937 resultados para Mediator


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The complement C3a anaphylatoxin is a major molecular mediator of innate immunity. It is a potent activator of mast cells, basophils and eosinophils and causes smooth muscle contraction. Structurally, C3a is a relatively small protein (77 amino acids) comprising a N-terminal domain connected by 3 native disulfide bonds and a helical C-terminal segment. The structural stability of C3a has been investigated here using three different methods: Disulfide scrambling; Differential CD spectroscopy; and Reductive unfolding. Two uncommon features regarding the stability of C3a and the structure of denatured C3a have been observed in this study. (a) There is an unusual disconnection between the conformational stability of C3a and the covalent stability of its three native disulfide bonds that is not seen with other disulfide proteins. As measured by both methods of disulfide scrambling and differential CD spectroscopy, the native C3a exhibits a global conformational stability that is comparable to numerous proteins with similar size and disulfide content, all with mid-point denaturation of [GdmCl](1/2) at 3.4-5M. These proteins include hirudin, tick anticoagulant protein and leech carboxypeptidase inhibitor. However, the native disulfide bonds of C3a is 150-1000 fold less stable than those proteins as evaluated by the method of reductive unfolding. The 3 native disulfide bonds of C3a can be collectively and quantitatively reduced with as low as 1mM of dithiothreitol within 5 min. The fragility of the native disulfide bonds of C3a has not yet been observed with other native disulfide proteins. (b) Using the method of disulfide scrambling, denatured C3a was shown to consist of diverse isomers adopting varied extent of unfolding. Among them, the most extensively unfolded isomer of denatured C3a is found to assume beads-form disulfide pattern, comprising Cys(36)-Cys(49) and two disulfide bonds formed by two pair of consecutive cysteines, Cys(22)-Cys(23) and Cys(56)-Cys(57), a unique disulfide structure of polypeptide that has not been documented previously.

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Matrix metalloproteinase-9 (MMP-9) cleaves collagen, allowing leukocytes to traffic toward the vasculature and the lymphatics. When MMP-9 is unregulated by tissue inhibitor of metalloproteinase-1 (TIMP-1), this can lead to tissue destruction. Dendritic cells (DCs) infiltrate the oral mucosa increasingly in chronic periodontitis, characterized by infection with several pathogens including Porphyromonas gingivalis. In this study, human monocyte-derived DCs were pulsed with different doses of lipopolysaccharide of P. gingivalis 381 and of Escherichia coli type strain 25922, as well as whole live isogenic fimbriae-deficient mutant strains of P. gingivalis 381. Levels of induction of MMP-9 and TIMP-1, as well as interleukin-10 (IL-10), which reportedly inhibits MMP-9 induction, were measured by several approaches. Our results reveal that lipopolysaccharide of P. gingivalis, compared with lipopolysaccharide from E. coli type strain 25922, is a relatively potent inducer of MMP-9, but a weak inducer of TIMP-1, contributing to a high MMP-9/TIMP-1 ratio.Whole live P. gingivalis strain 381, major fimbriae mutant DPG-3 and double mutant MFB were potent inducers of MMP-9, but minor fimbriae mutant MFI was not. MMP-9 induction was inversely proportional to IL-10 induction. These results suggest that lipopolysaccharide and the minor and the major fimbriae of P. gingivalis may play distinct roles in induction by DCs of MMP-9, a potent mediator of local tissue destruction and leukocyte trafficking.

