On the moderators of trait avoidance motivation in predicting cognitive biases and adjustment

The present research focused on motivational and personality traits measuring individual differences in the experience of negative affect, in reactivity to negative events, and in the tendency to avoid threats. In this thesis, such traits (i.e., neuroticism and dispositional avoidance motivation) are jointly referred to as trait avoidance motivation. The seven studies presented here examined the moderators of such traits in predicting risk judgments, negatively biased processing, and adjustment. Given that trait avoidance motivation encompasses reactivity to negative events and tendency to avoid threats, it can be considered surprising that this trait does not seem to be related to risk judgments and that it seems to be inconsistently related to negatively biased information processing. Previous work thus suggests that some variable(s) moderate these relations. Furthermore, recent research has suggested that despite the close connection between trait avoidance motivation and (mal)adjustment, measures of cognitive performance may moderate this connection. However, it is unclear whether this moderation is due to different response processes between individuals with different cognitive tendencies or abilities, or to the genuinely buffering effect of high cognitive ability against the negative consequences of high trait avoidance motivation. Studies 1-3 showed that there is a modest direct relation between trait avoidance motivation and risk judgments, but studies 2-3 demonstrated that state motivation moderates this relation. In particular, individuals in an avoidance state made high risk judgments regardless of their level of trait avoidance motivation. This result explained the disparity between the theoretical conceptualization of avoidance motivation and the results of previous studies suggesting that the relation between trait avoidance motivation and risk judgments is weak or nonexistent. Studies 5-6 examined threat identification tendency as a moderator for the relationship between trait avoidance motivation and negatively biased processing. However, no evidence for such moderation was found. Furthermore, in line with previous work, the results of studies 5-6 suggested that trait avoidance motivation is inconsistently related to negatively biased processing, implying that theories concerning traits and information processing may need refining. Study 7 examined cognitive ability as a moderator for the relation between trait avoidance motivation and adjustment, and demonstrated that cognitive ability moderates the relation between trait avoidance motivation and indicators of both self-reported and objectively measured adjustment. Thus, the results of Study 7 supported the buffer explanation for the moderating influence of cognitive performance. To summarize, the results showed that it is possible to find factors that consistently moderate the relations between traits and important outcomes (e.g. adjustment). Identifying such factors and studying their interplay with traits is one of the most important goals of current personality research. The present thesis contributed to this line of work in relation to trait avoidance motivation.

Impulsivity, health-related behaviour and disease : A prospective study

In clinical settings impulsivity refers to a symptom of psychiatric disorder, but nonclinically oriented research treats impulsivity as a personality and temperament dimension. This prospective study examined whether impulsivity predicts adverse health-related behaviour and increased risk of health problems in a large, nonclinical sample of 5433 subjects working in 12 Finnish hospitals. The data were collected using two questionnaire surveys at a 2-year interval. After controlling for alcohol use at baseline, higher impulsivity predicted increased alcohol consumption at follow-up in both genders (p < .01) and was associated with increased likelihood of becoming a heavy drinker or taking up smoking (p < .05). Impulsivity also predicted an increased number of cigarettes smoked per day in the follow-up among women (p < .001), but not among men, although adjustment for the number of cigarettes smoked at baseline attenuated these associations (p = .08 for women). In men, higher impulsivity was associated with shorter sleep duration and waking up several times per night independent of baseline characteristics (p < .01), whereas in women, higher impulsivity predicted difficulty in falling asleep and waking up feeling tired after the usual amount of sleep (p < .05). In women, these associations became nonsignificant after adjustment for pre-existing somatic and psychiatric diseases. Finally, higher impulsivity was associated with an increased 2-year incidence of physician-diagnosed peptic ulcer disease (adjusted odds ratio (OR) = 2.42, 95% confidence interval (CI) = 1.21 - 4.82) and onset of depression (OR = 1.95, 95% CI = 1.28 - 2.97) after adjustment for a variety of baseline covariates. In conclusion, this study shows that in a nonclinical population, impulsivity appears to be a risk factor for various unhealthy behaviour and health problems.

