Evidence that individuals distinguish between moral and conventional rules is reviewed. Moral rules prohibit actions that result in victims (e.g., violence, stealing, etc.). Conventional rules prohibit actions that do not result in victims (e.g., not saying please, dressing in opposite sex clothes). Previous theoretical accounts of the development of the moral/conventional distinction are discussed. These theories are contrasted with an approach that is developed here. It is proposed that there is a mechanism, a Violence Inhibition Mechanism (VIM), that is responsible for the previously observed aversive arousal response to the distress of others. It is proposed that this aversive arousal response is a prerequisite for the development of the moral/ conventional distinction, the moral emotions and the inhibition of violent behaviour. Previous accounts have stressed role taking as a prerequisite for the moral/ conventional distinction. However, this was found not to be the case. Autistics, already known to be lacking a 'Theory of Mind' and therefore unable to role take, were found to make the moral/ conventional distinction. It was hypothesized that Antisocial Personality Disorder (APD) might be a consequence of a lack of VIM; the clinical description of APD stresses their lack of the moral emotions and their inability to inhibit their violent actions. In line with this, APD subjects were not found to make a moral/conventional distinction. Two rival explanations of APD were investigated: that APD is due to an inability to role take and; that APD is due to frontal lobe damage. APD subjects were not found to be impaired in either of these respects in comparison to criminal controls. A final investigation focused on the emotion attributions of APD subjects. It was hypothesized, given the contention that VIM is a prerequisite for the development of the moral emotions, that APD subjects might make anomalous attributions in victim situations though their attributions of other situations should prove normal. This study observed that while the attributions of APD subjects and criminal controls did not differ if the emotions attributed were happiness, sadness or embarrassment there was significant difference in victim situations where APD subjects were less likely to attribute guilt and more likely to attribute indifference than criminal controls. This finding was taken as indirect support of the VIM position. Additional tests, and implications of the VIM model are then discussed.

A novel partial agonist of the exchange protein activated by cAMP isoform 1 (EPAC1), I942, was recently discovered and shown to reduce the guanine exchange factor activity of cAMP-bound EPAC1 to approximately 10% relative to cAMP activation. However, the inhibition mechanism of I942 remains unknown. Here, we utilize NMR spectroscopy to probe the inhibitory I942 - EPAC1 interactions at atomic resolution. The EPAC1 - I942 interface was mapped through intermolecular NOEs measured by 15N and 13C filtered NOESY-HSQC experiment. Intermolecular NOE mapping combined with other protein NMR methods, such as saturation transfer difference, transfer Nuclear Overhauser Effect spectroscopy and chemical shift mapping, we revealed that I942 interacts with the phosphate binding cassette (PBC) and base binding region (BBR) of the EPAC1 cyclic nucleotide binding (CNB) domain, similar to cAMP. The PBC controls the conformation of the hinge region, and subsequently, allosterically shifts the hinge region between its active/inactive states. Molecular dynamics simulation based on the NMR spectroscopy data revealed that EPAC1-CNB adopts an intermediate conformation between its inactive and active states, which explains the partial agonist nature of I942. / Thesis / Master of Science (MSc) / The exchange protein activated by cAMP (EPAC) is a receptor for the classical secondary messenger cAMP. EPAC is present in multiple human systems and plays a pivotal role in the development of a wide range of diseases. In this study, we aim to establish the inhibition mechanism of a novel small molecule EPAC inhibitor/partial agonist I942 using NMR spectroscopy with the goal of achieving a better understanding of EPAC inhibition and paving the way for new small molecule EPAC inhibitors that can potentially treat EPAC-related diseases such as heart failure and diabetes.

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京都大学 / 新制・課程博士 / 博士(薬科学) / 甲第24555号 / 薬科博第172号 / 新制||薬科||19(附属図書館) / 京都大学大学院薬学研究科医薬創成情報科学専攻 / (主査)教授 大野 浩章, 教授 小野 正博, 教授 掛谷 秀昭 / 学位規則第4条第1項該当 / Doctor of Pharmaceutical Sciences / Kyoto University / DFAM

Serine racemase (SR) is a pyridoxal-5'-phosphate-dependent enzyme responsible for biosynthesis of D-serine, a recognized neurotransmitter acting as a co-activator of N-methyl- D-aspartate (NMDA) type of glutamate receptors in the mammalian central nervous system. The hyperfunction of the mentioned receptors have been shown to be implicated in many neuropathological conditions including Alzheimer's disease, amyotrophic lateral sclerosis and epilepsy. To alleviate the symptoms of these diseases, several artificial blockers of NMDA receptors have been introduced into the clinical practice. However, many of these compounds cause undesirable side effects and it is thus necessary to search for either less harmful blockers or regulators of other targets of pharmaceutical intervention that are involved in NMDA receptor activation. In this context, specific inhibition of serine racemase seems to be a promising strategy for regulation of NMDA receptor overstimulation. Mouse serine racemase shares 89% identity with its human ortholog and it was also shown that both enzymes possess similar kinetic parameters and inhibitor specificity. Therefore, the mouse models can be used to search for a potent human serine racemase inhibitor. Although many different compounds for their inhibitory potency towards serine...

