Tesis sobre el tema "Interindividual difference"

The thiopurines, 6-mercaptopurine and its prodrug azathioprine, are used in the treatment of inflammatory bowel disease, ulcerative colitis and Crohn´s disease. The main active metabolites are the phosphorylated thioguanine nucleotides (6-TGNs) and methylated thioinosine monophosphate (meTIMP). Both groups contribute to the immunomodulatory effects. About 30-40% of patients fail to benefit from thiopurine treatment. A well-known cause of adverse reactions is decreased or absent thiopurine S-methyltransferase (TPMT) activity. Low TPMT activity is inherited as an autosomal codominant recessive trait and is present in approximately 10% of the population. Although several clinical issues can be solved from determination of TPMT activity, there are cases where it is not possible. In Sweden approximately 25% of IBD-patients display suboptimal 6-TGN concentrations and unexpectedly high concentrations of meTIMP despite a normal TPMT activity. A high meTIMP/6-TGN concentration ratio has been associated with both unresponsiveness to therapy and emergence of adverse reactions. Inosine 5’-monophosphate dehydrogenase (IMPDH) may constitute a candidate gene to explain this metabolite profile, as it is strategically positioned in the metabolic pathway of thiopurines where it competes with TPMT for their common substrate 6-TIMP. In paper I a pyrosequencing method was developed for genotyping of at that time all known genetic variants of TPMT. The concordance between genotype and phenotype in 30 individuals was 93%. The allele frequencies of TPMT*3A, *3B, *3C and *2 in a Swedish background population (n=800) were in agreement with those in other Caucasian or European populations. In Paper II-IV we explored the molecular basis of different metabolite profiles, i.e. low, normal and high meTIMP/6-TGN concentration ratios. The activity of IMPDH was measured in mononuclear cells (MNC). Patients with high metabolite ratios had lower IMPDH activity than patients with normal or low ratios, explained by an inverse correlation to red blood cells concentration of meTIMP. No correlation to 6-TGN was observed. Downregulation of IMPDH activity in HEK293 cells with genetically engineered TPMT activity was associated with an increase in meTIMP, but unexpectedly also of 6-TGN, irrespective of the TPMT status. These results suggest effects of pharmacogenes other than TPMT and IMPDH. A whole genome expression analysis was performed, (1) to identify new candidate genes that could explain differences in metabolite profiles, and (2) to study genes with known associations to the metabolic pathway of (thio)purines. The whole genome expression analysis did not identify any significant group differences. In analysis of the thiopurine related genes, three clusters of co-regulated genes were defined. A co-operation between expression levels of SLC29A1 and NT5E in explaining the meTIMP/6-TGN concentration ratio was observed, and individually SLC29A1 and NT5E correlated to 6-TGN and meTIMP, respectively. Pysosequencing is a convenient and flexible method which is now run in parallel to phenotyping in our laboratory. Our results also illustrate the complexity of the thiopurine metabolism and suggest that differences between metabolite profiles are explained either by interactions between several genes, each with a small contribution, or at the post-transcriptional level. Search for more precise tools to explain differences in metabolite profiles is needed. Furthermore, in order to investigate small effects it is necessary to analyse metabolite concentrations and gene expression levels, as well as enzyme activities in the target cells of therapy (MNC).

A number of studies have concluded that cognitive control is not fully established until late adolescence. The precise differences in brain function between adults and adolescents with respect to cognitive control, however, remain unclear. To address this issue, we conducted a study in which 185 adolescents (mean age (SD) 14.6 (0.3) years) and 28 adults (mean age (SD) 25.2 (6.3) years) performed a single task that included both a stimulus-response (S-R) interference component and a task-switching component. Behavioural responses (i.e. reaction time, RT; error rate, ER) and brain activity during correct, error and post-error trials, detected by functional magnetic resonance imaging (fMRI), were measured. Behaviourally, RT and ER were significantly higher in incongruent than in congruent trials and in switch than in repeat trials. The two groups did not differ in RT during correct trials, but adolescents had a significantly higher ER than adults. In line with similar RTs, brain responses during correct trials did not differ between groups, indicating that adolescents and adults engage the same cognitive control network to successfully overcome S-R interference or task switches. Interestingly, adolescents with stronger brain activation in the bilateral insulae during error trials and in fronto-parietal regions of the cognitive control network during post-error trials did have lower ERs. This indicates that those mid-adolescents who commit fewer errors are better at monitoring their performance, and after detecting errors are more capable of flexibly allocating further cognitive control resources. Although we did not detect a convincing neural correlate of the observed behavioural differences between adolescents and adults, the revealed interindividual differences in adolescents might at least in part be due to brain development.

