This study examined the relationship between interpersonal decentering and symptoms of psychopathology among 48 clients from the Psychology Clinic at the University of North Texas. The Thematic Apperception Test (TAT) and the Symptom Checklist 90-Revised (SCL-90-R®) instrument were administered to clients along with demographic packets. Interpersonal decentering was assessed using Melvin Feffer's Interpersonal Decentering Scoring System for the TAT. It was hypothesized that higher scores of global symptom severity would be associated with lower scores of interpersonal decentering. Higher scores of paranoid ideation, psychoticism, and hostility were also hypothesized to be associated with lower scores of interpersonal decentering. Results did not support these hypotheses. However, exploratory analyses revealed a significant correlation between higher scores of phobic anxiety and lower scores of interpersonal decentering. Results also provided information regarding the three methods for calculating interpersonal decentering summary scores.

In Axelrod's tournaments of the Prisoner's Dilemma, carried out in the 1980s, a strategy called Tit for Tat was declared the winner, and it has since then been thought of as the strategy to use to do as well as possible in different situations. In this thesis, we investigate whether Tit for Tat will still do as well if we change the game to the Hawk-Dove Game. This is done by comparing Tit for Tat to other strategies -- All C, All D, Joss and Random -- one at a time. First we analyse under which conditions each strategy will be an Evolutionary Stable Strategy, then if it is possible for a population of these two strategies to end up in a stable polymorphism, and finally, if we have a finite population instead of an infinite one, under which conditions selection will favour the fixation of each of the strategies. This leads to the conclusion that how well Tit for Tat will do depends a lot on the different conditions on the game, but in general, the more times that a pair of individuals will meet, and the higher the value of the resource is compared to the cost of fighting, the better Tit for Tat will do.

