The Interplay Between KSHV-encoded Viral Cyclin and CDK-inhibitors p27Kip1 and p21Cip1 -implications for Viral Lymphomagenesis

Cell division, which leads to the birth of two daughter cells, is essential for the growth and development of all organisms. The reproduction occurs in a series of events separated in time, designated as the cell cycle. The cell cycle progression is controlled by the activity of cyclin-dependent kinases (CDK). CDKs pair with cyclins to become catalytically active and phosphorylate a broad range of substrates required for cell cycle progression. In addition to cyclins, CDKs are regulated by inhibitory and activating phosphorylation events, binding to CDK-inhibitory proteins (CKI), and also by subcellular localization. The control of the CDK activity is crucial in preventing unscheduled progression of the cell cycle with mistakes having potentially hazardous consequences, such as uncontrolled proliferation of the cells, a hallmark of cancer. The mammalian cell cycle is a target of several DNA tumor viruses that can deregulate the host s cell cycle with their viral oncoproteins. A human herpesvirus called Kaposi s sarcoma herpesvirus (KSHV) is implicated in the cause of Kaposi s sarcoma (KS) and lymphoproliferative diseases such as primary effusion lymphomas (PEL). KSHV has pirated several cell cycle regulatory genes that it uses to manipulate its host cell and to induce proliferation. Among these gene products is a cellular cyclin D homologue, called viral cyclin (v-cyclin) that can activate cellular CDKs leading to the phosphorylation of multiple target proteins. Intriguingly, PELs that are naturally infected with KSHV consistently express high levels of CDK inhibitor protein p27Kip1 and still proliferate actively. The aim of this study was to investigate v-cyclin complexes and their activity in PELs, and search for an explanation why CKIs, such as p27Kip1 and p21Cip1 are unable to inhibit cell proliferation in this type of lymphoma. In this study, we found that v-cyclin binds to p27Kip1 in PELs, and confirmed this novel interaction also in the overexpression models. We observed that p27Kip1 associated with v-cyclin was also phosphorylated by a v-cyclin-associated kinase and identified cellular CDK6 as the major kinase partner of v-cyclin responsible for this phosphorylation. Analysis of the p27Kip1 residues targeted by v-cyclin-CDK6 revealed that serine 10 (S10) is the major phosphorylation site during the latent phase of the KSHV replication cycle. This phosphorylation led to the relocalization of p27Kip1 to the cytoplasm, where it is unable to inhibit nuclear cyclin-CDK complexes. In the lytic phase of the viral replication cycle, the preferred phosphorylation site on p27Kip1 by v-cyclin-CDK6 changed to threonine 187 (T187). T187 phosphorylation has been shown to lead to ubiquitin-mediated degradation of p27Kip1 and downregulation of p27Kip1 was also observed here. v-cyclin was detected also in complex with p21Cip1, both in overexpression models and in PELs. Phosphorylation of p21Cip1 on serine 130 (S130) site by v-cyclin-CDK6 functionally inactivated p21Cip1 and led to the circumvention of G1 arrest induced by p21Cip1. Moreover, p21Cip1 phosphorylated by v-cyclin-associated kinase showed reduced binding to CDK2, which provides a plausible explanation why p21Cip1 is unable to inhibit cell cycle progression upon v-cyclin expression. Our findings clarify the mechanisms on how v-cyclin evades the inhibition of cell cycle inhibitors and suggests an explanation to the uncontrolled proliferation of KSHV-infected cells.

Orphan nuclear receptor subfamily NR4A their interplay with other nuclear receptors and functions in osteoblasts