Ovarian cancer is one of the most common female cancer diseases in the world today and in Sweden more than 800 new cases are diagnosed every year. The standard treatment consists of chemotherapy with paclitaxel in combination with carboplatin after initial cytoreductive surgery. The response to treatment and the severity of adverse drug reactions after chemotherapy varies greatly among individuals, and one of the most important factors responsible for these differences is now recognized to be the genetic variability. One of the major obstacles to successful treatment is drug resistance. Several potential mechanisms have been suggested for the resistance to paclitaxel, such as mutations in the target protein β-tubulin, single nucleotide polymorphisms (SNPs) in the gene ABCB1, which encodes the transport protein P-glycoprotein. P-glycoprotein can mediate efflux of various drugs from cancer cells as well as from the circulation into the intestinal lumen, and overexpression and/or high activity leads to drug resistance and/or increased elimination. Another reason might be the high interindividual variability of paclitaxel plasma concentrations, which has been suggested to be influenced by variability in metabolic enzymes, such as CYP2C8 and CYP3A4, and transport proteins e.g. P-glycoprotein. In the studies constituting this thesis we have investigated the possibilities of predicting the pharmacokinetics of paclitaxel as well as the tumor response and adverse drug reactions after chemotherapy in the preparation of personalized chemotherapy. We studied the correlation between the response and the presence of mutations in the dominant β-tubulin gene and SNPs in ABCB1. DNA from 40 ovarian tumors was screened for sequence variations in the β-tubulin gene without finding any, showing that β-tubulin mutations are rare and unlikely to be a clinically relevant resistance mechanism for paclitaxel. The SNPs G2677T/A and C3435T in the ABCB1 gene were determined in 53 ovarian cancer tumors from patients with poor (progressive disease or relapse within one year) or good (disease-free survival of more than one year) response to paclitaxel-carboplatin chemotherapy. Patients homozygously mutated for G2677T/A had a higher probability of responding to chemotherapy. There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment. No correlation was found for the C3435T variant. By using a newly developed quantitative LC/MS method for the simultaneous determination of paclitaxel and its hydroxymetabolites in human plasma we assessed the individual elimination of paclitaxel in 33 ovarian cancer patients. The patients were genotyped for SNPs in the ABCB1, CYP2C8 and CYP3A4 genes and their in vivo CYP3A4 enzyme activity, tumor response and toxicity, especially the neurotoxicity, were determined. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than patients with the wild type or homozygously mutated, but not compared to patients carrying the G/T alleles. A lower clearance of paclitaxel was also found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. The CYP3A4 enzyme activity in vivo affected the relative influence of CYP2C8 and CYP3A4 on the metabolism, but not the total clearance of paclitaxel. The exposure to paclitaxel was correlated to the neurotoxicity, but not to the treatment response. In conclusion, our findings suggest that the SNP G2677T/A in the ABCB1 gene, but not β-tubulin mutations, might be a predictor for paclitaxel response and that the interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy.
Ovarialcancer (äggstockscancer) är en av de vanligaste cancerformerna hos kvinnor i Sverige idag. Behandlingen består vanligen av tumörreducerande kirurgi följd av kemoterapi med paklitaxel och karboplatin. Målsättningen med detta avhandlingsarbete har varit att förbättra cytostatikabehandlingen (cellgiftsbehandlingen) med framförallt paklitaxel vid ovarialcancer genom att lägga grunden för individualisering av doser och förutsäga tumörsvaret vid behandlingen. Ett problem med dagens cancerbehandling är att många cancerceller så småningom blir resistenta mot olika cytostatika. För att angripa den mest resistenta cellen innan den induceras att öka uttrycket av, eller utveckla, fler resistensmekanismer vore det en fördel om vi före behandlingen kunde prediktera vilken dos av cytostatika som är bäst lämpad för individen samt om tumören kommer att reagera på behandlingen eller ej. En av de viktigaste faktorerna för skillnader i behandlingseffekt tros vara genetiska variationer mellan olika individer. I våra studier har vi använt genetiska metoder för att studera om vi kan prediktera tumörsvaret vid behandlingen genom att bestämma mutationer i genen för paklitaxels målprotein, β-tubulin, samt bestämma genetiska variationer i ABCB1-genen, kodande för transportproteinet P-glykoprotein. Tanken är att ett förändrat målprotein eller en förändrad förmåga hos cancercellerna eller kroppen att