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INTRODUCTION: Task stressors typically refer to characteristics such as not having enough time or resources, ambiguous demands, or the like. We suggest the perceived lack of legitimacy as an additional feature of tasks as a source of stress. Tasks are “illegitimate” to the extent that it is perceived as improper to expect employees to execute them – not because of difficulties in executing them, but because of their content for a given person, time, and situation; they are illegitimate because a) they are not conforming to a specific occupational role, as in “non-nursing activities” (called unreasonable) or b) there is no legitimate need for them to exist (called unnecessary; Semmer et al., 2007). These features make illegitimate tasks a unique task-related stressor. The concept of illegitimate tasks grew from the “Stress-as-Offense-to-Self” theory (SOS; Semmer et al, 2007); it is conceptually related to role stress (Kahn et al., 1964; Beehr & Glazer, 2005) and the organizational justice tradition (Cropanzano et al., 2001; Greenberg, 2010). SOS argues that a threat to one’s self-image is at the core of many stressful experiences. Violating role expectations, illegitimate tasks can be regarded as a special case of role conflict. As roles shape identities, this violation is postulated to constitute a threat to one’s professional identity. Being assigned a task considered illegitimate is likely to be considered unfair. Lack of fairness, in turn, contains a message about one’s social standing, and thus, the self. However, the aspects discussed have not received much attention in the role stress or the justice/fairness tradition. OBJECTIVE: Illegitimate tasks are a rather recent concept that has to be established as a construct in its own right by showing that it is associated with well-being/strain while controlling for other stressors, most notably role conflict and lack of justice. The aim of the presentation is to present the evidence accumulated so far. METHODS AND RESULTS: We present several studies employing different designs, using different control variables, and testing associations with different criteria. Study 1 demonstrates associations of illegitimate tasks with self-esteem, feelings of resentment against one’s organization, and burnout, controlling for distributive justice, role conflict, and social stressors (i.e. tensions). Study 2 yielded comparable results, using the same outcome variables but controlling for distributive as well as procedural / interactional justice. Study 3 demonstrated associations between illegitimate tasks and feelings of stress, sleeping problems, and emotional exhaustion, controlling for demands, control, and social support among medical doctors. Study 4 showed that feeling appreciated by one’s superior acted as a mediator between illegitimate tasks and job satisfaction and resentments towards the military in Swiss military officers. Study 5 demonstrated an association of illegitimate tasks with counterproductive work behavior (Semmer et al. 2010). Studies 1 to 5 were cross-sectional. In Study 6, illegitimate demands predicted irritability and resentments towards one’s organization longitudinally. Study 7 also was longitudinal, focusing on intra-individual variation in multilevel modeling; occasion-specific illegitimate tasks predicted cortisol among those who judged their health as comparatively poor. Studies 1-3 and 6 used SEM, and measurement models that used unreasonable and unnecessary tasks as indicators (isolated parceling) yielded a good fit. IMPLICATIONS & CONCLUSIONS: These studies demonstrate that illegitimate tasks are a stressor in its own right that is worth studying. It illuminates the social meaning of job design, emphasizing the implications of tasks for the (professional) self, and thus combining aspects that are traditionally treated as separate, that is, social aspects and task characteristics. Practical implications are that supervisors and managers should be alerted to the social messages that may be contained in task assignments (cf. Semmer & Beehr, in press).

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Bronchial epithelial cells play a pivotal role in airway inflammation, but little is known about posttranscriptional regulation of mediator gene expression during the inflammatory response in these cells. Here, we show that activation of human bronchial epithelial BEAS-2B cells by proinflammatory cytokines interleukin-4 (IL-4) and tumor necrosis factor alpha (TNF-alpha) leads to an increase in the mRNA stability of the key chemokines monocyte chemotactic protein 1 and IL-8, an elevation of the global translation rate, an increase in the levels of several proteins critical for translation, and a reduction of microRNA-mediated translational repression. Moreover, using the BEAS-2B cell system and a mouse model, we found that RNA processing bodies (P bodies), cytoplasmic domains linked to storage and/or degradation of translationally silenced mRNAs, are significantly reduced in activated bronchial epithelial cells, suggesting a physiological role for P bodies in airway inflammation. Our study reveals an orchestrated change among posttranscriptional mechanisms, which help sustain high levels of inflammatory mediator production in bronchial epithelium during the pathogenesis of inflammatory airway diseases.

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This chapter explores cultural and individual religious roots of adolescents' family orientation on the basis of multilevel analyses with data from 17 cultural groups. Religion and the family are seen as intertwined social institutions. The family as a source of social support has been identified as an important mediator of the effects of religiosity on adolescent developmental outcomes. The results of the current study show that religiosity was related to different aspects of adolescents' family orientation (traditional family values. value of children, and family future orientation), and that the culture-level effects of religiosity on family orientation were stronger than the individual-level effects. At the cultural level, socioeconomic development added to the effect of religiosity, indicating that societal affluence combined with nonreligious secular orientations is linked to a lower family orientation, especially with regard to traditional family values. The authors suggest that individual religiosity may be of special importance for adolescents' family orientation in contexts where religiosity has lost some significance but religious traditions are still alive and can be (re-)connected to.