Nurr1, NGFI-B and Nor1 (NR4A2, NR4A1 and NR4A3, respectively) belong to the NR4A subfamily of nuclear receptors. The NR4A receptors are orphan nuclear receptors which means that activating or repressing ligands for these receptors have not been found. NR4A expression is rapidly induced in response to various stimuli including growth factors and the parathyroid hormone (PTH). The studies concerning the NR4A receptors in the central nervous system have demonstrated that they have a major role in the development and function of the dopaminergic neurons of the midbrain and in regulating hypothalamus-pituitary-adrenal-axis. However, the peripheral functions of the NR4A family are largely unknown. Cultured mouse primary osteoblasts, a preosteoblastic cell line and several osteoblastic cell lines were used to investigate the role of NR4A receptors in osteoblasts. NR4A receptors were shown to directly bind to and activate the promoter of the osteopontin gene (OPN) in osteoblastic cells, thus regulating its expression. OPN is a major bone matrix protein expressed throughout the differentiation of preosteoblastic cells into osteoblasts. The activation of the OPN promoter was shown to be dependent on the activation function-1 located in the N-terminal part of Nurr1 and to occur in both monomeric and RXR heterodimeric forms of NR4A receptors. Furthermore, PTH was shown to upregulate OPN expression through the NR4A family. It was also demonstrated that the fibroblast growth factor-8b (FGF-8b) induces the expression of NR4A receptors in osteoblasts as immediate early genes. This induction involved phosphatidylinositol-3 kinase, protein kinase C, and mitogen activated protein kinase, which are all major pathways of FGF signalling. Nurr1 and NGFI-B were shown to induce the proliferation of preosteoblastic cells and to reduce their apoptosis. FGF-8b was shown to stimulate the proliferation of osteoblastic cells through the NR4A receptors. These results suggest that NR4A receptors have a role both in the differentiation of osteoblasts and in the proliferation and apoptosis of preosteoblast. The NR4A receptors were found to bind to the same response element on OPN as the members of the NR3B family of orphan receptors do. Mutual repression was observed between the NR4A receptors and the NR3B receptors. This repression was shown to be dependent on the DNA-binding domains of both receptor families, but to result neither from the competition of DNA binding nor from the competition for coactivators. As the repression was dependent on the relative expression levels of the NR4As and NR3Bs, it seems likely that the ratio of the receptors mediates their activity on their response elements. Rapid induction of the NR4As in response to various stimuli and differential expression of the NR3Bs can effectively control the gene activation by the NR4A receptors. NR4A receptors can bind DNA as monomers, and Nurr1 and NGFI-B can form permissive heterodimers with the retinoid X receptor (RXR). Permissive heterodimers can be activated with RXR agonists, unlike non-permissive heterodimers, which are formed by RXR and retinoic acid receptor or thyroid hormone receptor (RAR and TR, respectively). Non-permissive heterodimers can only be activated by the agonists of the heterodimerizing partner. The mechanisms behind differential response to RXR agonists have remained unresolved. As there are no activating or repressing ligands for the NR4A receptors, it would be important to find out, how they are regulated. Permissiviness of Nurr1/RXR heterodimers was linked to the N-terminal part of Nurr1 ligand-binding domain. This region has previously been shown to mediate the interaction between NRs and corepressors. Non-permissive RAR and TR, permissive Nurr1 and NGFI-B, and RXR were overexpressed with corepressors silencing mediator for retinoic acid and thyroid hormone receptors (SMRT), and with nuclear receptor corepressor in several cell lines. Nurr1 and NGFI-B were found to be repressed by SMRT. The interaction of RXR heterodimers with corepressors was weak in permissive heterodimers and much stronger in non-permissive heterodimers. Non-permissive heterodimers also released corepressors only in response to the agonist of the heterodimeric partner of RXR. In the permissive Nurr1/RXR heterodimer, however, SMRT was released following the treatment with RXR agonists. Corepressor release in response to ligands was found to differentiate permissive heterodimers from non-permissive ones. Corepressors were thus connected to the regulation of NR4A functions. In summary, the studies presented here linked the NR4A family of orphan nuclear receptors to the regulation of osteoblasts. Nurr1 and NGFI-B were found to control the proliferation and apoptosis of preosteoblasts. The studies also demonstrated that cross-talk with the NR3B receptors controls the activity of these orphan receptors. The results clarified the mechanism of permissiviness of RXR-heterodimers. New information was obtained on the regulation and functions of NR4A receptors, for which the ligands are unknown.

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.