L’ensemble des travaux psychiatriques actuels se concentre essentiellement sur l’aspect symptomatiquement de la dépression chez les sujets schizophrènes. A l’inverse, nous avons tenté d’étudier non pas la dépression clinique, mais les problématiques de perte dans les fonctionnements psychiques des sujets marqués par le processus schizophrénique. Autrement-dit, nous avons interrogé le rôle et les fonctions de la perte au sein d’un moi ayant perdu ses frontières et le sentiment de son existence, dans un fonctionnement psychique où les limites soi/non-soi sont aléatoires, les défenses narcissiques précaires ou inefficaces. A travers l’examen de la perte chez le schizophrène, c’est donc l’étude des diverses modalités de la relation d’objet et des affects associés dans cette pathologie que nous avons étudié. Il s’agissait donc de passer au-delà de l’aspect purement symptomatologique et phénoménologique de la dépression chez le sujet schizophrène pour interroger sa fonction au niveau métapsychologique. Nous nous sommes intéressés aux diverses opérations psychiques mises en œuvre par les sujets atteint de schizophrénie pour faire face aux divers problématiques de perte. Par problématiques de perte, nous entendons toutes les situations où le sujet a perdu un objet, ou doit y renoncer, que ce soit dans les problématiques de séparation d'avec l'objet primaire, l’abord de la position dépressive, de mélancolie, de deuil. Nous avons donc interrogé les articulations et intrications entre problématiques de perte et problématiques dissociatives.Notre recherche est animée par l’idée que la schizophrénie est un processus qui détruit les liens objectaux et les représentations d’objet mais surtout qui empêche d’en reconstruire de nouveaux, en cela il s’attaque à l’objectalité même. Persuadé que les schizophrénies procèdent d’une incapacité à utiliser le dipôle narcissisme-objet, nous souhaitions observer les diverses « constellations relationnelles » au sein des fonctionnements psychiques marqués par la schizophrénie, à travers leur représentations. Notre idée était que les différentes formes de schizophrénies témoignaient des différentes modalités d’approche de l’objet ou de la relation à l’objet.Notre première hypothèse postule que, plus les fonctionnements psychiques marqués par le processus schizophrénique sont habités par des représentations d'objet, même si ces objets sont partiels, persécuteurs, mal différenciés ou incestueux, plus la pensée reste « vivante » même si elle est désorganisée. Une seconde hypothèse postule que chez les sujets atteints par un processus schizophrénique il n'y a pas de possibilité d'élaborer les problématiques de perte, même si on observe de grandes différences individuelles. Cependant la présence d’éléments témoignant de problématiques de perte peut venir signer un assouplissement partiel des défenses psychotiques et révéler un fonctionnement de l’appareil psychique moins abrasé. Une sous-hypothèse propose l’idée que la reconnaissance de problématiques de perte est possible, chez certains sujets atteints de schizophrénie, le traitement de la perte diffère alors de celui du deuil ou de la mélancolie. Enfin une troisième hypothèse porte sur l’existence d’un processus mélancolique que nous pourrions repérer dans certaines formes de schizophrénies (les formes dysthymiques) qui ne peut pas se constituer véritablement pour autant. / Our thesis does not deal with clinical depression but with the issue of loss within the psychic functioning of patients marked by a schizophrenic process. By issues of loss we mean all situations in which the patient has lost something, but also separation, depression, melancholy and grief. In order to examine the standard metapsychological function and to observe the articulations and entanglements existing between issues of loss and dissociative problems we surveyed the functions of loss associated with a personality that had lost its sense of confines and existence beyond the purely symptomatic aspect of depression. Our first hypothesis is that the more psychic functions are marked by a schizophrenic process inhabited by object representations, even if these representations are partial, persecuting, poorly differentiated or incestuous, the more the thought remains " alive " even if it is disorganised. A second hypothesis is that in schizophrenic patients there is no possibility of developing issues of loss. The presence of depressive elements can however signal a partial easing of psychotic defenses. A sub-hypothesis is that the recognition of the problem of loss is possible in dysthymic patients but that the treatment differs from that aimed at grief and melancholy. A third hypothesis centres around the existence of a melancholic process in some schizophrenics (dysthymia). To test these hypotheses we studied the psychic functioning of twenty patients diagnosed as " schizophrenic "according to CIM 10. This was based on projective mediation tests (Rorschach and TAT) looking at differences and invariables associated with the treatment of loss and depression. We demonstrated the specificity of psychic functioning for each schizophrenic in terms of relationships, emotions and sensations relating to the issue of loss. Our results demonstrate that the functioning of patients affected by schizophrenia, far from remaining focused on one object tends instead to defend itself from the influence of the object upon the ego. Behind a more delusional and hallucinatory appearance the mental functioning of patients with paranoid schizophrenia and dysthymia is more disorganised, but paradoxically " more alive ", more driven by representations of objects that appear as an outward expression of less deadly psychic functioning, this despite the noisier symptoms in the form of simple undifferentiated or hebephrenic schizophrenia. Our work shows that if problems and depressive effects can be seen they lead to different defensive treatments which are invariably underpinned by denials. The presence of isolated depressive effects does not lead to recognisable problems associated with loss for the patient. We therefore conclude that if schizophrenics recognise situations of loss then that cannot be the work of psychic integration. This impossibility depends on the intensity of the destructive schizophrenic process and the capacity to implement a narcissistic reinvestment in itself, even if only transitory, albeit with significant individual differences. Finally, if we examine the outlines of the melancholy movements within our participants, they cannot be carried through to the end because of the inconsistency of the object lost, its potentially persecuting character and the absence of self/non-self limits.

京都大学 / 0048 / 新制・課程博士 / 博士(教育学) / 甲第17804号 / 教博第151号 / 新制||教||141(附属図書館) / 30619 / 京都大学大学院教育学研究科臨床教育学専攻 / (主査)教授 河合 俊雄, 教授 桑原 知子, 准教授 松下 姫歌 / 学位規則第4条第1項該当 / Doctor of Philosophy (Education) / Kyoto University / DGAM

