This thesis involved Tetra Pak and corrugated cardboard suppliers in China at various locations to understand how this industry looks like, the reasons for inconsistent quality and analysis of the current state of whole industry, and recommendations for improvement. As innovation can bring competitive advantage to companies, our thesis focused upon making extended value of material flow from Tetra Pak and suppliers. The aim of this project is to investigate how strategic intelligence can create value and strengthen Tetra Pak business relationship with its customers in big emerging markets like China. Theoretical framework creates a foundation for how to structure the efficiently utilize intelligence in the decision-making process for a MNC. Another aspect of the thesis was to examine supply network management process and the supplier relationship development in China, as well as the strategic, social, macro economy aspects that influence change management in medium and large organizations. Corrugated cardboard industry in China is still in a transitioning to a mature market. One conclusion drawn from the trip to China is that the dairy producer should start emphasizing visual control on quality, and less concern on price. They should see their suppliers as long term partners but not just treat them as providers. Because it is fundamentally undercutting the ability of the organization to improve what it provides to customers through better quality and productivity. It hinders efforts from reducing cost. Finally, the research problems we focus throughout this thesis will be answered after the analysis. Moreover, we will provide some suggestions about corrugated industry and our case company-Tetra Pak.

Detta är en uppföljning av utbildningen i Psykodynamisk Affektfokuserad Korttidsterapi som gavs på psykoterapeutprogrammet med psykodynamisk inriktning 2004 -2007. Syftet är att följa upp om PAK fortfarande upplevs angeläget och om utbildningen har påverkat arbetet och rollen som psykoterapeut. Detta har gjorts via en enkät och intervjuer. Studien visar att PAK haft ett tydligt inflytande på arbetet och synen på rollen som psykoterapeut för de flesta av de intervjuade och att det finns en upplevelse av engagemang och vitalisering hos terapeuterna. En ansats till att få en bild av vad som är attraktivt i förhållningssättet görs och det förs en diskussion kring detta. Ett behov av att få fördjupa och vidareutveckla sina kunskaper lyfts fram.

<p>This thesis involved Tetra Pak and corrugated cardboard suppliers in China at various locations to understand how this industry looks like, the reasons for inconsistent quality and analysis of the current state of whole industry, and recommendations for improvement.</p><p>As innovation can bring competitive advantage to companies, our thesis focused upon making extended value of material flow from Tetra Pak and suppliers. The aim of this project is to investigate how strategic intelligence can create value and strengthen Tetra Pak business relationship with its customers in big emerging markets like China. Theoretical framework creates a foundation for how to structure the efficiently utilize intelligence in the decision-making process for a MNC.</p><p>Another aspect of the thesis was to examine supply network management process and the supplier relationship development in China, as well as the strategic, social, macro economy aspects that influence change management in medium and large organizations.</p><p>Corrugated cardboard industry in China is still in a transitioning to a mature market. One conclusion drawn from the trip to China is that the dairy producer should start emphasizing visual control on quality, and less concern on price. They should see their suppliers as long term partners but not just treat them as providers. Because it is fundamentally undercutting the ability of the organization to improve what it provides to customers through better quality and productivity. It hinders efforts from reducing cost.</p><p>Finally, the research problems we focus throughout this thesis will be answered after the analysis. Moreover, we will provide some suggestions about corrugated industry and our case company-Tetra Pak.</p>