transportera ut paklitaxel skulle leda till en skillnad i påverkan på tumören. DNA från 40 ovarialtumörer analyserades utan att en enda sekvensvariation hittades i genen för β-tubulin, vilket tyder på att genetiska förändringar i genen för β-tubulin sannolikt inte är en klinisk relevant resistensmekanism. De normalt förekommande genetiska variationerna G2677T/A och C3435T i ABCB1-genen bestämdes i DNA från 53 ovarialtumörer där behandlingen endera givit en bra (tumörfri minst ett år) eller dålig (progression av tumören eller tumörfri mindre än ett år) anti-tumöreffekt. Patienter som var dubbelmuterade i position 2677 dvs hade endera T/T eller T/A (A/A hittades inte i materialet) i denna position hade en högre sannolikhet att få ett bra anti-tumörsvar vid behandlingen. Även antalet muterade baser påverkade utfallet, ju fler muterade baser i position 2677, desto högre sannolikhet att få ett bra svar på behandlingen. Andelen T eller A var också högre i den grupp av patienter som fått en lyckad behandling. För att kunna prediktera patientens individuella förmåga att bryta ner paklitaxel studerade vi inverkan av sekvensvariationer i generna för de nedbrytande enzymerna, CYP2C8 och CYP3A4, och transportproteinet P-glykoprotein (genen ABCB1) på eliminationen av läkemedlet i kroppen. Vi utvecklade en metod för att mäta paklitaxelkoncentrationerna i blodet och använde den för att studera hur snabbt 33 ovarialcancer patienter eliminerade cytostatikat från blodbanan. Hos dessa patienter bestämde vi förekomsten av kända genetiska variationer i generna ABCB1, CYP2C8 och CYP3A4 samt deras CYP3A4 enzymaktivitet i kroppen. Biverkningarna och tumörsvaret vid behandlingen utvärderades också. Eliminationen av paklitaxel hos dessa patienter var beroende av vilken bas som fanns i position 2677 i ABCB1-genen och förekomsten av den genetiska varianten CYP2C8*3. Enzymaktiviteten hos CYP3A4 kunde inte påvisas påverka eliminationen av paklitaxel utan snarare vilket enzym, CYP2C8 eller CYP3A4, som var relativt dominant i respektive patient. Exponeringen av paklitaxel korrelerade till den neurologiska påverkan som patienten orsakades av cytostatikat, men kunde inte korreleras till tumörsvaret vid slutet av cytostatikabehandlingen. Sammanfattningsvis ger patientens genetiska variationer i ABCB1, men inte β-tubulin, information om behandlingsutfallet. Genetiska variationer i CYP2C8 och ABCB1 påverkar patientens förmåga att eliminera paklitaxel och kan förhoppningsvis användas för att individualisera doserna. Vår förhoppning är att resultaten i denna avhandling skall kunna användas för att individualisera och ytterligare förbättra cytostatikabehandlingen vid ovarialcancer.

In this thesis, we used the American cockroach study the relationship between animal personality and collective behaviour. These questions do not only regard domiciliary cockroaches or insects; in fact, the questions we discuss here have a large scope and concern most of the known gregarious species distributed in several taxa. One of our aims is to develop general tools, methods and analyses that could be used for the study of collective behaviour.We show evidence of personality in several behavioural traits and different contexts in the American cockroach. These behavioural differences were observed in a context without social interactions during the daytime (isolated condition) and nighttime (solitary exploration behaviour) and in a social context (rate of joining a shelter and sheltering time). Based on the short-term experiments, this personality can be understood as differences in the probability of joining a shelter. We show that the behavioural variability existing in a population of domiciliary cockroaches is very high. The composition of personalities within a group can lead to group personality – consistent differences in group behaviour. For instance, groups composed of different behavioural profiles show different collective dynamics. Regarding the long-term experiments, our results show that the individuals that were aggregated at a site that was repeatedly disturbed by a lighting stimulus during their resting period showed slow migration to a new shelter, which allowed the initial aggregation site to remain the site of choice for a few days. Moreover, the disturbance regime did not influence the group's global activity rhythm. At the individual level, we observed interindividual differences (personalities) in terms of their position prior to the disturbance but not for the different steps of the fleeing behaviour itself. In addition, we show that thigmotaxis affects the reaction time to the disturbance: individuals near the walls of the shelter react more slowly thanindividuals in the centre. Finally, an approach coupling modelling and experimental data shows that behavioural variability plays a secondary role during migration dynamics, thus highlighting the plasticity of personality traits depending on the context.
