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In addition to the lonely battles fought by Bomber Command crews in the night skies over Germany from February 1942 to May 1945 there was an equally intense if much less bloody struggle in the halls of power between the Air Staff and the AOC Bomber Command, concerning the best employment of the strategic bomber forces. The argument of this study is that the Royal Air Force s contribution to the strategic air offensive was badly mismanaged: that Air Chief Marshal Sir Arthur Harris, Air Officer Commanding-in-Chief Bomber Command, from 22 February 1942 to the end of the war, by ignoring, or often over-riding the Air Staff, affected not only the course but also the duration of the Second World War. Most histories of the bomber war provide the result of the disagreements between the Chief of the Air Staff, Marshal of the Royal Air Force Sir Charles Portal and Harris, but rarely are the problems discussed in detail. This thesis examines the arguments that were raised by the various authorities, together with the refutations presented not only by the major participants, but also by the advisers to those authorities. The significant feature of the disagreements was that while Harris acted unilaterally, the Air Staff reached consensus decisions. Unfortunately, the decisions reached by the Air Staff on major issues were all too frequently either ignored or subverted by the AOC Bomber Command. One significant feature of the refutations presented to Harris was their dependence on the operational experience gained earlier in the bomber war by junior members of the Air Staff. For too long the direction of the war had been left in the hands of senior officers whose previous service had become irrelevant to war requirements in the 1940s. By 1942, comparatively junior officers were thus tendering advice to senior officers who, in the case of AOC Bomber Command, resented the authority which, Harris argued, had apparently been accorded these juniors. Harris was unable to accept that they were advisers and were never in a position to issue orders: orders could only come from Portal. Finally, this thesis provides an analysis of the strengths and weaknesses of the major participants and argues that, had the war been conducted as the Air Staff required, victory would have been achieved earlier than May 1945.

Bombningen av Dresden är en av andra världskriget mest kontroversiella nyttjanden av luftstridskrafterna från den allierade sidan. Vissa argumenterade för att Dresden var ett civilt mål utan militärt eller strategiskt värde. Syftet med den här uppsatsen är att analysera Dresden som mål för de allierade luftstridskrafterna ur Giulio Douhet och John A.Warden IIIs luftmaktsteorier. Undersökningen bär mot att analysera hur och om man kan motivera Dresden som ett militärt och strategiskt mål ur två olika luftmakteoriers perspektiv. Uppsatsen genomförs med en kvalitativ innehållsanalys och komparativ analys för att jämföra teorierna med fallet. Resultatet av undersökningen visar hur man kan motivera Dresden som militärt och strategiskt mål. Warden och Douhets teorier är användbara för att analysera bombningen av Dresden. / The bombing of Dresden is one of the most controversial actions carried out by the allied air forces during World War 2. Some argue that Dresden was a civilian target, without strategic or military value. The purpose of this essay is to analyse Dresden as a target for the allied air forces using Giulio Douhets and John A. Warden IIIs theories of the use of air forces. This essay aims to investigate if and how one can justify Dresden as a military and strategic target by using Douhets and Wardens theories. The essay is conducted through qualitative content analysis and comparative analysis to compare the theories with case. The result shows how one can justify the bombing of Dresden using Douhets and Wardens theories.

Diss. (sammanfattning) Stockholm : Karol. inst., 2005. / Härtill 4 uppsatser.

Thesis (Ph. D.)--University of Washington, 1997. / Vita. Includes bibliographical references (leaves [74]-91).

Frankfurt (Main), Univ., Diss., 2002.

During World War II the British Royal Air Force undertook a campaign of area bombing of German cities, resulting in hundreds of thousands of civilian casualties. The debate over the ethics of this policy began at the time and has continued to the present. Area bombing clearly violated the traditional Just War norms of discrimination and noncombatant immunity. Apologists for the bombing have argued that such norms are no longer applicable in conditions of modern total war; critics of the bombing disagree. This dissertation defends the continuing relevance and applicability of these norms, and argues that area bombing constituted a violation of the moral laws governing the conduct of warfare. The dissertation also shows that the seeming intractability of the ethical debate on area bombing results from the participants' positions being informed by distinct and often incompatible ethical traditions. To understand and evaluate the different positions in the debate, it is necessary to engage critically with these underlying traditions. The dissertation shows how five ethical traditions touching on the norm of noncombatant immunity conditioned the positions taken by protagonists in the debate. The ethical traditions are Holy War / Crusade; Classical Realism; Christian Realism; Christian Just War / Jus in Bello; and Christian Pacifism. The first part of the dissertation explores the theoretical background and historical development of each of these traditions. The second part examines five protagonists in the British debate during World War II and analyzes how their positions were informed by the ethical traditions considered in the first part. The participants examined are Lord Vansittart (Holy War / Crusade), Captain Basil Liddell Hart (Classical Realism), Archbishop William Temple (Christian Realism), Bishop George Bell (Just War / Jus in Bello), and Vera Brittain (Christian Pacifism). The dissertation evaluates the strengths, weaknesses, and contributions of each of these traditions. By considering the voices raised against the area bombing at the time - especially those of Bishop Bell and Vera Brittain - the dissertation seeks to encourage theologically and ethically informed opposition to potential violations of the jus in bello norms in present and future conflicts.

