Alterations in c-Myc phenotypes resulting from dynamin-related protein 1 (Drp1)-mediated mitochondrial fission.

The c-Myc (Myc) oncoprotein regulates numerous phenotypes pertaining to cell mass, survival and metabolism. Glycolysis, oxidative phosphorylation (OXPHOS) and mitochondrial biogenesis are positively controlled by Myc, with myc-/- rat fibroblasts displaying atrophic mitochondria, structural and functional defects in electron transport chain (ETC) components, compromised OXPHOS and ATP depletion. However, while Myc influences mitochondrial structure and function, it is not clear to what extent the reverse is true. To test this, we induced a state of mitochondrial hyper-fission in rat fibroblasts by de-regulating Drp1, a dynamin-like GTPase that participates in the terminal fission process. The mitochondria from these cells showed reduced mass and interconnectivity, a paucity of cristae, a marked reduction in OXPHOS and structural and functional defects in ETC Complexes I and V. High rates of abortive mitochondrial fusion were observed, likely reflecting ongoing, but ultimately futile, attempts to normalize mitochondrial mass. Cellular consequences included reduction of cell volume, ATP depletion and activation of AMP-dependent protein kinase. In response to Myc deregulation, apoptosis was significantly impaired both in the absence and presence of serum, although this could be reversed by increasing ATP levels by pharmacologic means. The current work demonstrates that enforced mitochondrial fission closely recapitulates a state of Myc deficiency and that mitochondrial integrity and function can affect Myc-regulated cellular behaviors. The low intracellular ATP levels that are frequently seen in some tumors as a result of inadequate vascular perfusion could favor tumor survival by countering the pro-apoptotic tendencies of Myc overexpression.

[Dimensions and interpretative patterns of aging: attitudes about aging, being old and ways of living in old age]. / Dimensionen und Deutungsmuster des Alterns: Vorstellungen vom Altern, Altsein und der Lebensgestaltung im Alter.

Attitudes about older people and being old develop in the early and middle phases of life and influence the subsequent aging process. Because aging processes vary across different domains of life and functioning, one cannot assume unanimously negative or positive attitudes towards old age and aging. Thus, in the psychological part of the project Zones of Transition ("Zonen des Übergangs"), age stereotypes and views of the self in old age were assessed in different life domains and for different age groups, and their relation to well-being and the self-concept was investigated. The project also focused on the analysis of attitudes towards one's personal way of living in old age. A questionnaire was developed that assesses those attitudes on the basis of the dimensions "active commitment" and "pleasure and leisure". Our results support a multidimensional conception of attitudes towards aging and way of living in old age as well as of their influence on development across the lifespan.

Figure-ground asymmetries in the Implicit Association Test (IAT).

Based on the assumption that binary classification tasks are often processed asymmetrically (figure-ground asymmetries), two experiments showed that association alone cannot account for effects observed in the Implicit Association Test (IAT). Experiment 1 (N = 16) replicated a standard version of the IAT effect using old vs. young names as target categories and good and bad words as attribute categories. However, reliable compatibility effects were also found for a modified version of the task in which neutral words vs. nonwords instead of good vs. bad words were used as attribute categories. In Experiment 2 (N = 8), a reversed IAT effect was observed after the figure-ground asymmetry in the target dimension had been inverted by a previous go/nogo detection task in which participants searched for exemplars of the category "young." The experiments support the hypothesis that figure-ground asymmetries produce compatibility effects in the IAT and suggest that IAT effects do not rely exclusively on evaluative associations between the target and attribute categories.

Suppression of apoptosis and granulocyte colony-stimulating factor-induced differentiation by an oncogenic form of Cbl.

OBJECTIVE: The retroviral oncogene v-Cbl causes pre-B cell lymphomas and myeloid leukemias in mice, and its Drosophila homologue is oncogenic, causing enhanced receptor tyrosine kinase signaling. The human Cbl gene resides at 11q23. The aim of this study is to determine the effect of oncogenic Cbl on growth-regulating responses. MATERIALS AND METHODS: The oncogenic mutant of Cbl (CblDelta1-357) was transfected into factor-dependent 32Dcl3 myeloid cells. Consequently, cell survival and differentiation were measured. Lyn, Syk, MAP kinase, and phosphatidylinositol 3'(PI3')-kinase activities, protein phosphorylation, Bcl-2 promoter activity, ubiquitination, and levels of Bcl-2, Bax, Bad, and Bcl-x(L) were determined. In addition, the effect of v-Cbl on TF-1 cell survival upon granulocyte-macrophage colony-stimulating factor withdrawal was studied. RESULTS: 32Dcl3 and TF-1 cells expressing v-Cbl showed resistance to apoptosis upon growth factor withdrawal, and 32Dcl3 cells completely failed to respond to granulocyte colony-stimulating factor's induction of differentiation. Basal activities of Lyn, Syk, and PI3'-kinase were elevated in the v-Cbl line. There was neither enhanced tyrosine phosphorylation of cellular protein content, Cbl, or Jak2, nor serine phosphorylation of MAP kinase or Akt. After factor withdrawal, the level of Bcl-2 was greater in v-Cbl cells than in control cells. CONCLUSIONS: Neither increased Bcl-2 promoter activity nor decreased ubiquitination of Bcl-2 could account for increased Bcl-2 levels. v-Cbl-expressing 32Dcl3 cells were resistant to differentiation. v-Cbl suppresses apoptosis and differentiation, possibly through enhancement of Lyn, Syk, and PI3'-kinase activities and Bcl-2.