Doctor of Philosophy / Security Studies Interdepartmental Program / David R. Stone / Best known for being a ‘rollercoaster’ and a ‘marriage of convenience’, various scholars have tried to reflect upon the true nature of Pak-U.S. relationship under this banner. However, no matter how one examines this relationship one thing is certain –– the experience for both countries has been harrowing. After India settled for non-alignment early in the Cold War, Pakistan seized the opportunity and aligned itself with the United States in the East-West struggle and pledged allegiance to fight communism in Asia. But that was not the only motive –– Pakistan secretly hoped that an alliance with the U.S. would provide it security against India with whom Pakistan had an antagonistic relationship over their outstanding territorial dispute of Kashmir. When the U.S. did not rescue Pakistan as it had hoped for during its war with India in 1965 and sanctioned both countries with an arms embargo, Pakistan felt betrayed. From that period onwards, Pakistan’s list of grievances against the U.S. developed into a narrative of betrayal and abandonment fed by several episodes in their relationship during and after the Cold War –– a period in which Pakistan developed and tested its nuclear weapons –– duly exploited by Pakistani leaders as a tool for populist politics. This dissertation provides the first scholarly account of Pakistan’s narrative and tests its merit against the U.S. non-proliferation policy towards Pakistan under five administrations from Ford to Clinton and finds that Pakistan’s narrative of betrayal and abandonment is uneven and misleading with respect to the objectives and successes of U.S. non-proliferation policy. This dissertation uses multi-archival documents to offer a counter-narrative which argues that Pakistan, although a small state, was able to brilliantly maneuver its way through restricted spaces in its relationship with the U.S. in the past five decades to not only acquire a decent conventional capability through U.S. military assistance but also nuclear weapons due to the fickleness of U.S. non-proliferation policy. This research concludes that the compromises made by the U.S. to accommodate Pakistan and its inconsistency in enforcement of non-proliferation laws has implications for the efficacy and success of U.S. non-proliferation policy with prospective proliferants.

Einige der Polyzyklischen Aromatischen Kohlenwasserstoffe (PAK) weisen Krebs auslösende Eigenschaften auf. Die bekannteste karzinogene PAK-Verbindung ist das Benzo[a]pyren (BaP), welches bislang als Leitsubstanz verwendet wird. Mittlerweile bestehen jedoch Zweifel, ob BaP als alleinige Leitsubstanz geeignet ist. Daher empfiehlt die EU-Kommission die Untersuchung der PAK auf die so genannten 16 EFSA-PAK auszudehnen. Zur Überprüfung der Anwendbarkeit von BaP als Leitsubstanz war es notwendig, Erkenntnisse über das Verhältnis des Gehaltes an BaP zum PAKges-Gehalt sowie die einzelnen PAK-Profile zu gewinnen. Die zu untersuchenden Lebensmittelgruppen wurden eingeschränkt auf Fleischerzeugnisse, Rauchwürzer und Räuchersalze, Räucherdärme, Gewürze, Tee und Schokolade. Nach der Entwicklung und Überprüfung von Methoden zur Bestimmung der EFSA-PAK und der anschließenden Analytik einer Anzahl repräsentativer Proben verschiedener Lebensmittelgruppen konnte mit Hilfe einer Datensammlung zu den Gehalten der 16 EFSA-PAK die Beurteilung von BaP als Leitsubstanz erfolgen. Es konnte eine Abhängigkeit der PAKges-Gehalte vom BaP-Gehalt ermittelt werden, welche sich mit zunehmender Konzentration der PAK manifestierte. Aus analytischer Sicht eignet sich BaP am besten als Leitsubstanz, da sie chromatographisch mit den heutigen Methoden leicht von anderen möglichen coeluierenden Substanzen abgetrennt werden kann und in Konzentrationen vorkommt, die zuverlässiger quantifiziert werden können.