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Background: Given that an alarming 1 in 5 children in the USA are at risk of hunger (1 in 3 among black and Latino children), and that 3.9 million households with children are food insecure, it is crucial to understand how household food insecurity (HFI) affects the present and future well-being of our children. Purpose: The objectives of this review article are to: (i) examine the association between HFI and child intellectual, behavioral and psycho-emotional development, controlling for socio-economic indicators; (ii) review the hypothesis that HFI is indeed a mediator of the relationship between poverty and poor child development outcomes; (iii) examine if the potential impact of HFI on caregivers’ mental health well-being mediates the relationship between HFI and child development outcomes. Methods: Pubmed search using the key words “food insecurity children.” For articles to be included they had to: (i) be based on studies measuring HFI using an experience-based scale, (ii) be peer reviewed, and (iii) include child intellectual, behavioral and/or socio-emotional development outcomes. Studies were also selected based on backward and forward Pubmed searches, and from the authors’ files. After reviewing the abstracts based on inclusion criteria a total of 26 studies were selected. Results: HFI represents not only a biological but also a psycho-emotional and developmental challenge to children exposed to it. Children exposed to HFI are more likely to internalize or externalize problems, as compared to children not exposed to HFI. This in turn is likely to translate into poor academic/cognitive performance and intellectual achievement later on in life. A pathway through which HFI may affect child development is possibly mediated by caregivers’ mental health status, especially parental stress and depression. Thus, HFI is likely to foster dysfunctional family environments. Conclusion: Findings indicate that food insecure households may require continued food assistance and psycho-emotional support until they transition to a “stable” food secure situation. This approach will require a much better integration of social policies and access to programs offering food assistance and mental health services to those in need. Findings also fully justify increased access of vulnerable children to programs that promote early in life improved nutrition as well as early psycho-social and cognitive stimulation opportunities.

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Previous experiments had shown no differences in desensitization in cells with mutations of the adenylyl cyclase or the cAMP-dependent protein kinase and had ruled out this kinase as a mediator of desensitization; however, the assays of adenylyl cyclase had been made at high concentrations of free magnesium. The work presented in this dissertation documents a role for cAMP-dependent protein kinase which became apparent with assays at low concentrations of free magnesium. (1) The adenylyl cyclase in membranes from wild type S49 lymphoma cells showed substantial desensitization after incubation of the intact cells with low concentrations of epinephrine (5-20 nM). This desensitization was heterologous, that is it reduced the subsequent responses of the adenylyl cyclase to both epinephrine and prostaglandin-E$\sb1$. (2) The adenylyl cyclase in membranes of S49 cyc$\sp-$ cells, which do not make cAMP in response to hormones, and S49 kin$\sp-$ cells, which lack cAMP-dependent protein kinase activity, showed no heterologous desensitization following incubation of the intact cells with low concentrations of hormones. (3) Heterologous desensitization of the adenylyl cyclase was induced by incubations of wild type cells with forskolin, which activates the adenylyl cyclase downstream of the hormone receptors, or dibutyryl-cAMP, which activates the cAMP-dependent protein kinase directly. (4) Site-directed mutagenesis was used to delete the cAMP-dependent protein kinase consensus phosphorylation sequences on the $\beta$-adrenergic receptor. Heterologous desensitization occurred in intact L-cells expressing the wild type receptor or the receptor lacking the C-terminal phosphorylation site; however, only homologous desensitization occurred when the phosphorylation site on the third intracellular loop of the receptor was deleted. (5) To test directly the effects of cAMP-dependent protein kinase on the adenylyl cyclase the catalytic subunit of the kinase was purified from bovine heart and incubated with adenylyl cyclase in plasma membrane preparations. In this cell-free system the kinase caused rapid heterlogous reductions of the responsiveness of the S49 wild type adenylyl cyclase. Additionally, the adenylyl cyclase in kin$\sp-$ membranes, which showed only homologous desensitization in the intact cell, was desensitization by cell-free incubation with the kinase.^ The epinephrine responsiveness was not affected in L-cell membranes expressing the $\beta$-adrenergic receptor lacking the cAMP-dependent protein kinase consensus sequence on the third intracellular loop. ^

