Metabolism and cancer:Old and new players

[No abstract available

Proapoptotic activity of new glutathione S-transferase inhibitors

Selected 7-nitro-2,1,3-benzoxadiazole derivatives have been recently found very efficient inhibitors of glutathione S-transferase (GST) PI-1,(5) an enzyme which displays antiapoptotic activity and is also involved in the cellular resistance to anticancer drugs. These new inhibitors are not tripeptide glutathione-peptidomimetic molecules and display lipophylic properties suitable for crossing the plasma membrane. In the present work, we show the strong cytotoxic activity of these compounds in the following four different cell lines: K562 (human myeloid leukemia), HepG2 (human hepatic carcinoma), CCRF-CEM (human T-lymphoblastic leukemia), and GLC-4 (human small cell lung carcinoma). The LC50 values are in the micromolar/submicromolar range and are close to the ICs values obtained with GSTPI-1, suggesting that the target of these molecules inside the cell is indeed this enzyme. The cytotoxic mechanism of 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol, the most effective GSTPI-1 inhibitor, has been carefully investigated in leukemic CCRF-CEM and K562 cell lines. Western blot and immunoprecipitation analyzes have shown that 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanoI promotes in both cell lines the dissociation of the GSTPI-1 in a complex with c-jun NH2-terminal kinase (JNK). This process triggers a reactive oxygen species (ROS) -independent activation of the JNK-mediated pathway that results in a typical process of apoptosis. Besides this main pathway, in K562 cells, a ROS-mediated apoptosis partially occurs (about 30%) which involves the p38(MAPK) signal transduction pathway. The low concentration of this new compound needed to trigger cytotoxic effects on tumor cells and the low toxicity on mice indicate that the new 7-nitro-2,1,3-benzoxadiazole derivatives are promising anticancer agents

Age-related changes in matching novel objects across viewpoints

Peer reviewedPreprin

Gender and sexual orientation differences in cognition across adulthood : age is kinder to women than to men regardless of sexual orientation

Despite some evidence of greater age-related deterioration of the brain in males than in females, gender differences in rates of cognitive aging have proved inconsistent. The present study employed web-based methodology to collect data from people aged 20-65 years (109,612 men; 88,509 women). As expected, men outperformed women on tests of mental rotation and line angle judgment, whereas women outperformed men on tests of category fluency and object location memory. Performance on all tests declined with age but significantly more so for men than for women. Heterosexuals of each gender generally outperformed bisexuals and homosexuals on tests where that gender was superior; however, there were no clear interactions between age and sexual orientation for either gender. At least for these particular tests from young adulthood to retirement, age is kinder to women than to men, but treats heterosexuals, bisexuals, and homosexuals just the same

Aging and Error Processing: Age Related Increase in the Variability of the Error-Negativity Is Not Accompanied by Increase in Response Variability

Background: Several studies report an amplitude reduction of the error negativity (Ne or ERN), an event-related potential occurring after erroneous responses, in older participants. In earlier studies it was shown that the Ne can be explained by a single independent component. In the present study we aimed to investigate whether the Ne reduction usually found in older subjects is due to an altered component structure, i.e., a true alteration in response monitoring in older subjects. Methodology/Principal Findings: Two age groups conducted two tasks with different stimulus response mappings and task difficulty. Both groups received fully balanced speed or accuracy instructions and an individually adapted deadline in both tasks. Event-related potentials, Independent Component analysis of EEG-data and between trial variability of the Ne were combined with analysis of error rates, coefficients of variation of RT-data and ex-Gaussian fittings to reaction times. The Ne was examined by means of ICA and PCA, yielding a prominent independent component on error trials, the Ne-IC. The Ne-IC was smaller in the older than the younger subjects for both speed and accuracy instructions. Also, the Ne-IC contributed to a much lesser extent to the Ne in older than in younger subjects. RT distribution parameters were not related to Ne/ERP-variability. Conclusions/Significance: The results show a genuine reduction as well as a different component structure of the Ne in older compared to young subjects. This reduction is not reflected in behaviour, apart from a general slowing of olde