Interplay of Virulence Factors in Complement Resistance of Streptococcus pneumoniae

Streptococcus pneumoniae (pneumococcus) is a normal inhabitant of the human nasopharynx. Symptoms occur in only a small proportion of those who become carriers, but the ubiquity of the organism in the human population results in a large burden of disease. S. pneumoniae is the leading bacterial cause of pneumonia, sepsis, and meningitis worldwide, causing the death of a million children each year. Middle-ear infection is the most common clinical manifestation of mucosal pneumococcal infections. In invasive disease, S. pneumoniae gains access to the bloodstream and spreads to normally sterile parts of the body. The progression from asymptomatic colonization to disease depends on factors characteristic of specific pneumococcal strains as well as the status of host defenses. The polysaccharide capsule surrounding the bacterium is considered to be the most important factor affecting the virulence of pneumococci. It protects pneumococci from phagocytosis and also may determine its affinity to the respiratory epithelium. S. pneumoniae as a species comprises more than 90 different capsular serotypes, but not all of them are equally prevalent in human diseases. Invasive serotypes are rarely isolated from healthy carriers, but relatively often cause invasive disease. Serotypes that are carried asymptomatically for a long time behave like opportunistic pathogens, causing disease in patients who have impaired immune defenses. The complement system is a collection of blood and cell surface proteins that act as a major primary defense against invading microbes. Phagocytic cells with receptors for complement proteins can engulf and destroy pneumococcal cells opsonized with these proteins. S. pneumoniae has evolved a number of ways to subvert mechanisms of innate immunity, and this is likely to contribute to its pathogenicity. The capsular serotype, proteins essential for virulence, as well the genotype, may all influence the ability of pneumococcus to resist complement and its potential to cause disease. Immunization with conjugate vaccines produces opsonic antibodies, which enhance complement deposition and clearance of the bacteria. The pneumococcal vaccine included in the Finnish national immunization program in 2010 contains the most common serotypes causing invasive disease. Clinical data suggest that protection from middle-ear infection and possibly also from invasive disease depends largely on the capsular serotype, for reasons hitherto unknown. The general aim of this thesis is to assess the relative roles of the pneumococcal capsule and virulence proteins in complement evasion and subsequent opsonophagocytic killing. The main question is whether differences between serotypes to resist complement explain the different abilities of serotypes to cause disease. The importance of particular virulence factors to the complement resistance of a strain may vary depending on its genotype. Prior studies have evaluated the effect of the capsule and virulence proteins on complement resistance of S. pneumoniae by comparing only a few strains. In this thesis, the role of pneumococcal virulence factors in the complement resistance of the bacterium was studied in several genotypically different strains. The ability of pneumococci to inhibit deposition of the complement protein C3 on the bacterial surface was found to depend on the capsular serotype as well as on other features of the bacteria. The results suggest that pneumococcal histidine triad (Pht) proteins may play a role in complement inhibition, but their contribution depends on the bacterial genotype. The capsular serotype was found to influence complement resistance more than the bacterial genotype. A higher concentration of anticapsular antibodies was required for the opsonophagocytic killing of serotypes resistant to C3 deposition. The invasive serotypes were more resistant to C3 deposition than the opportunistic serotypes, suggesting that the former are better adapted to resist immune mechanisms controlling the development of invasive disease. The different susceptibilities of serotypes to complement deposition, opsonophagocytosis, and resultant antibody-mediated protection should be taken into account when guidelines for serological correlates for vaccine efficacy evaluations are made. The results of this thesis suggest that antibodies in higher quantity or quality are needed for efficient protection against the invasive serotypes.

Kansallisvaltion teräsmiehestä valtakunnan sovittelijaksi : Poliisikulttuurin psykohistorialliset solmukohdat 1930-1997

