculture assay in an attempt to isolate replication-competent virus from a cohort of 10 ES. We successfully cultured six replication-competent isolates from 4 of the 10 ES. The frequency of latently infected cells in these patients was more than a log lower than that seen in patients on highly active antiretroviral therapy with undetectable viral loads. Full-length sequencing of all six isolates revealed no large deletions in any of the genes. A few mutations and small insertions and deletions were found in some isolates, but phenotypic analysis of the affected genes suggested that their function remained intact. Furthermore, all six isolates replicated as well as standard laboratory strains in vitro. The results suggest that some ES are infected with HIV-1 isolates that are fully replication competent and that long-term immunologic control of replication-competent HIV-1 is possible. 相似文献