Un des comportements collectifs les plus répandus, qu’il s’agisse de vertébrés (mammifères, oiseaux, poissons), d’insectes ou encore de bactéries, est la tendance des individus à se regrouper. Les causes proximales de ces rassemblements ou agrégats, c'est-à-dire les mécanismes à leur origine, ont retenu moins d’attention que l’étude des causes ultimes. De plus, dans la plupart des études portant sur les processus d’agrégation, notamment chez notre organisme modèle, la blatte, la diversité des comportements individuels est souvent sous-estimée ou ignorée. L’objectif de cette thèse est l’étude du rôle des différences interindividuelles, également connues comme personnalité animale ou syndromes comportementales, dans les processus de prise de décision collective et notamment la formation des agrégats.Pour cela, nous avons utilisé des groupes de mâles de la blatte américaine Periplaneta americana. Ces insectes peuvent s’agréger dans un ou plusieurs abris et présenter des différences dans leur réponse au milieu, aux conspécifiques et dans le partage de l’information. Dans le cadre de prises de décisions collectives, nous avons mis en évidence une personnalité individuelle mais également au niveau du groupe. Celles-ci se manifestent dans la recherche d’un abri dont certains individus jouent un rôle clef. Nous avons montré que les groupes présentent une stabilité qui est observable au niveau de la dynamique d'agrégation et qui dépend de la distribution des personnalités au sein de ceux-ci. De plus, nous remarquons que ces différences de personnalités au sein des groupes affectent la prise de décision collective, notamment la vitesse du choix et le nombre total d’individus abrités. De manière surprenante, la composition des groupes n’affecte pas la probabilité que ceux-ci atteignent un consensus: la majorité des blattes étant agrégées sous le même abri.Concernant les influences croisées entre l’effet sociale et la personnalité des blattes, nous montrons que les effets sociaux tendent à supprimer les différences inter-individuelles et créent une corrélation entre le comportement de chaque individu et le comportement du groupe. De plus, nous observons que la présence de différentes personnalités dans un groupe augmente les amplifications sociales, celles-ci étant dues aux interactions entre les membres du groupe. Finalement, nous abordons la question du rôle de la personnalité sur le comportement de fuite lors des perturbations lumineuses et sur la dynamique d’émigration quand le site de repos est régulièrement perturbé. Nous avons montré l’existence de personnalités exprimées pendant la phase active nocturne et de différences interindividuelles au niveau du thigmotactisme pendant la journée (phase passive de repos et d’agrégation). Curieusement, ces différences inter-individuelles ne sont pas observées lors du comportement de fuite et au niveau de la dynamique global d’émigration. Dans la dernière partie de notre thèse, nous discutons, en particulier, des synergies et des conflits entre les différentes personnalités et les dynamiques collectives et avançons l’hypothèse que les phénomènes que nous avons mis en évidence sont partagés par de nombreuses espèces grégaires.
Doctorat en Sciences
info:eu-repo/semantics/nonPublished

Personen unterscheiden sich in dem, wie sie sich im Allgemeinen fühlen. Das Ziel dieser Dissertation ist es, die Prozesse, die diesen Personenunterschieden zugrunde liegen, zu verstehen. Es wurden insbesondere die affektiven Prozesse affektive Reaktivität und Emotionsregulation untersucht. In drei Studien wurden die folgenden Forschungsfragen untersucht: (1) Haben Personen mit höherem subjektiven Wohlbefinden einen stärkeren Anstieg in positivem Affekt, wenn sie auf positive Stimuli im Labor reagieren oder ihre positiven Emotionen hochregulieren? (2) Welches sind die neuronalen Korrelate, die diesen kurzfristigen Veränderungen in positivem Affekt zugrunde liegen, insbesondere während der Hochregulation positiver Emotionen? (3) Hängt ein höheres subjektives Wohlbefinden mit einer stärkeren oder geringeren Reaktion auf positive Ereignisse im Alltag zusammen? Die Befunde haben gezeigt, dass ein stärkerer Anstieg in positivem Affekt (durch eine stärkere Reaktion auf positive Ereignisse oder durch das Hochregulieren positiver Emotionen) nicht mit einem höheren subjektiven Wohlbefinden zusammenhängt. Stattdessen hatten Personen mit einem höheren subjektiven Wohlbefinden eine geringere Reaktivität auf positive Ereignisse im Alltag. Auf der neuronalen Ebene spiegelten sich die Veränderungen in positivem Affekt durch eine verstärkte neuronale Aktivierung in emotionsbezogenen Regionen (insbesondere des ventralen Striatums) wieder, sowie durch eine Deaktivierung in einem fronto-parietalen Kontrollnetzwerk. Ein Zusammenhang von neuronaler Aktivierung und Veränderungen in positivem Affekt im Alltag wurde nicht gefunden. Die Arbeit dieser Dissertation zeigt, dass nicht besonders intensives positives Erleben, sondern eher weniger Schwankungen in momentanen positiven Affekt wichtig für das Wohlbefinden sind. Darüber hinaus zeigt diese Dissertation die Wichtigkeit auf verschiedene Analyseebenen und Untersuchungsmethoden in die Erforschung von affektivem Erleben zu integrieren.