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Studies were performed to test the hypothesis that type I hypersensitivity underlies worm induced intestinal fluid secretion and the rapid rejection of Trichinella spiralis from immunized rats, and the two events may be related in a cause-effect manner.^ Two approaches were taken. One was to determine whether inhibition of anaphylaxis-mediated Cl$\sp{-}$ and fluid secretion accompanying a secondary infection impedes worm rejection from immune hosts. The other was to determine whether induction of intestinal fluid secretion in nonimmune hosts interfered with worm establishment. In both studies, fluid secretion was measured volumetrically 30 min after a challenge infection and worms were counted.^ In immunized rats indomethacin did not affect the worm-induced fluid secretion when used alone, despite inhibiting mucosal prostaglandin synthesis. Fluid secretion was reduced by treatment with diphenhydramine and further reduced by the combination of diphenhydramine and indomethacin. The paradoxical effects of indomethacin when used alone compared with its coadministration with diphenhydramine is explained by the enhancing effect of indomethacin on histamine release. Abolishing net fluid secretion in these studies had no effect on rapid worm rejection in immune hosts.^ Worm establishment was reduced in recipients of immune serum containing IgE antibodies. Net intestinal fluid secretion induced in normal rats by PGE$\sb2$, cholera toxin, or hypertonic mannitol solution had no effect on worm establishment compared with untreated controls.^ In a related experiment, worm-induced intestinal fluid secretion and worm rejection in immune rats were partially blocked by concurrent injection with 5-HT$\sb2$ and 5-HT$\sb3$ blockers (Ketanserin and MDL-72222), suggesting that 5-HT is involved. This possible involvement was supported in that treatment of nonimmune rats with 5-HT significantly inhibited worm establishment in the intestine.^ Results indicate that anaphylaxis is the basis for both worm-induced intestinal fluid secretion and rapid rejection of T. spiralis in immune rats, but these events are independent of one another. 5-HT is a possible mediator of worm rejection, however, its mechanism of action is related to something other than fluid secretion. ^

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The coordination of the apoptotic program necessitates the timely expression of sensor, effector, and mediator molecules. Fas/CD95, a transmembrane receptor which tethers the cell-death machinery, triggers apoptosis to maintain immune homeostasis, tolerance, and surveillance. Dysregulation in Fas-mediated apoptosis, either from disproportionate expression or disruptions in the downstream signaling pathway, manifests in autoimmune disorders and certain malignant progression. ^ In this project, the transcriptional requirements underlying two modulators of Fas expression were investigated. In T-lymphocytes, activation results in potent Fas upregulation followed by an acquisition of sensitivity towards FasL-mediated apoptosis. Human fas promoter cloning and analysis have identified a cis-element critical for inducible Fas expression. EMSA studies using this region demonstrated a constitutive association with the transcription factor Sp1 and inducible NF-κB binding in response to activation. These interactions were mutually exclusive, as the rB/Sp1 element bound with recombinant Sp1 was readily displaced by increasing amounts of NF-κB p50. Thus, Fas upregulation by T-cell activation stimuli is dependent upon NF-κB binding at the fas promoter. ^ The capacity of Sp1 to direct basal Fas expression was examined through mutagenesis of several GC-rich regions within the core fas promoter. Reporter analysis of single or combinatorial mutant GC-box constructs revealed usage of a particular GC-element in moderating over 50% of basal fas transcription. Inducible expression was Sp1-independent, however, since activated Jurkat cells containing fas Sp1-mutant constructs retained equivalent reporter induction. Overall, a dual-level of transcriptional control exists in fas, where constitutive activity is monitored through Sp1 binding, whereas T-cell activation obligates NF κB transactivation. ^ In response to genotoxic damage, p53 modulates Fas levels partly by a transcription-dependent mechanism. Reconstitution of wild-type p53 in the hepatoma cell line Hep3B readily induced Fas transcription. Furthermore, fas promoter analysis identified an undescribed p53 responsive element which, when deleted, ablated p53-mediated reporter activity. Therefore, the pro-apoptotic function mediated by p53 is driven partially through the enhancement of Fas expression. ^ Altogether, events elicting Fas transcription may invoke single or overlapping mechanisms that converge at the level of promoter activity. Agents that enhance or attenuate these pathways may be therapeutically beneficial in modulating the expression and sensitivity towards Fas-dependent apoptosis. ^