From Steely Nation-State Superman to Conciliator of Economical Global Empire – A Psychohistory of Finnish Police Culture 1930-1997 My study concerns the way police culture has changed within the societal changes in Finnish society between 1930 and 1997. The method of my study was psycho-historical and post-structural analysis. The research was conducted by examining the psycho-historical plateaus traceable within Finnish police culture. I made a social diagnosis of the autopoietic relationship between the power-holders of Finnish society and the police (at various levels of hierarchical organization). According to police researcher John P. Crank, police culture should be understood as the cognitive processes behind the actions of the police. Among these processes are the values, beliefs, rituals, customs and advice which standardize their work and the common sense of policemen. According to Crank, police culture is defined by a mindset which thinks, judges and acts according to its evaluations filtered by its own preliminary comprehension. Police culture consists of all the unsaid assumptions of being a policeman, the organizational structures of police, official policies, unofficial ways of behaviour, forms of arrest, procedures of practice and different kinds of training habits, attitudes towards suspects and citizens, and also possible corruption. Police culture channels its members’ feelings and emotions. Crank says that police culture can be seen in how policemen express their feelings. He advises police researchers to ask themselves how it feels to be a member of the police. Ethos has been described as a communal frame for thought that guides one’s actions. According to sociologist Martti Grönfors, the Finnish mentality of the Protestant ethic is accentuated among Finnish policemen. The concept of ethos expresses very well the self-made mentality as an ethical tension which prevails in police work between communal belonging and individual freedom of choice. However, it is significant that it is a matter of the quality of relationships, and that the relationship is always tied to the context of the cultural history of dealing with one’s anxiety. According to criminologist Clifford Shearing, the values of police culture act as subterranean processes of the maintenance of social power in society. Policemen have been called microcosmic mediators, or street corner politicians. Robert Reiner argues that at the level of self-comprehension, policemen disparage the dimension of politics in their work. Reiner points out that all relationships which hold a dimension of power are political. Police culture has also been called a canteen culture. This idea expresses the day-to-day basis of the mentality of taking care of business which policing produces as a necessity for dealing with everyday hardships. According to police researcher Timo Korander, this figurative expression embodies the nature of police culture as a crew culture which is partly hidden from police chiefs who are at a different level. This multitude of standpoints depicts the diversity of police cultures. According to Reiner, one should not see police culture as one monolithic whole; instead one should assess it as the interplay of individuals negotiating with their environment and societal power networks. The cases analyzed formed different plateaus of study. The first plateau was the so-called ‘Rovaniemi arson’ case in the summer of 1930. The second plateau consisted of the examinations of alleged police assaults towards the Communists during the Finnish Continuation War of 1941 to 1944 and the threats that societal change after the war posed to Finnish Society. The third plateau was thematic. Here I investigated how using force towards police clients has changed culturally from the 1930s to the 1980s. The fourth plateau concerned with the material produced by the Security Police detectives traced the interaction between Soviet KGB agents and Finnish politicians during the long 1970s. The fifth plateau of larger changes in Finnish police culture then occurred during the 1980s as an aftermath of the former decade. The last, sixth plateau of changing relationships between policing and the national logic of action can be seen in the murder of two policemen in the autumn of 1997. My study shows that police culture has transformed from a “stone cold” steely fixed identity towards a more relational identity that tries to solve problems by negotiating with clients instead of using excessive force. However, in this process of change there is a traceable paradox in Finnish policing and police culture. On the one hand, policemen have, at the practical level, constructed their policing identity by protecting their inner self in their organizational role at work against the projections of anger and fear in society. On the other hand, however, they have had to safeguard themselves at the emotional level against the predominance of this same organizational role. Because of this dilemma they must simultaneously construct both a distance from their own role as police officers and the role of the police itself. This makes the task of policing susceptible to the political pressures of society. In an era of globalization, and after the heyday of the welfare state, this can produce heightened challenges for Finnish police culture.