This dissertation investigates the affective processes – affective reactivity and emotion regulation – underlying short-term changes in positive affective experiences and their relation to interindividual differences in subjective well-being. The main research objectives that were addressed in the empirical studies of this dissertation concerned (1) whether stronger increases in positive affect when reacting to and when up-regulating in response to positive stimuli in the laboratory relate to higher subjective well-being, (2) which brain regions underlie changes in positive affective experiences, particularly during the up-regulation of positive emotions, and (3) whether enhanced or reduced affective reactivity to positive events in daily life relates to higher subjective well-being. Findings showed that greater increases in positive affect were not related to higher subjective well-being, both when investigated in the laboratory and in daily life. Instead, people with higher levels of subjective well-being showed reduced affective reactions to positive events in daily life, pointing to the importance of a relative greater emotional stability. At the neural level, changes in positive affective experiences were mirrored by increased activations in emotion-related (e.g., ventral striatum) regions as well as deactivation in a fronto-parietal control network. These neural activations were not related to changes in positive affective experiences in daily life. The work in this dissertation indicates that not the experience of particularly intense positive affective states, but rather less fluctuation in momentary positive affective experiences seems to be essential to the overall composition of subjective well-being. The present dissertation further emphasizes the need to integrate different methods in the study of emotion. Concluding, this dissertation advances our understanding of the processes underlying subjective well-being.

Abstract Risk assessment of chemicals needs reliable scientific information and one source of information is the characterization of the metabolic fate and toxicokinetics of a chemical. Metabolism is often the most important factor contributing to toxicokinetics. Cytochrome P450 (CYP) enzymes are a superfamily of microsomal proteins playing a pivotal role in xenobiotic metabolism. In the present study, pesticides were used as representative xenobiotics since exposure to pesticides is a global challenge to risk assessment. Human and animal in vitro hepatic models were applied with the advantage of novel analytical techniques (LC/TOF-MS and LC/MS-MS) to elucidate the in vitro metabolism and interaction of selected pesticides. The results of these studies demonstrate that CYP enzymes catalyze the bioactivation of profenofos, diuron and carbosulfan into their more toxic metabolites desthiopropylprofenofos, N-demethyldiuron and carbofuran, respectively. The suspected carcinogenic metabolite of metalaxyl, 2,6-dimethylaniline, was not detected. CYP3A4 and CYP2C19 activities may be important in determining the toxicity arising from exposure to profenofos and carbosulfan. Individuals with high CYP1A2 and CYP2C19 activities might be more susceptible to diuron toxicity. Qualitative results of in vitro metabolism were generally in agreement with the results obtained from the published in vivo data, at least for the active chemical moiety and major metabolites. Considerable differences in the quantities of the metabolites produced within the species, as well as in the ratios of the metabolites among the species, were observed. These findings illustrate that in vitro screening of qualitative and quantitative differences are needed to provide a firm basis for interspecies and in vitro-in vivo extrapolations. Based on our findings, in vitro-in vivo extrapolation based on the elucidation of the in vitro metabolic pattern of pesticides in human and animal hepatic models could be a good model for understanding and extending the results of pesticides metabolism studies to human health risk assessment.

La présente thèse se compose de trois études en lien avec le développement du langage chez les enfants sourds profonds porteurs d'un implant cochléaire. La première étude a pu mettre en lumière le développement des échanges conversationnels chez un groupe de 28 enfants implantés sur une période de deux ans suivant l'implantation. La tendancerelevée est un développement des habilités conversationnelles vers un profil plus autonome et actif ; en particulier, nous notons que les enfants implantés ne se distinguent plus significativement des enfants entendants du même âge en ce qui concerne les initiatives deux ans après l'implantation. La deuxième étude se proposait, quant à elle, d'explorer la question des différences interindividuelles. C'est chez un groupe de 21 enfants sourds profonds, implantés depuis en moyenne 6 ans 1 mois, que l'origine des différences interindividuelles au niveau du lexique (réception et production) a été mise enquestion. Il ressort que les facteurs " âge à l'implantation " et " timidité de l'enfant " jouent un rôle dans ces différences : une implantation précoce et un faible niveau de timidité chez l'enfant apparaissent en effet favoriser le développement dulexique. Enfin, la troisième étude s'intéressait à l'ajustement mutuel, variable fondamentale lorsqu'on s'intéresse au développement du langage dans une perspective socio‐constructiviste. Il s'agissait, à l'aide d'une méthodologie originale inspirée de la théorie des systèmes dynamiques, d'analyser l'évolution de l'ajustement mutuel chez 23 dyades enfantimplanté/mère entendante au cours d'un suivi longitudinal de deux années. Nos résultats confirment l'influence positive de l'implant cochléaire dans la mise en place d'échanges harmonieux entre les enfants implantés et leur mère, traduisantl'acquisition d'habilités conversationnelles importantes pour le développement ultérieur de la langue de l'enfant