Growth differentiation factor 9 signalling in the ovary

In the ovary, two new members of the large TGF-beta superfamily of growth factors were discovered in the 1990s. The oocyte was shown to express two closely related growth factors that were named growth differentiation factor 9 (GDF-9) and growth differentiation factor 9B (GDF-9B). Both of these proteins are required for normal ovarian follicle development although their individual significance varies between species. GDF-9 and GDF-9B mRNAs are expressed in the human oocytes from the primary follicle stage onwards. This thesis project was aimed to define the signalling mechanisms utilized by the oocyte secreted GDF-9. We used primary cultures of human granulosa luteal cells (hGL) as our cell model, and recombinant adenovirus-mediated gene transfer in manipulating the TGF-b family signalling cascade molecules in these cells. Overexpression of the constitutively active forms of the seven type I receptors, the activin receptor-like kinases 1-7 (ALK1-7), using recombinant adenoviruses caused a specific activation of either the Smad1 or Smad2 pathway proteins depending on the ALK used. Activation of both Smad1 and Smad2 proteins also stimulated the expression of dimeric inhibin B protein in hGL cells. Treatment with recombinant GDF-9 protein induced the specific activation of the Smad2 pathway and stimulated the expression of inhibin betaB subunit mRNA as well as inhibin B protein secretion in our cell model. Recombinant GDF-9 also activated the Smad3-responsive CAGA-luciferase reported construct, and the GDF-9 response in hGL cells was markedly potentiated upon the overexpression of Alk5 by adenoviral gene transduction. Alk5 overexpression also enhanced the GDF-9 induced inhibin B secretion by these cells. Similarly, in a mouse teratocarcinoma cell line P19, GDF-9 could activate the Smad2/3 pathway, and overexpression of ALK5 in COS7 cells rendered them responsive to GDF-9. Furthermore, transfection of rat granulosa cells with small interfering RNA for ALK5 or overexpression of the inhibitory Smad7 resulted in dose-dependent suppression of GDF-9 effects. In conclusion, this thesis shows that both Smad1 and Smad2 pathways are involved in controlling the regulation of inhibin B secretion. Therefore, in addition to endocrine control of inhibin production by the pituitary gonadotropins, also local paracrine factors within in the ovary, like the oocyte-derived growth factors, may contribute to controlling inhibin secretion. This thesis shows as well that like other TGF-beta family ligands, also GDF-9 signalling is mediated by the canonical type I and type II receptors with serine/threonine kinase activity, and the intracellular transcription factors, the Smads. Although GDF-9 binds to the BMP type II receptor, its downstream actions are specifically mediated by the type I receptor, ALK5, and the Smad2 and Smad3 proteins.

Activator Protein-1 and Epidermal Growth Factor Receptor Interplay : In Vivo & In Vitro Studies

Critical cellular decisions such as should the cell proliferate, migrate or differentiate, are regulated by stimulatory signals from the extracellular environment, like growth factors. These signals are transformed to cellular responses through their binding to specific receptors present at the surface of the recipient cell. The epidermal growth factor receptor (EGF-R/ErbB) pathway plays key roles in governing these signals to intracellular events and cell-to-cell communication. The EGF-R forms a signaling network that participates in the specification of cell fate and coordinates cell proliferation. Ligand binding triggers receptor dimerization leading to the recruitment of kinases and adaptor proteins. This step simultaneously initiates multiple signal transduction pathways, which result in activation of transcription factors and other target proteins, leading to cellular alterations. It is known that mutations of EGF-R or in the components of these pathways, such as Ras and Raf, are commonly involved in human cancer. The four best characterized signaling pathways induced by EGF-R are the mitogen-activated protein kinase cascades (MAPKs), the lipid kinase phosphatidylinositol 3 kinase (PI3K), a group of transcription factors called Signal Transducers and Activator of Transcription (STAT), and the phospholipase Cγ; (PLCγ) pathways. The activation of each cascade culminates in kinase translocation to the nucleus to stimulate various transcription factors including activator protein 1 (AP-1). AP-1 family proteins are basic leucine zipper (bZIP) transcription factors that are implicated in the regulation of a variety of cellular processes (proliferation and survival, growth, differentiation, apoptosis, cell migration, transformation). Therefore, the regulation of AP-1 activity is critical for the decision of cell fate and their deregulated expression is widely associated with many types of cancers, such as breast and prostate cancers. The aims of this study were to characterize the roles of EGF-R signaling during normal development and malignant growth in vitro and in vivo using different cell lines and tissue samples. We show here that EGF-R regulates cell proliferation but is also required for regulation of AP-1 target gene expression in fibroblasts in a MAP-kinase mediated manner. Furthermore, EGF-R signaling is essential for enterocyte proliferation and migration during intestinal maturation. EGF-R signaling network, especially PI3-K-Akt pathway mediated AP-1 activity is involved in cellular survival in response to ionizing radiation. Taken together, these results elucidate the connection of EGF-R and AP-1 in various cellular contexts and show their importance in the regulation of cellular behaviour presenting new treatment cues for intestinal perforations and cancer therapy.