HIV infection has been shown to predispose patients to accelerated development of heart disease. One mechanism for this pathology may involve endothelial activation either by HIV itself or by its secreted proteins, gp120 (a viral envelope protein) and tat (a protein that upregulates transcription of viral genes). We have studied the effects of gp120 and tat on signaling and production of inflammatory cytokines by Human Pulmonary Artery Endothelial Cells (HPAEC). HPAEC were stimulated at varying time points with combinations of gp120, tat, and monokines (IL-1β and TNFα). Cell lysate fractions were analyzed for MAP Kinase activity and NFκB activation, and culture supernatants were assayed for inflammatory cytokines (IL-6 and IL-8). The production of IL-6 and IL-8 was significantly enhanced by tat but not by gp120. Both gp120 and tat, however, induced significant morphological changes in HPAEC. The only synergy noted was between high levels of tat and TNFα acting on the production of IL-6. When HPAEC were stimulated with IL-1β and TNFα, peak phosphorylation of p38 MAP Kinase was found at 45 minutes, while NFκB was maximally activated at two hours. Both the ERK1,2 and p38 cascades of MAP Kinase were activated by tat, and an increase in NFκB phosphorylation and translocation were noted. We conclude that the HIV tat protein could be involved in inflammatory changes in endothelium leading to the accelerated development of heart disease in HIV patients.

Neuronal homeostasis is an essential process to protect neurons from over/under-stimulation driven from systematic changes such as synapsis plasticity or tissue damage. Functional stability in neurons relays on the homeostatic plasticity that its disturbance causes irreversible injuries. Hence, a large body of studies elaborated to investigate the underlying mechanism for changes in synaptic connectivity and neuronal function. HIV-1 Tat (Transactivation of transcription), is a well-established neurotoxic protein, released by HIV-1 infected cells in the brain and disturbs neuronal homeostasis. The effects of Tat have been addressed in numerous studies investigating the molecular events associated with neuronal cell survival and death. The emergence of lncRNAs as critical players in disease etiology placed them in the spotlight to study pathogenesis of human diseases. Due to its capacity to modulate host transcriptome, HIV-1 Tat protein has been subjected to increasing genome-wide examinations. This study showed that exposing primary rat neurons to Tat resulted in the up-regulation of an uncharacterized long-non-coding RNA (lncRNA), LOC102549805 (lncRNA-U1). Evidence exists that increased expression of lncRNA-U1 in neurons disrupts bioenergetic pathways by dysregulating homeostasis of Ca2+, mitigating mitochondrial oxygen reduction, and decreasing ATP production leading to mitochondrial impairment in neurons. These changes were associated with imbalances in autophagy and apoptosis pathways via the Tat-mediated lncRNA-U1 induction. Additionally, this study showed the ability of Tat to modulate the expression of the neuropeptide B/W receptor 1 (NPBWR1) gene via the up-regulation of lncRNA-U1. Collectively, my results identified the Tat-mediated lncRNA-U1 elevation disturbs neuronal homeostasis. Our observations of lncRNA-U1 knock-down experiments indicated the novel lncRNA LOC102549805 (U1) as a viable therapeutic target to prevent HIV-1 Tat neurotoxicity. / Biology

Depuis sa découverte il y a plus de 30 ans, le Virus de l’Immunodéficience Humaine est à l’origine d’une importante mortalité dans le monde. De par la difficulté de tester l’efficacité de formulations thérapeutiques et/ou vaccinales directement chez l’homme, des études d’infections modèles du VIH, comme celle du Virus de l’Immunodéficience Féline (FIV), ont été entreprises ces dernières années. Au-delà de son intérêt vétérinaire, l’étude du FIV représente un avantage important pour trouver un moyen de contrôler les infections par les lentivirus tel que le VIH. Elle peut permettre de développer et surtout de tester l’efficacité des vaccins et/ou thérapies spécifiques chez le chat, dont le SIDA mime les symptômes et les modifications hématologiques rencontrés chez l’homme. Ce manuscrit s’est intéressé à l’étude structurale de deux familles de protéines virales de ces virus, les protéines lentivirales précoces (protéine Tat du VIH) et tardives (domaines Capside CA et Matrice MA de Gag du FIV). L’étude structurale de ces protéines et leur compréhension fonctionnelle au sein de l’hôte pourront à l’avenir ouvrir de nouvelles voies thérapeutiques et/ou vaccinales contre les lentivirus, palliant ainsi les problèmes existants de résistances virales / Since its discovery 30 years ago, the Human Immunodeficiency Virus is the cause of an important mortality worldwide. Because of the difficulty to test the efficiency of therapeutical and/or vaccinal formulations directly in humans, studies of models of HIV infections, such as the Feline Immunodeficiency Virus (FIV), have been performed in recent years. In addition to its veterinary interest, the study of FIV is an important issue to find a way to control infections by lentiviruses such as HIV. It can help to develop and test the efficiency of specific therapies and/or vaccines for cats, where AIDS mimics the symptoms and hematologic changes observed in humans. This manuscript describes the structural study of two types of viral proteins of these viruses, early lentiviral proteins (HIV Tat protein) and late lentiviral proteins (CA capsid and MA Matrix domains of FIV Gag). The structural study of these proteins and their functional understanding into the host will open new therapeutic and/or vaccine strategies against these lentiviruses in the future, in order to overcome the existing problems of viral resistance