Sekä että : Ironia koherenssina ja inkoherenssina

The interpretation of irony in this study is seen as being crucially dependent on the notion of coherence. Coherence depends on a complex interplay of contextual features, which is why all interpretations must be seen as socio-cultural processes. An utterance is perceived as coherent if it makes sense and if it hangs together. Incoherent utterances can result in an ironic interpretation; however, the incoherence must also be perceived as being intentional, and intentionality in turn is a sign of the ironist's rejecting stance. The study does not encompass the notion of irony of fate nor situational irony that is unintentional. Irony is defined in this study as a combination of five components. It is seen as (1) a negative attitude that reflects (2) the intention of the ironist, and (3) has a target and most often (4) a victim too. Essential to irony is its fifth component, the fact that one or more of these four components must be inferred from co- or context. The componential definition of irony is crucial in deciding whether an interpretation is ironic or not, and the definition makes it possible to discern the differences as well as the similarities between different kinds of irony. The method of the study is experimental: 12 Finnish newspaper texts that could be considered to be ironic were interpreted by 107 informants. The interpretation of one of the texts was based on unelicited feedback given by readers of a weekly magazine. The responses were analyzed to determine (a) whether the texts were perceived as being coherent or incoherent and (b) whether the informants appealed to any of the five components of irony. The results of the analyses of the informants' responses indicate that differences between the ironic and non-ironic interpretations of the texts can be explained in terms of whether or not the informant regarded the text as being coherent. The thesis also discusses the shortcomings of other accounts of irony: the Gricean theory of conversational implicature, speech act theory, irony as rhetoric, irony as pretense, irony as echoic mention, and irony as framing. In contrast to these other accounts, the study focuses on irony as a textual phenomenon and underlines the importance of socio-cultural context in the interpretation of irony. Key words: irony, coherence, incoherence, the componential definition of irony, interpretation of linguistic utterances.

Konstruktioiden dynamiikkaa

Dynamic constructions Dynamic constructions is a study of the dynamism of Finnish grammar. Dynamism as a linguistic phenomenon is studied on both the diachronic and synchronic level. The study therefore focuses not only on the temporal changes of grammar but also on the conventionality of grammatical structures and on the interplay between closely related constructions. Dynamism is also treated as a phenomenon occurring between different varieties of Finnish. All in all, dynamism is shown to be a key feature of the nature of grammar. The study is set within the framework of cognitive linguistics and construction grammar. Both theories emphasise the role of constructions pairings of form with semantic or discourse function in the composition and development of grammar. The grammar of a language is understood to be a structured inventory of such constructions. I argue that the constructions are best studied in their original contexts of use. Thus, the study is usage-based in a strict sense. The data is compiled from various corpora consisting of both written and spoken as well as standard and non-standard Finnish. The dissertation consists of an introduction and four empirical studies. The four papers examine various Finnish constructions and thereby shed light on different aspects of the dynamism of a grammar. The first paper focuses on the diachronic development of the Finnish temporal converb essa. The second paper discusses a specific construction which includes the essa converb, that is, the mikäs on ollessa construction. Some closely related constructions and their semantic interplay are also examined. The third paper extensively studies what is generally regarded as an ellipsis of the negation verb in Finnish. By using present day Finnish data, I show that the omission of the negation verb is not an instance of mere ellipsis but rather a construction. The final paper combines the themes of the second and the third paper by focusing on closely related constructions of the negative ellipsis construction.

Kuvan ja tekstin välissä : Kuvateksti uutiskuvan ja lehtijutun elementtinä

The study focuses on picture captions: their grammar and interplay with photographs and their position as semi-independent elements of the news stories. The research was conducted in the framework of critical discourse analysis, social semiotic visual theory and fennistic syntactical research. The data consist of 441 press photographs, 1,815 captions and a number of news items from Finnish dailies. The generic structure potential of the caption includes the caption headline, the caption proper, i.e. the verbalization of the picture content, and the frame. In the data, 41 per cent of the captions have a headline, and 44 per cent contain a caption proper. Characteristic of the caption proper is omission of the finite verb and the use of the present tense, both of which have decreased in Finnish papers during the 20th century. The caption proper is typically a main clause, and both subordinate clauses and participal phrases occur mostly in the frame. While comparing caption variants attached to the same pictures, the processes and their participants proved to be identified considerably identically, following the news agency captions. Instead, the reader?s interpretations of a picture could be directed by framing it in different ways. For example, the caption may focus on the only person depicted, deal with a whole group, or give an abstract account of the situation. The caption is a paratext, a typographically marked, semi-independent element of a news story. Between the headline and the caption, four semantic relations have been identified. The caption may be a paraphrase of the headline, or a close-up illustrating an abstract headline with a concrete example. If the name of the person depicted is their only common factor, the relation between the caption and the headline is additive. A specifying caption will give more details than the headline. The caption may complete, repeat, or summarize the body copy. Naturally, most captions completing the story verbalize the content of the picture. As the caption is often based on the story, it may even repeat the body copy verbatim. The summarizing function is probably becoming increasingly important, as most Finnish newspapers have abandoned the use of a separate standfirst.