Stimulus-feature specific negative priming.

We report the results of two experiments that showed that the time needed to respond to a feature of a stimulus increases when that particular feature of that particular stimulus previously had to be ignored. The data of Experiment 2 argue against the hypothesis that the observed stimulus-feature specific negative priming was due to a response conflict instigated by automatic episodic retrieval of prime responses. Experiment 2 also showed that the effects were not caused by difficulties in switching between prime and probe tasks and provided additional evidence for the fact that priming effects were stimulus-feature specific. The present results suggest that the selective inhibition or episodic encoding mechanisms that are assumed to underlie negative priming can operate in a more specific and powerful manner than has been previously assumed.

Automatic vigilance: the attention-grabbing power of approach- and avoidance-related social information.

The automatic processing of information was investigated, varying valence (positive vs. negative) and relevance (other-relevant traits [ORT] vs. possessor-relevant traits [PRT]; G. Peeters, 1983) of stimuli. ORTs denote unconditionally positive or negative consequences for persons in the social environment of the holder of the trait (e.g., honest, brutal) whereas PRTs denote unconditionally positive or negative consequences for the trait holder (e.g., happy, depressive). In 2 experiments using the Stroop paradigm, larger interference effects were found for ORTs than PRTs. This is due to the behavior-relatedness of ORTs. In a go/no-go lexical decision task (Experiment 3), participants either had to withdraw their finger from a pressed key (i.e., "avoid") or had to press a key (i.e., "approach") if a word was presented. Responses to negative ORTs were relatively faster in the withdraw condition, whereas positive ORTs were relatively faster in the press condition.

[A fair test of the spreading activation hypothesis: a study of affective congruency effects in the Stroop test]. / Ein fairer Test für die Aktivationsausbreitungshypothese: Untersuchung affektiver Kongruenzeffekte in der Stroop-Aufgabe.

It is argued that the Stroop color-naming task is especially suited to investigate affective priming effects in the sense of an automatic spreading of activation to other concepts of the same valence, because (a) the Stroop task is not prone to an explanation of affective congruency effects on the basis of reaction priming or reaction interference, and (b) it is possible to detect specific (fast and efficient stimulus processing due to heightened accessibility) as well as nonspecific (cognitive interference, triggering of global action tendencies) effects of an activation of valenced concepts in the Stroop task. Two experiments were conducted to investigate associative and affective priming effects with the Stroop task. In a first experiment (N = 36, SOA = 300 ms) a standard priming procedure was chosen; the primes were presented without any processing instructions. In a second experiment (N = 48, SOA = 500ms) the primes had to be reproduced after naming the color of the target. In both experiments significant association effects were found for the associative material. For the valenced material no affective congruency effects were found in either experiment. The present results are not compatible with the hypothesis of an automatic affective spreading of activation that was given as an explanation of affective congruency effects in previous studies using different tasks.

Characterization of the effects of polyamines on the modulation of the N-methyl-D-aspartate receptor by glycine.

We have investigated the effects of polyamine agonists and antagonists on the modulation of the N-methyl-D- aspartate receptor by glycine using a [3H]dizocilpine ([3H]MK801) binding assay. We monitored the non-equilibrium binding of [3H]dizocilipine in the presence of 5,7-dichlorokynurenate to preclude occupation of the glycine site by endogenous glycine. Using this assay, spermine and spermidine increased both the affinity and the maximum effect of glycine. Similar effects are produced by other polyamine agonists including 1,5-diethylaminopiperidine, neomycin and Ca2+. These actions are reversed by the polyamine glycine produced by polyamine agonists appears to be due to an increase in the equilibrium affinity of [3H]dizocilpine, and cannot therefore be attributed solely to modulation of glycine binding. Interestingly, 1,5-diethylaminopiperidine increases the maximum effect of glycine to a greater extent than it alters glycine affinity, suggesting that the two effects may be mediated by different sites or mechanisms. These studies will help to define the role of the glycine site in the modulation of the N-methyl-D-aspartate receptor by polyamines.

