<p>This thesis contributes to the research on optimization algorithms for nonlinear programming, and to the application of such algorithms to nonlinear model predictive control.</p><p>Regarding the contribution to research on algorithms for nonlinear programming, a novel algorithm is put forward with a complete theory for global and local convergence. This is the main contribution of the thesis. The algorithm, named rFSQP, is a reduced Hessian Feasible Sequential Quadratic Programming method. It remains feasible with respect to nonlinear inequalities at all SQP iterations, but nonlinear equality constraints are treated as in general reduced Hessian SQP methods. The rFSQP algorithm is implemented in MATLAB and tested on a number of small scale problems with encouraging results. However, the algorithm is designed for large scale problems with few degrees of freedom. Some preliminary testing of the algorithm on large scale problems are investigated.</p><p>The thesis also contributes to the understanding of the relation between sequential and simultaneous reduced gradient methods, and to the understanding of the relation between discretization methods for dynamical systems and the choice of optimization algorithms.</p><p>The thesis also contributes to model based control approaches of grate sintering. Grate sintering is a complex metallurgical process, where melting of solids and fast gas dynamics give rise to stiff process models, i.e. the "time constants" of the system differ by many decades in magnitude. Hence, application of real-time optimization methods like nonlinear model predictive control to the grate sintering process is challenging. The thesis gives a framework for implementing nonlinear model based control of grate sintering by giving a control objective, a nonlinear model and choosing an appropriate discretization scheme. The thesis gives a reduced order model which is less computationally demanding. Data from industrial experiments are used to adapt the model and to assess the control objective.</p>

Suite à une stimulation de macrophages au LPS, TANK est phosphorylé en C-terminal et polyubiquitiné de manière non dégradative en N-terminal. Ces deux phénomènes sont indépendants mais dépendent tout deux des kinases IKKe/TBK1. TANK comme ces deux kinases est indispensable à l'activations des facteurs transcriptionnels IRF3/7. Le signalosome COP9/CSN semble aussi intervenir dans la régulation de cette activation via l'interaction TANK/IKKe/CSN5.

This thesis contributes to the research on optimization algorithms for nonlinear programming, and to the application of such algorithms to nonlinear model predictive control. Regarding the contribution to research on algorithms for nonlinear programming, a novel algorithm is put forward with a complete theory for global and local convergence. This is the main contribution of the thesis. The algorithm, named rFSQP, is a reduced Hessian Feasible Sequential Quadratic Programming method. It remains feasible with respect to nonlinear inequalities at all SQP iterations, but nonlinear equality constraints are treated as in general reduced Hessian SQP methods. The rFSQP algorithm is implemented in MATLAB and tested on a number of small scale problems with encouraging results. However, the algorithm is designed for large scale problems with few degrees of freedom. Some preliminary testing of the algorithm on large scale problems are investigated. The thesis also contributes to the understanding of the relation between sequential and simultaneous reduced gradient methods, and to the understanding of the relation between discretization methods for dynamical systems and the choice of optimization algorithms. The thesis also contributes to model based control approaches of grate sintering. Grate sintering is a complex metallurgical process, where melting of solids and fast gas dynamics give rise to stiff process models, i.e. the "time constants" of the system differ by many decades in magnitude. Hence, application of real-time optimization methods like nonlinear model predictive control to the grate sintering process is challenging. The thesis gives a framework for implementing nonlinear model based control of grate sintering by giving a control objective, a nonlinear model and choosing an appropriate discretization scheme. The thesis gives a reduced order model which is less computationally demanding. Data from industrial experiments are used to adapt the model and to assess the control objective.