5 mutations responsables de retard mental ont été identifiées dans le gène p21-activated kinase 3 (pak3). Nous avons récemment identifiés dans pak3 deux exons alternatifs très conservés appelés b et c. Ainsi, en plus du variants PAK3a (dépourvu des inserts b ou c), le gène pak3 code pour 3 nouveaux variants d’épissage PAK3b, PAK3c et PAK3cb qui sont constitutivement actifs et insensibles aux GTPases. De plus, contrairement à PAK1 et PAK3a, leur domaine d’auto-inhibition est incapable d’inhiber un domaine kinase. Ainsi, le but de ce projet était de comprendre le mécanisme de régulation de la kinase PAK3. Un modèle de régulation a récemment été proposé dans lequel PAK1 forme des homodimères pouvant être dissociés par les GTPases, permettant ainsi l’activation de la kinase. En se basant sur ces observations j’ai cherché à identifier les dimères PAK3 et j’ai montré que les kinases PAK3a, b, c et cb forment préférentiellement des hétérodimères avec PAK1. J’ai démontré l’existence de ces dimères dans le cerveau et j’ai mis en évidence que ces hétérodimères permettent à chaque monomère de réguler l’activité kinase de son partenaire in vitro. Ce travail permet de proposer un modèle de régulation symétrique pour PAK3a qui forme des hétérodimères avec PAK1 et un nouveau modèle de régulation asymétrique pour les variants d’épissage, également basé sur leur hétérodimérisation avec PAK1. Mes résultats montrant une corégulation des kinases PAK neuronales suggèrent d'une part que leur activation puisse être synchronisée et d'autre part que dans certaines situations physiopathologiques (Cancer et maladies neurologiques) leur dérèglement puissent interférer. / 5 mutations responsible for mental retardation have been identified in p21-activated kinase 3 (pak3) gene. We recently identified in pak3, two highly conserved alternative exons called b and c. In addition to the classical PAK3a variant (without any alternative exon), the pak3 gene encodes 3 new splice variants PAK3b, PAK3c and PAK3cb which are constitutively active and insensitive to GTPase activation. Moreover, unlike PAK1 or PAK3a, their autoinhibitory domain is unable to inhibit a kinase domain. The aim of this project was to understand how PAK3 regulation occurs. A model of regulation was recently proposed in which PAK1 forms homodimers that can be dissociated through GTPase binding, leading to kinase activation. Given these observations, I searched to identify PAK3 dimers and I showed that PAK3a, b, c and cb preferentially form heterodimers with PAK1. I demonstrated the existence of such dimers in the brain and that the different heterodimers allow each monomer to regulate the kinase activity of its partner. Through this study, I propose a symmetric regulation model for PAK3a which heterodimerizes with PAK1 and a new asymmetric regulation model for splice variants, also based on heterodimerization with PAK1. My results showing a co-regulation of neuronal PAK kinases suggest that their activation may be synchronized but also that, in some physiopathological situations (cancers and neurologic diseases), their misregulation may interfere.

Nouvelles voies de modulation des canaux calciques de type T.Grâce à leur rôle dans l'excitabilité cellulaire et l'homéostasie calcique, les canaux calciques de type T participent à différentes fonctions physiologiques telles que le sommeil ou le contrôle du rythme cardiaque et de la pression artérielle. Ils sont également impliqués dans certaines pathologies comme la douleur ou l'épilepsie. La régulation de l'activité des canaux de type T est encore mal connue et c'est l'enjeu de cette thèse. Dans une première partie, nous avons caractérisé l'effet de certains lipides endogènes sur ces canaux, en particulier les métabolites de l'acide arachidonique, et identifié le 5,6-EET comme un nouveau bloqueur des canaux de type T. Nous avons ensuite évalué l'existence d'un site de liaison des lipoamino acides sur les canaux de type T à l'aide d' d'expériences de compétitions réalisées avec un inhibiteur spécifique de ces canaux, la molécule TTA-A1.Dans une deuxième partie, nous avons étudié la régulation par le calcium des canaux de type T. Nous avons montré que l'entrée de calcium par les canaux T eux-mêmes ou par activation des récepteurs P2X4 et NMDA induisait une inhibition du courant de type T. Le calcium activerait une phosphatase qui provoquerait un déplacement de la courbe d'inactivation à l'état stable vers les potentiels négatifs, réduisant ainsi la disponibilité des canaux. Ce phénomène d'inhibition du courant lié à l'entrée du calcium pourrait être un mécanisme de rétrocontrôle négatif limitant l'entrée de calcium dans la cellule afin d'éviter une toxicité provoquée par une concentration de calcium intracellulaire trop élevée. Suite à cette inhibition, lorsque l'entrée de calcium est arrêtée, le courant augmente. Cette augmentation semble être due à l'intervention de la protéine kinase Pak qui rendrait les canaux de type T disponibles.En conclusion, nous avons identifié et caractérisé deux nouveaux mécanismes endogènes de régulation des canaux de type T : une modulation par les lipides, et une modulation par les calcium et la protéine kinase Pak. / New pathways of regulation of T-type calcium channels.Thanks to their role in cellular excitability and calcium homeostasis, T-type calcium channels are involved in several physiological functions such as sleep or control of cardiac rythmicity and vascular tone. They are also involved in some diseases such as pain or epilepsy. The regulation of T-type calcium channels is still poorly understood and that is the challenge of this thesis.In a first part of the study, we caracterised the effect of some endogenous lipids on these channels, particularly the metabolites of arachidonic acid, and identified the 5,6-EET as a new blocker of T-type channels. We then evaluated the existence of a binding site of lipoamino acids on T-type channels using binding experiments made with a specific inhibitor of these channels, the TTA-A1 molecule.In a second part, we studied the regulation of T-type channels by calcium. We showed that a calcium entry through T-type channels or through P2X4 and NMDA receptors activation induced an inhibition of T-type current. Calcium would activate a phosphatase which would trigger a shift of the steady-state inactivation curve toward negative potentials, reducing the availability of channels. This phenomenon of current inhibition due to calcium entry may be a feedback mechanism limiting calcium entry in the cell to avoid toxicity due to a too high intracellular calcium concentration. After this inhibition, when calcium entry is stopped, the current increases. This increase seems to be due to the intervention of the Pak protein kinase which would make T-type channels available again.In conclusion, we studied and caracterised tow new mechanisms of T-type channels regulation: a modulation by lipids, and a modulation by calcium and the Pak protein kinase.