[Experimental analysis of processing stressful information: differential and age-related psychological aspects]. / Experimentelle Analysen zur Verarbeitung belastender Informationen: differential- und alternspsychologische Aspekte.

In two experimental studies with older subjects, the differential accessibility of palliative interpretations of negative situations was investigated using a scenario paradigm. Short episodes (formulated in a self-referent manner) were presented on a CRT-screen. Each story contained a palliative and distressing interpretation of a negative life situation. In a recognition test, the reaction time and the error variable were used as an index of accessibility of those aspects. In a pilot study (N = 62; age of subjects 49-79 years), it was found that the dispositional tendency to reinterpret negative life situations flexibly correlates positively with the accessibility of palliative information. Using a priming approach in the main study, it was shown that this result is based on a differential moderated association of the negative life-event and the type of information (i.e., palliative or distressing) (N = 120; age of subjects: 56-80 years). Especially with respect to scenarios which are centered on age-related declines, results were more pronounced with increasing age. The results are discussed in terms of a theory which contrasts active-instrumental efforts of coping with accommodative mechanisms of adjustment and reinterpretation.

Self-percepts of control in middle and later adulthood: buffering losses by rescaling goals.

The authors propose a model of how a sense of control is maintained in later adulthood through shifts in the subjective importance of developmental goals. Developmental goals and control beliefs were repeatedly assessed over an 8-year interval on a core sample of 735 participants (initial age range: 30-59 years). The findings reveal a high degree of stability in generalized perceptions of control even in the transition to later adulthood. In line with predictions, moderated multiple regressions indicated(a) that the degree to which self-percepts of control within a particular goal domain affect an individual's general sense of control depends on the personal importance of that domain, and (b) that losses of control within a goal domain affect general perceptions of control to a lesser degree if the importance of the respective domain is downscaled within the same longitudinal interval. Implications for theories of depression as well as for successful aging are discussed.

Studies on the effects of several pentamidine analogues on the NMDA receptor.

We have investigated the interactions of six analogues of pentamidine with the N-methyl-D-aspartate (NMDA) receptor complex. All six compounds were effective NMDA receptor antagonists based upon their ability to inhibit [3H]dizocilpine binding to rat brain membranes. IC50 values ranged from 2 to 18 microM, and all compounds had Hill coefficients in excess of 1 suggesting a non-competitive interaction with [3H]dizocilpine. All compounds also inhibited NMDA- and glycine-induced intracellular Ca2+ changes measured in cultured rat forebrain neurons using the fluorescent indicator, fura-2. IC50 values in this assay ranged from 0.4 to 4.7 microM. Whereas pentamidine is directly toxic to cultured neurons, this was not a consistent finding with the pentamidine analogues tested, indicating that the toxic effects are not related to NMDA receptor antagonism. Finally, all of the agents tested were also effective in protecting neurons from NMDA-induced neurotoxicity. These data emphasize the possible utility of pentamidine-like drugs as neuroprotective agents and suggest that it is possible to generate compounds with a wider margin of safety than pentamidine itself.

[125I]thienylphencyclidine, a novel ligand for the NMDA receptor.

We have monitored the binding of [125I]thienylphencyclidine ([125I]TCP), a novel high affinity radioiodinated ligand that specifically recognizes the NMDA (N-methyl-D-aspartate) receptor in rat brain membranes. [125I]TCP binds with an affinity of about 30 nM, and recognizes a similar number of binding sites to previously employed ligands for this receptor. [125I]TCP binding is characterized by slow association and dissociation rates, and the latter can be modified by the addition of Mg2+ or Zn2+, as previously described for [3H]dizocilpine ([3H]MK801). Other phencyclidine-like ligands displaced [125I]TCP binding with the order of potency dizocilpine greater than thienylphencyclidine greater than ITCP greater than phencyclidine greater than ketamine. The binding of [125I]TCP was also increased by NMDA and glycine-site agonists and inhibited by antagonists of these sites. Surprisingly, however, the polyamines spermidine and spermine did not increase [125I]TCP, even though the polyamine antagonist arcaine was an effective inhibitor of binding. These results show that [125I]TCP is a useful ligand for the NMDA receptor complex that binds to the receptor in a manner that is qualitatively distinct from previously described ligands.