Les accidents vasculaires cérébraux (AVC) sont la seconde cause d'invalidité à long terme et de mortalité dans le monde entier qui résulte d'une perte de sang au cerveau. Il y a actuellement peu de médicaments pour traiter les accidents vasculaires cérébraux. Pourtant, il y a un intérêt pour trouver un traitement, ciblant spécifiquement la cascade post-inflammatoire. Il y a une attention particulière pour inhiber les protéines peroxyrédoxines humaines (hPrx) qui sont des initiateurs clés de l'inflammation. Les protéines hPrx sont des enzymes qui dégradent les peroxydes et aussi protègent les cellules du stress oxydatif. Cette thèse est centrée sur l'étude de ligands potentiels des hPrx, dérivés du catéchol, susceptibles de devenir des agents thérapeutiques potentiels pour traiter les AVC. Premièrement, différents ligands potentiels ont été criblés par RMN et modélisation moléculaire pour savoir s'ils pouvaient se lier à différents isoformes des peroxirédoxines. Ces études ont révélé que ces dérivés du catéchol pouvaient se lier à plusieurs hPrx. Deuxièmement, la capacité des dérivés du catéchol à inhiber l'activité des hPrx a été examinée au travers de tests enzymatiques in vitro. Il a été montré que tous les dérivés du catéchol étudiés étaient capables de les inhiber. En utilisant des simulations de dynamique moléculaire, nous avons pu expliquer le mécanisme d'action moléculaire d'inhibition. En général, cette recherche fournit un aperçu des ligands qui pourrait être développés pour devenir un médicament pour aider dans le processus de rétablissement de patients atteints d'attaque cérébrale / Strokes are the second leading cause of long-term disability and death worldwide that result from a sudden loss of blood to the brain. Currently, there are limited drugs to treat patients when having a stroke. However, there is now interest focused on treatment after a stroke, specifically the post-inflammation cascade. In particular, there is attention to inhibit human peroxiredoxin proteins, which are key initiators of inflammation. Human peroxiredoxins are enzymes that degrade peroxides and also, protect the cells against oxidative stress. This thesis focuses on studying ligands, catechol derivatives, to bind and inhibit human peroxiredoxin proteins to become potential therapeutic agents for strokes. First, the ligands were screened to identify if they could bind to various human peroxiredoxin isoforms with NMR and computational modeling techniques. This study revealed the catechol derivatives could indeed bind to several human peroxiredoxins. Second, the ability for the catechol derivatives to inhibit human peroxiredoxin peroxidase activity was examined through an in vitro enzymatic assay. All the catechol derivatives were determined to inhibit several human peroxiredoxins. In utilizing molecular dynamic simulations, it assisted in explaining the in vitro inhibition molecular mechanism of action. Overall, this research provides insight of molecules that could be further developed to become possibly a drug to aid in stroke patients recovery process

本論文嘗試以行為引發機制與行為抑制機制的觀點，探討非法且屬人際層面的男性攻擊行為，從中評估常表現攻擊行為個體的認知、情緒與行為缺陷。由於攻擊行為的特殊性，個體表現攻擊行為時，相關的行為機制包括表現該行為可能得到獎賞的行為引發機制﹔表現該行為可能得到懲罰的行為抑制機制﹔與攻擊他人時，被害者的非語文訊息引發的個體的暴力抑制機制。研究一根據暴力抑制機制的理論內容發展實驗工具，透過違反道德與違反慣例圖片組的呈現，了解高、中、低攻擊組的表現差異。結果發現高攻擊組對兩違反情境的嚴重程度評估較低，同時，在違反道德圖片組刺激下，高攻擊組表現較少的道德情緒與較少的同理行為。研究二則透過研究一發展的圖片組評估個體的暴力抑制機制運作能力，並結合Patterson與Newman的四階段理論發展實驗刺激，透過情境的操弄，了解高攻擊組之行為引發機制與行為抑制機制運作情形。結果發現經由兩套理論(暴力抑制機制與四階段理論)的結合，可將高攻擊組分為兩類，一類為暴力抑制機制運作正常，但行為引發機制運作過強﹔另一類為暴力抑制機制無法運作者。以認知、情緒與行為缺陷評估兩類高攻擊行為者發現，具有認知、情緒與行為缺陷的高攻擊行為者只有第二類。 / Based on a behavioral activation mechanism and two behavioral inhibition mechanisms, unlawful and interpersonal male aggression was studied. Moreover, the possibility of individuals’ cognitive, emotional, and behavioral deficiencies was evaluated. Due to the special quality of aggressive behavior, when a person acts aggressively, there will be three processes involved. They are the behavioral activation mechanism activated by reward, the behavioral inhibition mechanism induced by punishment, and the Violence Inhibition Mechanism (VIM) triggered by victims’ cues of distress. In order to study these three processes, two sets of pictures were developed from study 1 in order to evaluate how participants functioned their VIM. The results showed differences between High, Medium, and Low Aggression Group. The High Aggression Group evaluated incidents of moral/ conventional transgression less serious than the other two groups did. Also, they showed less moral emotions and less empathic behaviors than the other two groups did. Based on the sets of pictures developed from Study 1, a group of young offenders were divided into two groups based on their VIM functioning. Further, a survival game was developed from Patterson and Newman’s four-stage model. By manipulating situations to present reward/punishment, those young offenders showed different aggressive patterns. Young offenders with good VIM functioning behaved more aggressively when there were rewards. Relatively, young offenders with poor VIM functioning were less likely to be influenced by either reward or punishment. The implications were discussed in the article.