This thesis aims to bridge between the theoretical concept of motor intelligence and its practice. Particularly, I seek to affront the problematic regarding to its quantification. As any transition between theory and practice, the theoretical framework must first be established. When it comes to Motor Intelligence specifically, though the theoretical groundwork had existed for a long time, the practicality of which had remained behind. This thesis begins by first examining the reasons for the discrepancy between theory and practice for motor intelligence, continuing by a proposal for a practical approach based on the successful implementation of the concepts of intelligence (Chapter 1). The approach presented here is made on two fronts; the first front consists of the identification of suitable tasks for quantification of various aspects of motor control (Chapters 2-4). Specifically, Chapter 2 examines the potential of drawing and tracing tasks as tools for assessment of fine motor control, tested on a large number of subjects with specific attention to individual differences and the implications of these tasks to motor control. The results evidence that there is no correlation in terms of precision between the two tasks and that this lack of correlation is task dependent and not shape dependent. This allows for a classification of subjects, based on their level of tasks precision, as either drawers or tracers. Results obtained from the study suggest that for an accurate evaluation of fine motor control, both tasks should be used integrating their results. Chapter 3, extends the findings in Chapter 2 to elementary children, investigating the development of components of fine motor control using a tracing and a drawing task. The study demonstrates that, while tracing capacity improves greatly with age, drawing capacity improves only slightly. This trend may be due to possible involvement of attention as well as maturation patterns of the nervous system. The tasks, by being simple, economic and rapid, may represent a good instrument for motor control quantification during development, especially for population screening of eventual delays in maturation of motor control. Chapter 4, assesses the sensitivity of a tracing task following specific interventions, examining how the manipulation of objects, specifically fidget spinner, may influence fine motor control using a spiral tracing task. Results suggest that while fidget spinners do improve precision in tracing, it does not appear to be due to any inherent characteristic of the spinners themselves, as Sham group also demonstrated improvements. The second front consists of the creation of instruments and methodological approaches that could be used for quantification (Chapters 5-7). Chapter 5 introduces a novel quantification method for 3D analysis of movement using a single camera, with a specific attention to the widespread implementation of movement analysis. Chapter 6, introduces a novel approach for the quantification of motor adaptation, using a simple continuous task which seeks to facilitate testing, and consequently used also in clinical settings. The adequacy of the task was evaluated by examining for aftereffects and generalizations (considered as indicators for motor adaptation). Results affirm the suitability of the task for examining adaptation, specifically, long-lasting after effects and generalization both for size and shift were found. Chapter 7 introduces a novel quantification approach during motor learning which is aimed to evidence individual differences in strategy selection during learning. This execution-centric approach is able to predict behavior during learning, regardless of outcome. Finally, Chapter 8 closes this thesis by discussing the approach presented here in a general context along with some concluding remarks and possible future directions.

Dissertação de mestrado integrado em Psicologia
Este estudo testa o efeito do sexo, do tempo e da interação entre sexo e tempo na inteligência emocional. Recorreu-se a uma amostra de 1069 participantes, 542 raparigas e 527 rapazes, entre os 11 e os 23 anos, do norte, centro e sul de Portugal. Responderam ao Emotional Quotient Inventory: Youth Version (EQ-i:YV; Bar-On & Parker, 2004, adapt. por Candeias et al., 2013) no primeiro e terceiro períodos do ano escolar e no primeiro período do ano letivo seguinte. Testou-se o efeito do sexo, do tempo e da interação entre sexo e tempo nas cinco dimensões do EQ-i:YV, humor geral, adaptabilidade, intrapessoal, interpessoal e gestão de stress, através da two-way mixed MANOVA. Os resultados indicam um efeito multivariado estatisticamente significativo do sexo, do tempo e da interação sexo e tempo em diferentes dimensões da inteligência emocional. Os resultados discutiram-se com base nas investigações existentes e na sua aplicabilidade para a prática da psicologia escolar, e sugeriram-se investigações futuras.
This study tests the effect of sex, time and the interaction between sex and time on emotional intelligence. The sample comprised 1069 participants, 542 girls and 527 boys, aged 11-23 years of the north, center and south of Portugal. The Emotional Quotient Inventory: Youth Version (EQ-i:YV; Bar-On & Parker, 2004, adapt. to Candeias et al., 2013) was applied in the first and third periods of the school year and in the first period of next school year. We tested the effect of sex, time and the interaction between sex and time in the five dimensions of the EQ-i:YV, interpersonal general mood, adaptability, intrapersonal and stress management through a two-way mixed MANOVA. The results indicate a statistically significant multivariate effect of sex, time and the interaction of sex with time in different dimensions of emotional intelligence. The results were discussed on the basis of existing research and its applicability to the practice of school psychology, and future research is suggested.