京都大学 / 0048 / 新制・課程博士 / 博士(生命科学) / 甲第22591号 / 生博第424号 / 新制||生||56(附属図書館) / 京都大学大学院生命科学研究科統合生命科学専攻 / (主査)教授 河内 孝之, 教授 福澤 秀哉, 教授 荒木 崇 / 学位規則第4条第1項該当 / Doctor of Philosophy in Life Sciences / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(理学) / 甲第19884号 / 理博第4211号 / 新制||理||1605(附属図書館) / 32961 / 京都大学大学院理学研究科生物科学専攻 / (主査)教授 杤尾 豪人, 教授 高田 彰二, 教授 青山 卓史 / 学位規則第4条第1項該当 / Doctor of Science / Kyoto University / DFAM

La voie de signalisation RAS-ERK régule la prolifération et la différenciation cellulaire par la propagation séquentielle d’un signal jusqu’au noyau, aboutissant à la régulation des gènes cibles. Après réception d’un stimulus extracellulaire conduisant à l’activation de la petite GTPase RAS (Rat Sarcoma), la transduction du signal s’effectue par les phosphorylations successives de RAF (Rapid Accelerated Fibrosarcoma), MEK (MAPK/ERK Kinase 1/2) et ERK (Extracellular signal-Regulated Kinase 1/2). Chez les mammifères, la famille élargie des protéines RAF comprend les trois kinases ARAF, BRAF, CRAF et les pseudokinases KSR1, KSR2 pour Kinase Suppressor of Ras 1/2. En l’absence de stimuli, les kinases RAF adoptent une forme auto-inhibée où leur région régulatrice N-terminale (N-terminal Region ou NTR) inhibe l’activité catalytique de leur domaine kinase (Kinase Domain ou KD). L’activation des GTPases RAS ancre les kinases RAF à la membrane plasmique via le domaine RBD (Ras Binding Domain) de leur NTR. Ce phénomène favorise la dérépression des KD et dévoile leur interface de dimérisation. L’association de deux protéines RAF l’une avec l’autre induit l’activation des kinases RAF et la phosphorylation de leur substrat MEK. Bien que dénuées d’activité kinase intrinsèque, les pseudokinases KSR sont néanmoins capables de dimériser avec les kinases RAF et de les activer. Des mutations des protéines clés de la voie RAS-ERK conduisent à son activation anormale et sont directement responsables du développement et de la progression tumorale. Notamment, la kinase BRAF est altérée dans 7 % des cancers. L’échec des stratégies thérapeutiques permettant d’inhiber les kinases RAF a mis en lumière l’importance de la dimérisation dans la régulation de leur activité. Ainsi, les processus favorisant la formation d’hétérodimères RAF/KSR ne sont, à ce jour, pas bien compris. La problématique de la thèse a été d’identifier les mécanismes moléculaires régissant la formation spécifique du dimère BRAF/KSR1 aboutissant à la phosphorylation du substrat MEK1. Les objectifs de la thèse ont donc été 1) de déterminer ce qui permet au substrat MEK1 de se lier aux différentes protéines de la famille RAF, 2) d’identifier les domaines nécessaires à l’interaction spécifique de BRAF et KSR1, 3) de développer des stratégies de purification du dimère BRAF/KSR1 pour en faire une analyse structurale. Ce travail a dans un premier temps montré que le substrat MEK1 est l’activateur de sa propre kinase BRAF, en favorisant sa transactivation par KSR1 via des interactions au niveau des domaines kinases. De manière inattendue, nous avons par la suite établi que ce sont les NTR des protéines BRAF et KSR1 qui guident leur hétérodimérisation. Le dimère BRAF/KSR1 repose ainsi sur l’interaction directe du domaine BRS de BRAF et du domaine CC-SAM de KSR1. Nous avons montré que le domaine CRD de BRAF exerce une influence sur l’interaction BRS/CC-SAM et par extension, sur la dimerisation de BRAF avec KSR1. Enfin, nous avons testé plusieurs stratégies de purification du dimère BRAF/KSR1 qui nous ont permis d’optimiser une technique de purification à partir de cellules de mammifères et de générer des constructions pour des cellules d’insectes. Ainsi, ce travail nous a permis d’améliorer la compréhension des mécanismes de formation de l’hétérodimère BRAF/KSR1 et son lien avec le substrat MEK1. Nous avons découvert