HACE1 est une E3 ubiquitine ligase qui contrôle notamment l’activité de la petite GTPase Rac1 en catalysant son ubiquitination dégradative. Rac1 contrôle de nombreux processus cellulaires tels que l’adhérence, la migration et la prolifération. Aussi, la perte d’expression d’HACE1 dues à des altérations génétiques ou épigénétiques est associée à des pathologies humaines tels que le cancer, des syndromes neurodégénératifs et des maladies développementales. Pourtant, malgré l’importance de HACE1 en physiopathologie, rien n’est connu sur la régulation post-traductionnelle de son activité. Au cours de ce travail, nous avons montré que la serine 385 de HACE1 est phosphorylée par les kinases PAKs de groupe I en réponse à l’activation de Rac1 et de Cdc42. Nous montrons que le mutant phospho-mimetic HACE1(S385E) présente une activité réduite d’ubiquitination de Rac1. De plus, nous mettons en évidence un rôle centrale de la régulation de la Ser-385 par phosphorylation dans l’oligomérisation de HACE1, définissant ainsi les bases moléculaires de la relation entre structure et fonction de HACE1. En parallèle, nous avons déterminé que la perte d’expression d’HACE1 altère la cohésion des jonctions entre cellules épithéliales. Cet effet de dissociation s’apparente à une transition épithelio-mésenchymateuse (EMT) caractérisée par un échange d’expression de la E-cadhérine par la N-cadhérine régulé au niveau transcriptionnel. L’ensemble de ce travail a donc permis de mettre en évidence un mode inédit de régulation par phosphorylation de l’activité de HACE1 contrôlée par les kinases PAK du groupe I, ainsi qu’un rôle majeur de HACE1 dans la régulation de la cohésion cellulaire et l’EMT. / The E3 ubiquitin ligase HACE1 is a key regulator of cellular homeostasis best-characterized for its ability to control the activity of the Rho GTPase Rac1. This GTPase is encoded by an essential gene whose product controls a wide array of cellular processes such as cell adhesion, migration and proliferation. Accordingly, the repression of HACE1 expression due to genetic and epigenetic alterations has been associated with numerous pathologies, including cancer, neurodegenerative and developmental diseases. However, nothing is known about the posttranslational regulation of HACE1 activity. Here, we unveiled that HACE1 gets phosphorylated at serine Ser-385 by Group-I Pak kinases in response to Rac1/Cdc42 activation. Mechanistically, we define that the phospho-mimetic mutant HACE1(S385E) displays a lower capacity to ubiquitinate Rac1 in cells. In addition, our work attributes to the phosphorylation of Ser-385 a pivotal role in the state of HACE1 oligomerization, which sets the basis for deciphering the relationship between HACE1 structure and activity. In parallel, we have found that the loss of HACE1 expression leads to the disruption of epithelial monolayer cohesion characterized by disrupted of cell-cell junctions. Accordingly, we determined that loss of HACE1 results in the acquisition of epithelial-mesenchymal transition (EMT) features, including a transcriptionally regulated switch of expression between E-cadherin and N-cadherin. Altogether, this work reveals a phospho-mediated regulation of HACE1 activity that is under the control of Group I PAKs and implicates HACE1 in the balance between epithelium integrity versus EMT.