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While many studies confirm that positive emotions, including enjoyment, lead to better student achievement, less empirical evidence exists about possible mediator variables that link achievement to enjoyment. It is proposed that achievement and enjoyment form a circular dependency; enjoyment in learning leads to higher achievement but a degree of achievement is required to enjoy learning. This study provides insight into the reverse of the much studied enjoyment to achievement link and provides practical recommendations on how to use these findings. Founded in Control-value theory, which suggests that control and value cognitions are important variables that mediate the connection between enjoyment and achievement, this study explores the reciprocal achievement-cognition-enjoyment link. The reciprocal link was investigated by applying a one year longitudinal design to students of grade 6 and 7 (N = 356). This age group was chosen because early adolescence represents a critical period during which a strong decrease in positive learning emotions is observed. Part of the work involved identifying factors that might be responsible for this negative development. Results of cross-lagged path analysis identified reciprocal effects between student achievement and enjoyment with control and value cognitions functioning as partial mediators. High achievement goes with high control and value cognitions, which in turn positively affect enjoyment. However, cross-lagged correlations could only be partly confirmed. The results are discussed in terms of theoretical and practical implications.

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There is empirical evidence showing that positive emotional and motivational factors in formal learning contexts decrease at the stage of young adolescence. According to Stage-Environment-Fit Theory and Self-Determination Theory, this change should be explained by a non-fulfilment of students' needs. By combining two different methods (questionnaires and day-to-day diaries) and applying a longitudinal design, this study aimed to explore the change in and the determinants of habitual and actual learning enjoyment. The sample consisted of 356 students. Quantitative results indicated that learning enjoyment and classroom practices decreased between Grades 6 and 7. Path analyses revealed that classroom practices are the source of students' learning enjoyment, while self-efficacy functions as a partial mediator. Data from students' diaries showed that a teacher's neglect of students' needs for competence and relatedness were significant sources of impeded learning enjoyment. Practical implications suggest the relevance of adjusting learning conditions to the needs of young adolescents in order to provide a facilitating basis for learning enjoyment.

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Research has shown repeatedly that the “feeling better” effect of exercise is far more moderate than generally claimed. Examinations of subgroups in secondary analyses also indicate that numerous further variables influence this relationship. One reason for inconsistencies in this research field is the lack of adequate theoretical analyses. Well-being output variables frequently possess no construct definition, and little attention is paid to moderating and mediating variables. This article integrates the main models in an overview and analyzes how secondary analyses define well-being and which areas of the construct they focus on. It then applies a moderator and/or mediator framework to examine which person and environmental variables can be found in the existing explanatory approaches in sport science and how they specify the influence of these moderating and mediating variables. Results show that the broad understanding of well-being in many secondary analyses makes findings difficult to interpret. Moreover, physiological explanatory approaches focus more on affective changes in well-being, whereas psychological approaches also include cognitive changes. The approaches focus mostly on either physical or psychological person variables and rarely combine the two, as in, for example, the dual-mode model. Whereas environmental variables specifying the treatment more closely (e.g., its intensity) are comparatively frequent, only the social support model formulates variables such as the framework in which exercise is presented. The majority of explanatory approaches use simple moderator and/or mediator models such as the basic mediated (e.g., distraction hypothesis) or multiple mediated (e.g., monoamine hypotheses) model. The discussion draws conclusions for future research.

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BACKGROUND Histamine is an ubiquitous inflammatory mediator of numerous physiological processes. Histamine and its receptors have been implicated in multiple sclerosis (MS) disease pathogenesis. We prospectively enrolled 36 MS patients and 19 age and gender-matched healthy volunteers for cerebrospinal fluid (CSF) histamine analysis. FINDINGS CSF HISTAMINE LEVELS IN MS PATIENT SAMPLES WERE SIGNIFICANTLY HIGHER (MEDIAN: 35.6 pg/ml) than in controls (median: 5.5 pg/ml; Beta = 0.525, p < 0.001). In addition, histamine increased with age (Pearson's correlation, p < 0.003). CONCLUSIONS Histamine may be an important factor for both the initiation and maintenance of chronic inflammatory diseases of the central nervous system. Our observation encourages a deeper investigation of the role of histamine in MS.