des nouveaux moyens de régulation de la signalisation RAS-ERK. À terme, les résultats obtenus s’avèreront utiles pour le développement de nouvelles stratégies thérapeutiques efficaces pour inhiber la voie RAS-ERK dans des contextes pathologiques. / The RAS-ERK signaling pathway regulates cell proliferation and differentiation by signal propagation from the cell surface to the nucleus, resulting in the regulation of targeted genes. After receiving an extracellular stimulus leading to the activation of the small GTPase RAS (Rat Sarcoma), signal transduction is mediated by the successive phosphorylations of RAF (Rapid Accelerated Fibrosarcoma), MEK (MAPK/ERK Kinase 1/2) and ERK (Extracellular signal-Regulated Kinase 1/2) kinases. In mammals, the extended family of RAF proteins is comprised of the three kinases ARAF, BRAF, CRAF and the two pseudokinases KSR1, KSR2 from Kinase Suppressor of Ras 1/2. In the absence of a stimulus, RAF kinases are in an auto-inhibited conformation wherein their N-terminal regulatory region (NTR) inhibits the catalytic activity of their kinase domain (KD). Activation of the RAS GTPases anchors RAF kinases to the plasma membrane through binding of the RBD (Ras Binding Domain), present in their NTR. This phenomenon induces the release of the KDs and unveils their dimerization interfaces. The association of two RAF proteins with each other stimulates the activation of RAF kinases and the phosphorylation of their substrate MEK. Although lacking an intrinsic kinase activity, KSR pseudokinases are nevertheless able to stimulate RAF kinase activity through dimerization and transactivation. Mutations of core members of the RAS-ERK pathway led to its abnormal activation and are directly responsible for tumor development and progression. In particular, the BRAF isoform is mutated in 7 % of cancers. Unsuccessful therapeutic strategies developed to inhibit RAF kinases have highlighted the importance of dimerization in the regulation of the catalytic activity of RAF kinases. Moreover, the process favoring the formation of RAF/KSR heterodimers is not fully understood. The focus of this Ph.D. was to identify the molecular mechanisms governing the specific formation of the BRAF/KSR1 dimer leading to the phosphorylation of the MEK1 substrate. Our main objectives were therefore to 1) determine what allows the substrate MEK1 to bind to the different members of the RAF family of proteins, 2) identify the domains necessary for the specific interaction of BRAF and KSR1 3) develop a new approach to purify the BRAF/KSR1 dimer for structural analysis. This work showed that the substrate MEK1 stimulates the activation of its own kinase, by promoting BRAF transactivation by KSR1 through interactions at the kinase domain level. Unexpectedly, we subsequently established that the NTRs of BRAF and KSR1 guide their heterodimerization. BRAF/KSR1 dimer formation is thus based on direct interaction of the BRS domain of BRAF and the CC-SAM domain of KSR1. We then showed that the CRD domain of BRAF has an influence on the BRS/CC-SAM interaction which overall modulates the dimerization of BRAF with KSR1. Finally, we tested several BRAF/KSR1 dimer purification strategies that allowed us to optimize a purification technique from mammalian cells. We also generated constructs enhanced for insect cells expression in the hope of successfully stabilizing BRAF/KSR1 in a signaling complex. Thus, this work allowed us to improve the understanding of the mechanisms underlying the formation of BRAF/KSR1 heterodimer and its link with its MEK1 substrate. We have discovered new ways of regulating the RAS-ERK signaling pathway. Ultimately, theses results will prove useful for the development of new effective therapeutic strategies to inhibit the RAS-ERK pathway in pathological contexts.