Le benzo-a-pyrène (BaP) est un cancérogène reconnu pour l'homme, contaminant présent dans notre environnement. Il cause des dommages à l'ADN que nous avons mesurés dans les lymphocytes exposés à de faibles concentrations de BaP, provenant de 20 jeunes volontaires non fumeurs et en santé. Suite à l’exposition, la fréquence des micronoyaux (MN) augmente significativement et décrit une courbe dose-réponse non linéaire, suggérant le déclenchement du processus de détoxification et la réparation de l’ADN. Des différences entre les individus et entre les sexes sont présentes dans la réponse génotoxique produite par le BaP. Le test des aberrations chromosomiques montre que le pourcentage de chromosomes cassés augmente significativement dans les cellules exposées au BaP. Combinés avec l'augmentation de la fréquence des MN, nos résultats confirment l'effet clastogène du BaP déjà rapporté dans la littérature. L’hybridation in situ en fluorescence (FISH) des MN avec une sonde pancentromérique est aussi utilisée pour établir leur mécanisme de formation. La FISH révèle que la majorité des MN formés après une exposition au BaP contient un centromère et plus, ce qui est significativement différent de la condition non exposée. Plus précisément, dans nos conditions expérimentales, les MN induits par le BaP contiennent surtout trois centromères et plus, indiquant également la présence d'un effet aneugène. L'effet clastogène du BaP est relié à son rôle d'initiateur dans la cancérogenèse, alors que l'effet aneugène le relierait à l'étape de progression. Ces résultats sont importants puisque l'exposition aux composés de la classe du BaP est de longue durée (cigarette, air pollué).
Benzo-a-pyrene (BaP) is a known human carcinogen, contaminating all spheres of our environment. In human cells, BaP can induce various genotoxic effects on DNA, such as micronuclei (MNs) and chromosomal aberrations (CAs). MNs and CAs are measured in human lymphocytes in vitro exposed to low BaP concentrations, taken from 20 young healthy non-smoking subjects. Following BaP exposure, MN frequency increases significantly and shows a non-linear dose-response curve, suggesting the induction of detoxification process and/or DNA repair. Also, interindividual and sex differences in BaP-induced genotoxic damages are present. CA test shows that chromosome breaks increase significantly in cells exposed to BaP even at low concentrations. Combined to the observed MN frequency increase, our results confirm the clastogenic properties of BaP, as already reported in literature. In addition, fluorescence in situ hybridization (FISH) on MN using a pancentromeric probe is done to assess MN content. FISH reveals that most BaP-induced MNs contain centromeres, and specifically three or more centromeres. This difference is significant when compared to the unexposed condition, and suggest presence of an aneugenic effect. Clastogenic effect of BaP is associated with initiation step of carcinogenesis, while the aneugenic effect would link it with cancer progression. These results could be particularly important because exposure to BaP and other member of its chemical class usually last for decades (smoking, air pollution, etc.), and need to be confirm in future studies.