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.

On the environmental genetics of depressive symptoms : Focus on two serotonergic genes

Depression is a complex psychiatric disorder influenced by several genes, environmental factors, and their interplay. Serotonin receptor 2A (HTR2A) and tryptophan hydroxylase 1 (TPH1) genes have been implicated in vulnerability to depression and other psychiatric disorders, but the results have been inconsistent. The present study examined whether these two genes moderated the influence of different depressogenic environmental factors on subthreshold depressive symptoms (assessed on a modified version of Beck s Depression Inventory, BDI) and depression-related temperament, i.e., harm avoidance (assessed on the Temperament and Character Inventory, TCI). The environmental factors included measures of childhood and adolescence exposure, i.e., maternal nurturance and parental socioeconomic status, and adulthood social circumstances, i.e., perceived social support and urban/rural residence. The participants were two randomly selected subsamples (n = 1246, n = 341) from the longitudinal population-based Cardiovascular Risk in Young Finns study (n = 3596). Childhood environmental factors were assessed when the participants were 3 to 18 years of age, and three years after the baseline. Adulthood environmental factors and outcome measures were assessed 17 and 21 years later when the participants were 21 to 39 years of age. The T102C polymorphism of the HTR2A gene moderated the association between childhood maternal nurturance and adulthood depressive symptoms, such that exposure to high maternal nurturance predicted low depressive symptoms among individuals carrying the T/T or T/C genotypes, but not among those carrying the C/C genotype. Likewise, high parental SES predicted low adulthood harm avoidance in individuals carrying the T/T or T/C genotype, but not in C/C-genotype carriers. Individuals carrying the T/T or T/C genotype were also sensitive to urban/rural residence, such that they had lower depressive symptoms in urban than in rural areas, whereas those carrying the C/C genotype were not sensitive to urban/rural residence difference. HTR2A did not moderate the influence of social support. TheA779C/A218C haplotype of the TPH1 gene was not involved in the association between childhood environment and adulthood outcomes. However, individuals carrying A alleles of the TPH1 haplotype were more vulnerable to the lack of adulthood social support in terms of high depressive symptoms than their counterparts carrying no A alleles. Furthermore, individuals living in remote rural areas and carrying the A/A haplotype had higher depressive symptoms than those carrying other genotypes of the TPH1. The findings suggest that the HTR2A and TPH1 genes may be involved in the development of depression by influencing individual s sensitivity to depressogenic environmental influences.

How to design educational settings to promote collaborative inquiry: Pedagogical infrastructures for technology-enhanced progressive inquiry

Strategies of scientific, question-driven inquiry are stated to be important cultural practices that should be educated in schools and universities. The present study focuses on investigating multiple efforts to implement a model of Progressive Inquiry and related Web-based tools in primary, secondary and university level education, to develop guidelines for educators in promoting students collaborative inquiry practices with technology. The research consists of four studies. In Study I, the aims were to investigate how a human tutor contributed to the university students collaborative inquiry process through virtual forums, and how the influence of the tutoring activities is demonstrated in the students inquiry discourse. Study II examined an effort to implement technology-enhanced progressive inquiry as a distance working project in a middle school context. Study III examined multiple teachers' methods of organizing progressive inquiry projects in primary and secondary classrooms through a generic analysis framework. In Study IV, a design-based research effort consisting of four consecutive university courses, applying progressive inquiry pedagogy, was retrospectively re-analyzed in order to develop the generic design framework. The results indicate that appropriate teacher support for students collaborative inquiry efforts appears to include interplay between spontaneity and structure. Careful consideration should be given to content mastery, critical working strategies or essential knowledge practices that the inquiry approach is intended to promote. In particular, those elements in students activities should be structured and directed, which are central to the aim of Progressive Inquiry, but which the students do not recognize or demonstrate spontaneously, and which are usually not taken into account in existing pedagogical methods or educational conventions. Such elements are, e.g., productive co-construction activities; sustained engagement in improving produced ideas and explanations; critical reflection of the adopted inquiry practices, and sophisticated use of modern technology for knowledge work. Concerning the scaling-up of inquiry pedagogy, it was concluded that one individual teacher can also apply the principles of Progressive Inquiry in his or her own teaching in many innovative ways, even under various institutional constraints. The developed Pedagogical Infrastructure Framework enabled recognizing and examining some central features and their interplay in the designs of examined inquiry units. The framework may help to recognize and critically evaluate the invisible learning-cultural conventions in various educational settings and can mediate discussions about how to overcome or change them.