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Crosslinking of immunoglobulin E antibodies (IgE) bound at the surface of mast cells and subsequent mediator release is considered the most important trigger for allergic reactions. Therefore, the genetic control of IgE levels is studied in the context of allergic diseases, such as asthma, atopic rhinitis, or atopic dermatitis (AD). We performed genome-wide association studies in 161 Labrador Retrievers with regard to total and allergen-specific immunoglobulin E (IgE) levels. We identified a genome-wide significant association on CFA 5 with the antigen-specific IgE responsiveness to Acarus siro. We detected a second genome-wide significant association with respect to the antigen-specific IgE responsiveness to Tyrophagus putrescentiae at a different locus on chromosome 5. A. siro and T. putrescentiae both belong to the family Acaridae and represent so-called storage or forage mites. These forage mites are discussed as major allergen sources in canine AD. No obvious candidate gene for the regulation of IgE levels is located under the two association signals. Therefore our studies offer a chance of identifying a novel mechanism controlling the host's IgE response.

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Einleitung und Fragestellung In der Forschung zum Selbstgespräch im Sport dominiert die Frage nach dessen Wir-kung auf die Leistung. Der Einfluss des während der Leistungserbringung geäußerten Selbstgesprächs auf (un-)beteiligte Personen (z.B. Zuschauer, Gegenspieler oder Dop-pelpartner) wurde bislang kaum untersucht. Van Raalte, Brewer, Cornelius und Petitpas (2006) konnten immerhin zeigen, dass Zuschauer einen Tennisspieler als kompetenter einschätzen, wenn er in einem Laborexperiment mit positivem statt mit negativem Selbst-gespräch gezeigt wurde. In unserer Studie stehen Dyaden im Zentrum, in der eine Person eine andere beobach-tet, die mit sich selbst spricht. Untersucht wird, ob bei einer additiven Teamaufgabe sol-che Beobachtungen einen Effekt auf die Kompetenzeinschätzung und die Anstren-gungsbereitschaft haben. Es wird vermutet, dass die beobachtende Person dann eine höhere Anstrengungsbereitschaft (AV) zeigt, wenn sie einen Teampartner mit positivem Selbstgespräch (UV) beobachtet, da sie ihren Partner als kompetenter einschätzt und diese Einschätzung als Mediator wirkt. Methode Es wurde ein randomisierter Zweigruppen-Versuchsplan mit zwei Experimentalgruppen (je n=20) durchgeführt. Das Treatment bestand aus einem Video, das den (jeweils identi-schen) Teampartner bei der Bewältigung der zu absolvierenden visuomotorisch-koordinativen Testaufgabe zeigt (Test 2HAND des Wiener Testsystems). Das Video wur-de abhängig von der Gruppenzugehörigkeit mit negativen respektive positiven Selbstge-sprächsaussagen unterlegt. Die Mediatorvariable wahrgenommene Kompetenz wurde mittels eines Fragebogens erhoben, der in Anlehnung an Van Raalte et al. (2006) entwi-ckelt wurde. Das Vorgehen zur Erhebung der abhängigen Variable Anstrengungsbereit-schaft wurde von Ohlert (2009) übernommen: Die Probanden erhielten die Möglichkeit, sich auf die spätere Testphase vorzubereiten. Erfasst wurde dabei die Zeit, die sie für die Vorbereitung in Anspruch nahmen, und die Genauigkeit, mit der sie eine Reihe von Aufwärmaufgaben absolvierten. Ergebnisse Die Datenerhebung wurde soeben abgeschlossen. Die Ergebnisse der noch ausstehen-den regressionsanalytischen Auswertung werden auf der Tagung präsentiert. Literatur Ohlert, J. (2009). Teamleistung. Social Loafing in der Vorbereitung auf eine Gruppenaufgabe. Hamburg: Dr. Kovac. Van Raalte, J. L., Brewer, B. W., Cornelius, A. E. & Petitpas, A. J. (2006). Self-presentational effects of self-talk on perceptions of tennis players. Hellenic Journal of Psychology, 3, 134-149.