Das HIV-1 Tat-Protein hemmt die Peptidase-Aktivität des 20S Proteasoms durch Konkurrenz mit dem 11S Regulator/PA28 um die Bindungsstelle am Proteasom. Aus den kinetischen Daten und durch Strukturvergleiche geht hervor, dass die Aminosäuren Lys51, Arg52 und Asp67 des Tat-Proteins für den Effekt auf das 20S Proteasom verantwortlich sind und die REG/Tat-Proteasom-Bindungsstelle bilden. Eine in der 11S Regulator alpha-Untereinheit (REG alpha) identifizierte vergleichbare Struktur wird von den Aminosäuren Glu235, Lys236 und Lys239 gebildet. Durch eine Mutation der REG alpha Aminosäuren Glu235 und Lys236 zu Ala geht die Fähigkeit des REG alpha die Peptidase-Aktivität des 20S Proteasoms zu stimulieren verloren, während die Bindungsfähigkeit an den 20S Komplex erhalten bleibt. Die Bindungsstelle in REG alpha ist für die verstärkte Präsentation eines Epitops des Cytomegalovirus pp89 durch MHC Klasse I essentiell. Das Tat-Protein und das Tat-Peptid 37-72 unterdrücken die 11S-Regulator vermittelte Antigenpräsentation des pp89 Epitops. Im Gegensatz dazu weist das Tat-Peptid mit Mutation der Aminosäuren Lys51, Arg52 und Asp67 zu Ala keine Reduktion der Antigenpräsentation auf. / The HIV-1 Tat protein inhibits the peptidase activity of the 20S proteasome and competes with the 11S regulator/PA28. Kinetic assays and structural comparison found amino acids Lys51, Arg52 and Asp67 of Tat to be responsible for the effects on proteasomes, forming the REG/Tat-proteasome-binding site. A similar site identified in the 11S regulator alpha subunit (REG alpha) consists of the residues Glu235, Lys236 and Lys239. Mutation of the REG alpha amino acids Glu235 and Lys236 to Ala resulted in a REG alpha mutant that lost the ability to activate the 20S proteasome even though it still binds to the 20S complex. The site in REG alpha is needed to enhance the presentation of a cytomegalovirus pp89 protein-derived epitope by MHC class I molecules. Full-length Tat and the Tat peptide 37-72 suppressed 11S regulator-mediated presentation of the pp89 epitope. In contrast, a Tat peptide with mutation of amino acids Lys51, Arg52 and Asp67 to Ala was not able to reduce antigen presentation.

This thesis copes with the research of empathy of deliquent youngsters-specifically their emotional and congitive part, it also evaluates the egoism or altruism of these individuals and their compassion level. The main purpose of this thesis is therefore to find out, what is the level and structure of empathy in these deliquent youngsters. The data was acquired by a specific TAT test and was evaluated according to the five subscales of SCORS ,which resemblance to empathy is proven in this work. Moreover, the content analysis of the acquired TAT protocols was carried out. The results of protocol evaluation according to SCORS system show low,yet not pathological values of emotional and cognitive empathy of youngster deliquents, additionally, they show their mainly egoistic motives across their social interactions as well as a pathological low level of compassion with others. In this thesis, the results, describing the level of cognitive and emotional empathy, are being compared to the Smith's theory (2006), which copes with the possibility of having a disorder caused by general lack of empathy in youngster deliquents. TAT protocols of respondents were also subjects of the content analysis, and its result show for example uncertainity in the external manifestation of respondents, "black and white"...