Noviisiopettajana peruskoulussa : Aloittelevien opettajien autenttisia kokemuksia ensimmäisestä opettajavuodesta

As a Novice Teacher at Comprehensive School: The authentic experiences of the beginning teachers during their first year of teaching The aim of this study is to explicate the novice year of teaching in the light of teachers´ authentic experiences. The subject of this investigation is the teachers´ subjective world of experience during their first academic year of teaching and the sharing of these experiences in collaborative consulting meetings. The themes discussed in the meetings were introduced into the collaborative group by the novice teachers themselves, and the progress of discussion was con-trolled by them. The research data was gathered in a consultative working group where the way a novice teacher starts to interpret, analyze and identify his/her own complex and dynamic teaching situations was observed. The research data gathered in this way illuminates novice teachers´ world of experience and mental picture as well as the unconscious sides of school life. In a theoretical frame of reference, the work of a teacher is identified, according to systemic scientific thought, as a dynamic triangle in which the basic elements are the personality of the teacher, the role of the teacher and the school as an organization. These basic elements form a whole within which the teacher works. The dynamics of this triangle in a teacher’s work are brought to light through the study of the phenomena of groups and group dynamics since a teacher works either as a member of a group (working community), as a leader of a group (teaching situations) or in a network (parent – teacher cooperation). Therefore, tension and force are always present in teaching work. The main research problem was to explain how a novice teacher experiences his/her first working year as a teacher. The participants (n=5) were teaching at five different comprehensive schools in the city of Helsinki. This was their first long-term post as a teacher. The research data consists of seven collaborative consulting meetings, as well as recordings and transcripts of the meetings. A classificatory framework was developed for data analysis which enabled a sys-tematic qualitative content analysis based on theory and material. In addition to the consulting meetings, the teachers were interviewed at the beginning and at the end of the process of collecting the research material. The interviews were used to interpret the meanings of the content analysis based on raw data. The findings show that there is a gap between teacher education and the reality of school life, which causes difficulties for a novice teacher during his/her first teaching year. The gap is rather a global educational problem than a national one, and therefore it is independent of cultural factors. Novice teachers desire a well-structured theory of teacher education and a clear programme where the themes and content delve deeper and deeper into the subject matter during the study years. According to the novice teachers, teacher education frequently consists of sporadic and unconnected study and class situations. An individual content weakness of teacher education is the lack of insufficient initiation into evaluation processes. The novice teachers suggest that a student must be provided good-quality and competent guidance during the study years and during his or her induction. There should be a well-organized, structured and systematic induction program for novice teachers. The induction program should be overseen by an organization so that the requirements of a qualified induction can be met. The findings show that the novice teachers find the first year of teaching at comprehensive school emotionally loaded. The teachers experienced teaching as difficult work and found the workload heavy. Nevertheless, they enjoyed their job because, as they said, there were more pleasant than unpleasant things in their school day. Their main feeling at school was the joy of success in teaching. The novice teachers felt satisfaction with their pupils. The teachers experienced the more serious feelings of anger and disgust when serious violence took place. The most difficult situations arose from teaching pupils who had mental health problems. The toughest thing in the teacher´s work was teaching groups that are too heterogeneous. The most awkward problems in group dynamics happened when new immigrants, who spoke only their own languages, were integrated into the groups in the middle of the school year. Teachers wanted to help children who needed special help with learning but restated at the same time that the groups being taught shouldn’t be too heterogeneous. The teachers wished for help from school assistants so that they could personally concentrate more on teaching. Not all the parents took care of their children according to the comprehensive school law. The teachers found it hard to build a confidential relationship between home and school. In this study, novice teachers found it hard to join the teaching staff at school. Some of the teachers on staff were very strong and impulsive, reacting loudly and emotionally. These teachers provoked disagreement, conflicts, power struggles and competition among the other teachers. Although the novice teachers of the study were all qualified teachers, three of them were not interested in a permanent teaching job. For these teachers teaching at a primary school was just a project, a short period in their working life. They will remain in the teaching profession as long as they are learning new things and enjoying their teaching job. This study is an independent part of the research project on Interplay – Connecting Academic Teacher Education and Work, undertaken by the Department of Applied Sciences of Education at the University of Helsinki. Key words: novice teacher, emotions, groups and group dynamics, authority, co-operation between home and school, teacher community, leadership at school, induction, consulting