Neutrophils form a first line of defence against infections. These short-lived, terminally differentiated cells perform many important functions, including chemotaxis, degranulation, reactive oxygen species (ROS) release and cytokine production. Whilst neutrophils are essential for host immunity, their inappropriate recruitment, activation and/or removal can contribute to excessive inflammation and host damage, as exemplified in autoimmune diseases such as rheumatoid arthritis. It is therefore essential that neutrophil function is tightly regulated. Neutrophils are activated by a range of stimuli, including immune complexes. Neutrophil functions are tightly regulated by intracellular signalling events that are induced by the ligation of cell surface receptors, for example, the binding of immune complexes to Fc receptors. Phosphoinositide 3-kinase (PI3K) and extracellular signal-regulated kinase (Erk) are key signalling intermediates that act downstream of many cell surface receptors. They are involved in the regulation of numerous biological processes in the neutrophil. Using pharmacological interventions, I analysed PI3K signalling in immune complex-stimulated human neutrophils and uncovered a previously uncharacterised, noncanonical signalling pathway, PI3K-Cdc42-Pak-Mek-Erk. This represents an unusual situation where Pak acts as the MAP3K downstream of Cdc42 in a PI3K-dependent fashion. By performing a range of functional experiments, I showed that this unconventional signalling pathway promotes apoptosis in human neutrophils by regulating the ratio between anti- and pro-apoptotic members of the Bcl-2 family proteins. No other immune complex-induced, PI3K-dependent neutrophil function tested depended on PI3K-Cdc42-Pak-Mek-Erk signalling. Mouse knock-outs of all components of this signalling pathway have been described. Immune complex-induced apoptosis was also PI3K-dependent in mouse neutrophils, but experiments performed with inhibitors showed that, in contrast to human neutrophils, this was not dependent on PI3K-Cdc42-Pak-Mek-Erk signalling. The myeloid leukaemia cell line, PLB-985 is amenable to knock-down and can be differentiated to become neutrophil-like. These cells are not notably activated by immune complexes, perhaps because they do not express the major Fcγ receptor, CD16. Since retroviral expression of CD16 in PLB985 cells did not improve their response to activation by immune complexes, I was not able to confirm my observations with human neutrophils genetically. Collectively, I showed that a novel, pro-apoptotic signalling pathway operates downstream of Fcγ receptors in the human neutrophil. The fact that this signalling pathway appears to regulate apoptosis specifically suggests uncoupling pro- and anti-inflammatory effects induced by immune complexes might be possible. This may be helpful in the design of improved therapies of autoimmune diseases such as rheumatoid arthritis, in which immune complex-driven neutrophilic inflammation contributes to disease pathogenesis and where neutrophil apoptosis is disturbed.

The molecular mechanisms that coordinate postnatal brain enlargement, synaptic properties and cognition remain an enigma. This study demonstrates that neuronal complexity controlled by p21-activated kinases (PAKs) is a key determinant for postnatal brain enlargement and synaptic properties. Double knockout (DK) mice lacking both PAK1 and PAK3 were severely impaired in postnatal brain growth, resulting in a dramatic reduction in brain volume at maturity. Remarkably, the reduced brain was accompanied by minimal changes in total cell count, due to a significant increase in cell density. However, the DK neurons have smaller soma, markedly simplified dendritic arbors/axons and reduced synapse density. Surprisingly, the DK mice were elevated in basal synaptic responses due to enhanced individual synaptic potency, but severely impaired in bi-directional synaptic plasticity. The PAK1/3 action is likely mediated by cofilin-dependent actin regulation because the activity of cofilin and the properties of actin filaments were specifically altered in the DK mice.