La chimie de clic est devenue indispensable dans les nombreux domaines de chimie associée à la conception de médicament. Dans ce contexte, comme nous savons(connaissons) l'étude concernant l'impact d'insertion triazole sur la conformation de peptaibol est limitée, nous avons conduit l'étude pour examiner l'impact et l'adaptabilité de 1, 1 4-disubstituted, 2, l'insertion 3-triazole dans peptaibols différent. Selon le résultat de cette expérience touchant à l'activité réduite et la conformation perturbée de l'analogue peptaibol, le substitut dipeptide décoré du fragment triazole portant substituents hydrophobe divers a été inséré à très N-ter la partie du peptaibol. L'amélioration du bioactivity et de la restauration de la conformation pour les analogues peptaibol a été observée et le fait a été aussi soutenu par les résultats obtenus de l'étude biophysique des analogues choisis d'ALM F50/5. Nous avons plus loin prolongé notre étude pour employer notre stratégie à être appliqué sur le peptide P42 thérapeutique qui souffre de la limitation de manque de perméabilité et de stabilité. Le peptide P42 est impliqué dans le pathophysiology de la maladie d'Huntington neurodégénératif. Un total de 12 analogues de peptide de P42-camelote a été synthétisé par SPPS par notre protocole optimize. Dans la deuxième partie, nous avons développé une stratégie pour synthétiser lipopeptide cyclique produit de l'espèce cynaobacterial marine. Notre objectif principal était de synthétiser Hormothamnin A, undecapeptide cyclique consistant de plusieurs acides aminés artificiels incluant dehydroamino acide (Dhaa) qui fait la synthèse de ce peptide compliqué. En raison de cette raison, premièrement, nous avons voulu appliquer notre stratégie de synthétiser Trichormamide A, une sorte relativement plus simple de cylic lipopeptide. Après l'accomplissement de cette tâche, une première tentative a été faite pour synthétiser Hormothamnin A. Le résultat préliminaire de ceci est présenté dans cette section. Enfin, nous avons essayé de développer une méthodologie robuste pour synthétiser Fmoc-Dhaa dans la phase de solution et son insertion dans l'ordre peptaibol par une norme(un standard) SPPS le protocole. Les résultats préliminaires que nous avons concernant la synthèse Dhaa et son insertion dans peptaibol sont aussi discutés ici de plus avec la synthèse de phase solide de Bergofungin naturel D. / The click chemistry has become indispensible in the many areas of chemistry associated with drug design. In this context, as we know the study concerning the impact of triazole insertion on the conformation of peptaibol is limited, we have conducted the study to investigate the impact and adaptability of the 1, 4-disubstituted 1, 2, 3-triazole insertion into different peptaibols. Depending on the outcome of this experiment relating to reduced activity and perturbed conformation of the peptaibol analogue, the dipeptide surrogate decorated with the triazole moiety bearing various hydrophobic substituents was inserted at the very N-ter part of the peptaibol. The improvement of the bioactivity and restoration of the conformation for the peptaibol analogues was observed and the fact was also supported by the results obtained from the biophysical study of the selected analogues of ALM F50/5. We have further extended our study to employ our strategy to be applied on the therapeutic P42 peptide which suffers from the limitation of lack of permeability and stability. P42 peptide is involved in the pathophysiology of neurodegenerative Huntington’s disease. A total of 12 analogues of P42-TAT peptide were synthesized through SPPS by our optimized protocol. In the second part, we have developed a strategy for synthesizing the cyclic lipopeptide originated from marine cynaobacterial species. Our main objective was to synthesize Hormothamnin A, a cyclic undecapeptide consisting of several unnatural amino acids including dehydroamino acid (Dhaa) which makes the synthesis of this peptide complicated. Due to this reason, firstly, we have chosen to apply our strategy to synthesize Trichormamide A, a relatively simpler kind of cylic lipopeptide. After accomplishing this task, a first attempt was made to synthesize Hormothamnin A. The preliminary result of this is presented in this section. At last, we have tried to develop a robust methodology to synthesize Fmoc-Dhaa in solution phase and its insertion into the peptaibol sequence through a standard SPPS protocol. The preliminary results we have got concerning the Dhaa synthesis and its insertion into peptaibol are also discussed here in addition with the solid phase synthesis of natural Bergofungin D