Tracking of unpredictable moving stimuli by pigeons

Despite being observed throughout the animal kingdom, catching a moving object is a complex task and little is known about the mechanisms that underlie this behavior in non-human animals. Three experiments examined the role of prediction in capture of a moving object by pigeons. In Experiment 1, a stimulus moved in a linear trajectory, but sometimes made an unexpected 90o turn. The sudden turn had only a modest effect on capture and error location, and the analyses suggested that the birds had adjusted their tracking to the novel motion. In Experiment 2, the role of visual input during a turn was tested by inserting disappearances (either 1.5 cm or 4.5 cm) on both the straight and turn trials. The addition of the disappearance had little effect on capture success, but delayed capture location with the larger disappearance leading to greater delay. Error analyses indicated that the birds adapted to the post-turn, post-disappearance motion. Experiment 3 tested the role of visual input when the motion disappeared behind an occluder and emerged in either a straight line or at a 90o angle. The occluder produced a disruption in capture success but did not delay capture. Error analyses indicated that the birds did not adjust their tracking to the new motion on turn trials following occlusion. The combined results indicate that pigeons can anticipate the future position of a stimulus, and can adapt to sudden, unpredictable changes in motion but do so better after a disappearance than after an occlusion

Lifespan development of stimulus-response conflict cost: similarities and differences between maturation and senescence

Age gradient of the mechanism of stimulus-response conflict cost was investigated in a population-based representative sample of 291 individuals, covering the age range from 6 to 89 years. Stimulus-response conflict cost, indicated by the amount of additional processing time required when there is a conflict between stimulus and response options, follows a U-shaped function across the lifespan. Lifespan age gradient of conflict cost parallels closely those of processing fluctuation and fluid intelligence. Individuals at both ends of the lifespan displayed a greater amount of processing fluctuation and at the same time a larger amount of conflict cost and a lower level of fluid intelligence. After controlling for chronological age and baseline processing speed, conflict cost continues to correlate significantly with fluid intelligence in adulthood and old age and with processing fluctuation in old age. The relation between processing fluctuation and conflict cost in old age lends further support for the neuromodulation of neuronal noise theory of cognitive aging as well as for theories of dopaminergic modulation of conflict monitoring

MUC1 Limits Helicobacter pylori Infection both by Steric Hindrance and by Acting as a Releasable Decoy

The bacterium Helicobacter pylori can cause peptic ulcer disease, gastric adenocarcinoma and MALT lymphoma. The cell-surface mucin MUC1 is a large glycoprotein which is highly expressed on the mucosal surface and limits the density of H. pylori in a murine infection model. We now demonstrate that by using the BabA and SabA adhesins, H. pylori bind MUC1 isolated from human gastric cells and MUC1 shed into gastric juice. Both H. pylori carrying these adhesins, and beads coated with MUC1 antibodies, induced shedding of MUC1 from MKN7 human gastric epithelial cells, and shed MUC1 was found bound to H. pylori. Shedding of MUC1 from non-infected cells was not mediated by the known MUC1 sheddases ADAM17 and MMP-14. However, knockdown of MMP-14 partially affected MUC1 release early in infection, whereas ADAM17 had no effect. Thus, it is likely that shedding is mediated both by proteases and by disassociation of the non-covalent interaction between the α- and β-subunits. H. pylori bound more readily to MUC1 depleted cells even when the bacteria lacked the BabA and SabA adhesins, showing that MUC1 inhibits attachment even when bacteria cannot bind to the mucin. Bacteria lacking both the BabA and SabA adhesins caused less apoptosis in MKN7 cells than wild-type bacteria, having a greater effect than deletion of the CagA pathogenicity gene. Deficiency of MUC1/Muc1 resulted in increased epithelial cell apoptosis, both in MKN7 cells in vitro, and in H. pylori infected mice. Thus, MUC1 protects the epithelium from non-MUC1 binding bacteria by inhibiting adhesion to the cell surface by steric hindrance, and from MUC1-binding bacteria by acting as a releasable decoy

Aging Affects the Mental Rotation of Left and Right Hands

BACKGROUND:Normal aging significantly influences motor and cognitive performance. Little is known about age-related changes in action simulation. Here, we investigated the influence of aging on implicit motor imagery. METHODOLOGY/PRINCIPAL FINDINGS:Twenty young (mean age: 23.9+/-2.8 years) and nineteen elderly (mean age: 78.3+/-4.5 years) subjects, all right-handed, were required to determine the laterality of hands presented in various positions. To do so, they mentally rotated their hands to match them with the hand-stimuli. We showed that: (1) elderly subjects were affected in their ability to implicitly simulate movements of the upper limbs, especially those requiring the largest amplitude of displacement and/or with strong biomechanical constraints; (2) this decline was greater for movements of the non-dominant arm than of the dominant arm. CONCLUSIONS/SIGNIFICANCE:These results extend recent findings showing age-related alterations of the explicit side of motor imagery. They suggest that a general decline in action simulation occurs with normal aging, in particular for the non-dominant side of the body