Teacher Education, School Effectiveness and Improvement : A Study of Academic and Professional Qualification on Teachers' Job Effectiveness in Nigerian Secondary Schools

This academic work begins with a compact presentation of the general background to the study, which also includes an autobiography for the interest in this research. The presentation provides readers who know little of the topic of this research and of the structure of the educational system as well as of the value given to education in Nigeria. It further concentrates on the dynamic interplay of the effect of academic and professional qualification and teachers' job effectiveness in secondary schools in Nigeria in particular, and in Africa in general. The aim of this study is to produce a systematic analysis and rich theoretical and empirical description of teachers' teaching competencies. The theoretical part comprises a comprehensive literature review that focuses on research conducted in the areas of academic and professional qualification and teachers' job effectiveness, teaching competencies, and the role of teacher education with particular emphasis on school effectiveness and improvement. This research benefits greatly from the functionalist conception of education, which is built upon two emphases: the application of the scientific method to the objective social world, and the use of an analogy between the individual 'organism' and 'society'. To this end, it offers us an opportunity to define terms systematically and to view problems as always being interrelated with other components of society. The empirical part involves describing and interpreting what educational objectives can be achieved with the help of teachers' teaching competencies in close connection to educational planning, teacher training and development, and achieving them without waste. The data used in this study were collected between 2002 and 2003 from teachers, principals, supervisors of education from the Ministry of Education and Post Primary Schools Board in the Rivers State of Nigeria (N=300). The data were collected from interviews, documents, observation, and questionnaires and were analyzed using both qualitative and quantitative methods to strengthen the validity of the findings. The data collected were analyzed to answer the specific research questions and hypotheses posited in this study. The data analysis involved the use of multiple statistical procedures: Percentages Mean Point Value, T-test of Significance, One-Way Analysis of Variance (ANOVA), and Cross Tabulation. The results obtained from the data analysis show that teachers require professional knowledge and professional teaching skills, as well as a broad base of general knowledge (e.g., morality, service, cultural capital, institutional survey). Above all, in order to carry out instructional processes effectively, teachers should be both academically and professionally trained. This study revealed that teachers are not however expected to have an extraordinary memory, but rather looked upon as persons capable of thinking in the right direction. This study may provide a solution to the problem of teacher education and school effectiveness in Nigeria. For this reason, I offer this treatise to anyone seriously committed in improving schools in developing countries in general and in Nigeria in particular to improve the lives of all its citizens. In particular, I write this to encourage educational planners, education policy makers, curriculum developers, principals, teachers, and students of education interested in empirical information and methods to conceptualize the issue this study has raised and to provide them with useful suggestions to help them improve secondary schooling in Nigeria. Though, multiple audiences exist for any text. For this reason, I trust that the academic community will find this piece of work a useful addition to the existing literature on school effectiveness and school improvement. Through integrating concepts from a number of disciplines, I aim to describe as holistic a representation as space could allow of the components of school effectiveness and quality improvement. A new perspective on teachers' professional competencies, which not only take into consideration the unique characteristics of the variables used in this study, but also recommend their environmental and cultural derivation. In addition, researchers should focus their attention on the ways in which both professional and non-professional teachers construct and apply their methodological competencies, such as their grouping procedures and behaviors to the schooling of students. Keywords: Professional Training, Academic Training, Professionally Qualified, Academically Qualified, Professional Qualification, Academic Qualification, Job Effectiveness, Job Efficiency, Educational Planning, Teacher Training and Development, Nigeria.