MRE11 by either MRN component or by MDC1 (Fig. 3C). However, upon immobilization of NBS1 or MRE11, the accumulation of the downstream factors MDC1 and 53BP1 was strongly impaired in the absence of H2AX (Fig. 3C). Recruitment of MDC1 by ATM 1300-3060 was similarly decreased, suggesting that phosphorylation of H2AX is an important step in recruiting and maintaining these factors at sites of damage (17, 19).To finally test whether individual repair factors are sufficient to induce a physiological DDR, we assessed the effect of immobilization on cell cycle progression (Fig. 4). Upon targeting of NBS1, MRE11, MDC1, or ATM, but not Chk1 or Chk2, to chromatin, cells accumulated in G 2 phase as determined by staining of pericentromeric heterochromatin with an antibody to phosphoS10H3 (Fig. 4A) (20). Cell cycle delay was confirmed by increased phosphorylation of retinoblastoma protein at Ser 807 /Ser 811 ( fig. S6). Furthermore, the cell cycle delay was sensitive to the presence of Chk2 and required ATM activity, suggesting involvement of the checkpoint kinase Chk2 (Fig. 4A). H2AX −/− cells were resistant to G 2 /M delays upon immobilization of repair factors (Fig. 4B). This observation is in line with the finding that cells lacking H2AX manifest a G 2 /M checkpoint defect after exposure to low doses of irradiation (21).We report here that activation of cellular DNA damage response pathways does not require DNA damage but can be triggered by stable association of single repair factors with chroma-tin. Our observations suggest that the physical interaction of DNA repair factors with chromatin is a key step in activation of the DDR signaling cascade, and that the observed buildup at DNA damage foci probably contributes appreciably to establishing the cellular response to damaged DNA (4). Our observation that immobilized downstream factors can recruit upstream components indicates that activation of a full DDR involves amplification via formation of multiple repair complexes and perpetuation of gH2AX phosphorylation. A critical role for signal amplification on DNA is also suggested by the findings that in the absence of gH2AX or MDC1, several repair factors, including NBS1 and 53BP1, are recruited to sites of double-strand breaks, but do not accumulate and are not efficiently retained (16, 19). Our observation of phosphorylation of several key components of the DDR, including H2AX, NBS1, and ATM, and the appearance of cell cycle delays upon tethering indicate that the observed cellular response mimics to a large extent the physiological DDR. Given the apparent importance of the physical interaction of DNA repair factors with chromatin, it will be essential to uncover the precise role of higher-order chromatin structure and chromatin-remodeling complexes in triggering the DDR.Process-specific training can improve performance on untrained tasks, but the magnitude of gain is variable and often there is no transfer at all. We demonstrate transfer to a 3-back test of working memory after 5 weeks of training in updating. The trans...
The authors investigated immediate training gains, transfer effects, and 18-month maintenance after 5 weeks of computer-based training in updating of information in working memory in young and older subjects. Trained young and older adults improved significantly more than controls on the criterion task (letter memory), and these gains were maintained 18 months later. Transfer effects were in general limited and restricted to the young participants, who showed transfer to an untrained task that required updating (3-back). The findings demonstrate substantial and durable plasticity of executive functioning across adulthood and old age, although there appear to be age-related constraints in the ability to generalize the acquired updating skill.
Cognitive studies show that both younger and older adults can increase their memory performance after training in using a visuospatial mnemonic, although age-related memory deficits tend to be magnified rather than reduced after training. Little is known about the changes in functional brain activity that accompany training-induced memory enhancement, and whether age-related activity changes are associated with the size of training-related gains. Here, we demonstrate that younger adults show increased activity during memory encoding in occipito-parietal and frontal brain regions after learning the mnemonic. Older adults did not show increased frontal activity, and only those elderly persons who benefited from the mnemonic showed increased occipitoparietal activity. These findings suggest that age-related differences in cognitive reserve capacity may reflect both a frontal processing deficiency and a posterior production deficiency.T he existence of age-related deficits in episodic memory functioning are well documented (1). Given the impact of such deficits, much research has been directed at examining possible means of enhancing memory performance in older adults by various forms of cognitive support (2). One approach that has received considerable attention involves estimation of latent cognitive potential, or cognitive reserve capacity, in older age (3). In one variant of this approach, younger and older participants are given training in using a classical mnemonic, the method of loci (4), to memorize and retrieve words. This method involves learning to visualize a series of mental landmarks (e.g., places along one's route to work). After acquisition of the landmarks, the to-be-remembered information is linked to the various loci at the time of encoding. At test, the landmarks are mentally revisited in serial order, and the information associated with each locus is retrieved.Serial recall is substantially enhanced by the loci mnemonic for both younger and older adults (5, 6), demonstrating cognitive reserve capacity in aging (i.e., cognitive reserve capacity is defined as the ability to enhance one's memory performance after learning a mnemonic). However, the most striking aspect of previous findings is that age differences in memory performance are magnified rather than reduced after training (7). This pattern of results suggests an age-related decrease in cognitive reserve capacity. Little is known about the basis for this phenomenon. Baltes and Kliegl (7) hypothesized that older adults may have difficulty in forming novel relations between the landmarks and the to-be-remembered information (i.e., a difficulty in using rather than acquiring the mnemonic), and they proposed neurobiological constraints as a determinant of this deficit. However, no direct evidence for this account has been provided. Here, we present the results from an age-comparative positron emission tomography (PET) study of the neural underpinnings of acquisition and use of the loci method. MethodsTasks and Procedure. The whole experiment,...
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.