Le benzo-a-pyrène (BaP) est un hydrocarbure aromatique polycyclique (HAP) cancérogène pour l’homme, qui contamine toutes les sphères de notre environnement. Son métabolite, le BaP-7,8-diol-9,10-époxyde (BPDE) est considéré comme son cancérogène ultime. Le BPDE se lie à l’ADN, formant des adduits qui doivent être réparés et qui seraient responsables des dommages à l’ADN et de la cancérogenèse induite par le BaP. Les adduits BPDE-ADN et les dommages à l’ADN (bris simple-brin [BSB] à l’ADN, aberrations chromosomiques [AC], échanges entre chromatides-sœurs [ÉCS] et micronoyaux [MN]) ont été mesurés dans les lymphocytes humains exposés à de faibles concentrations de BaP, provenant de jeunes volontaires non-fumeurs et en santé. Suite à l’exposition au BaP, le niveau d’adduits BPDE-ADN et la fréquence des AC et des MN augmentent significativement, puis diminuent aux concentrations les plus élevées de BaP testées, suggérant une induction du métabolisme de phase II du BaP. Lors de la mesure des ÉCS, nous obtenons une courbe dose-réponse linéaire, indiquant la production d’un autre type de lésions devant être réparées par le système de réparation par recombinaison homologue. Ces lésions pourraient être des bris à l’ADN ou des bases oxydées (8-OH-dG), ce qui est suggéré par l’analyse des corrélations existant entre nos biomarqueurs. Par ailleurs, la comparaison de la courbe dose-réponse des hommes et des femmes montre que des différences existent entre les sexes. Ainsi, les ÉCS, les AC et les MN sont significativement augmentés chez les hommes à la plus faible concentration de BaP, alors que chez les femmes cette augmentation, quoique présente, est non significative. Des différences interindividuelles sont également observées et sont plus importantes pour les adduits BPDE-ADN, les MN et les AC, alors que pour les ÉCS elles sont minimes. Les analyses statistiques effectuées ont permis d’établir que quatre facteurs (niveau d’exposition au BaP, adduits BPDE-ADN, fréquence des AC et nombre de MN par cellule micronucléée) expliquent jusqu’à 59 % de la variabilité observée dans le test des ÉCS, alors qu’aucun facteur significatif n’a pu être identifié dans le test des AC et des MN. L’analyse du mécanisme de formation de nos biomarqueurs précoces permet de suggérer que les bris à l’ADN et les bases oxydées devraient être classées comme biomarqueurs de dose biologique efficace, au sein des biomarqueurs d’exposition, dans le continuum exposition-maladie du BaP, étant donné qu’ils causent la formation des biomarqueurs de génotoxicité (ÉCS, AC et MN). Par ailleurs, le test des AC et des MN ont permis de confirmer l’action clastogénique du BaP en plus de mettre en évidence des effets aneugènes affectant surtout la ségrégation des chromosomes lors de la division cellulaire. Ces effets aneugènes, reliés à l’étape de progression dans la cancérogenèse, pourraient être particulièrement importants puisque l’exposition au BaP et aux HAP est chronique et dure plusieurs années, voire des décennies. La compréhension des mécanismes régissant la formation des biomarqueurs étudiés dans cette étude, ainsi que des relations existant entre eux, peut être appliquée à de nombreux contaminants connus et émergents de notre environnement et contribuer à en évaluer le mode d’action.
Benzo-a-pyrene (BaP) is a polycyclic aromatic hydrocarbon (PAH) classified as carcinogenic to human, and is present throughout our environment. Metabolic activation of BaP leads to production of BaP-7,8-diol-9,10-epoxide (BPDE), considered as its ultimate carcinogenic metabolite. BPDE can bind to DNA, forming BPDE-DNA adducts at the origin of BaP-induced DNA damage and carcinogenesis. BPDE-DNA adducts and DNA damages (DNA single-strand breaks [SSBs], chromosomal aberrations [CAs], sister chromatid exchanges [SCEs] and micronuclei [MNs]) are measured in human lymphocytes exposed to low BaP concentrations, taken from non-smoking healthy young subjects. Following BaP exposure, BPDE-DNA adduct levels, as well as CA and MN frequencies raise significantly, and then decrease to the higher BaP concentrations tested, suggesting metabolic enzyme saturation or induction of BaP phase II metabolism. As for SCEs test, a linear dose response curve is obtained, suggesting that production of additional DNA lesions requiring homologous recombination repair may occur. These lesions could be DNA breaks or oxidized DNA bases (8-OH-dG), as indicated by correlation analysis performed between our biomarkers. Additionally, when comparing the dose-response curves for men and women separately, some differences show up. Indeed, SCEs, CAs, and MNs are significantly increased in men at the lowest BaP concentration tested, while in women, this increase is present but not significant. Interindividual differences are also present and are more considerable for BPDE-DNA adducts, MNs and CAs, whereas they are very low for SCEs. Statistical analysis showed that four factors (BaP exposure level, BPDE-DNA adducts, CA frequency and number of MN per micronucleated cell) significantly explained up to 59 % of observed variability in SCE test, while no such factors could explain the observed variability in CA and MN test. Following analysis of mechanisms underlying the formation of early biomarkers, we suggest a modification of the Exposure-Disease Continuum of BaP. We propose that DNA breaks and oxidized DNA bases should be classified as biomarkers of biologically effective dose (part of the exposure biomarkers), as their presence are at origin of early biomarkers of genotoxicity (SCEs, CAs and MNs). On the other hand, CA and MN tests confirmed clastogenic properties of BaP, and highlighted aneugenic effects influencing mostly chromosome segregation during cell division. These aneugenic effects, linked to the progression step of carcinogenesis, could be of particular importance given that exposure to BaP and other PAHs (smoking, occupational exposure) are chronic and may last for decades. Understanding the mechanisms playing a role in early biomarkers formation, as well as the relations existing between them, can be largely applied in our environment to many known and emerging contaminants, thus contributing to characterize their mode of action.