<p>Internasjonal forskning har gjennom flere studier koblet menns helse til mannsrollen, mens det finnes få norske studier innen dette feltet. Hensikten med foreliggende studie er å få økt kunnskap om hvordan menn opplever helse, aktiviteter og sosialt nettverk når yrkesrelatert aktivitet ikke lenger er hovedinnholdet i hverdagen. Studien er gjennomført blant faste deltagere i et uformelt sosialt nettverk, etablert for og av menn bosatt i en middels stor norsk by. Mennenes møteplass var en hytte i skogen omkring 15 minutters gange fra nærmeste bilvei og parkeringsplass. Nettverket besto av ca 25 ikke-yrkesaktive menn i aldersgruppen fra rett over 60 til godt over 80 år som møttes nesten hver dag året rundt i forbindelse med turaktivitet på dagtid. Data ble samlet gjennom 10 gruppeintervjuer samt deltagende og ikke-deltagende observasjon i miljøet. Komparativ analyse inspirert av metoden “grounded theory” ble gjennomført for å komme frem til mest mulig dekkende kategorier av innholdet i intervjudataene. Resultatene viser at nettverket og hytten med omgivelsene blir mennenes ”eget rom” med et kameratslig felleskap som de daglig oppsøker i en bevisst og aktiv ivaretakelse av egen helse og mestring. Deltagelse i et miljø hvor den enkelte mann kan fremtre slik han vil og klarer til en hver tid, skaper trivsel og opplevelse av sammenheng og mening som gir egenopplevd god helse. Undersøkelsen viser hvordan sammenhenger mellom helse, aktivitet og nettverk kan være mulig å forklare ved at enkeltindividet internaliserer nettverkets verdier og omdanner dem til positiv helseeffekt gjennom en følelse av velvære og fellesskap.</p> / <p>Internationally several studies have focused on men’s health connected to masculinity ideology. In Norway there is a lack of knowledge about men’s health related to gender. This study aimed at exploring retired men’s experiences of health, activities and social network. Data were collected by 10 group interviews with participants in an informal social network, established for and by men inhabiting a medium-sized Norwegian town. The men gathered at a cabin in the town woods about 15 minutes walking distance from the nearest road and parking lot. This social network consisted of 25 retired males, aged from 60 to well past 80 years. This group of men was meeting on a regular basis nearly every day all year connected to daytime hiking activities. Comparative analysis inspired by Grounded Theory was conducted to extract relevant categories from the interview data. The results showed that the social network and the cabin in the woods had become the men’s ‘own room’ combining friendship with conscious and active caring for ones own health and coping. Participation in an accepting environment allowed every man to appear as he wanted. The companionship at the cabin in beautiful surroundings created a feeling of wellbeing and a sense of coherence supporting the men’s experiences of having good health in spite of their relative high age and, for some, severe medical diagnosis. The study showed how connections between health, activity and social network in terms of individuals internalizing the values of the network can be transformed into personal health and feeling of wellbeing.</p>

Internasjonal forskning har gjennom flere studier koblet menns helse til mannsrollen, mens det finnes få norske studier innen dette feltet. Hensikten med foreliggende studie er å få økt kunnskap om hvordan menn opplever helse, aktiviteter og sosialt nettverk når yrkesrelatert aktivitet ikke lenger er hovedinnholdet i hverdagen. Studien er gjennomført blant faste deltagere i et uformelt sosialt nettverk, etablert for og av menn bosatt i en middels stor norsk by. Mennenes møteplass var en hytte i skogen omkring 15 minutters gange fra nærmeste bilvei og parkeringsplass. Nettverket besto av ca 25 ikke-yrkesaktive menn i aldersgruppen fra rett over 60 til godt over 80 år som møttes nesten hver dag året rundt i forbindelse med turaktivitet på dagtid. Data ble samlet gjennom 10 gruppeintervjuer samt deltagende og ikke-deltagende observasjon i miljøet. Komparativ analyse inspirert av metoden “grounded theory” ble gjennomført for å komme frem til mest mulig dekkende kategorier av innholdet i intervjudataene. Resultatene viser at nettverket og hytten med omgivelsene blir mennenes ”eget rom” med et kameratslig felleskap som de daglig oppsøker i en bevisst og aktiv ivaretakelse av egen helse og mestring. Deltagelse i et miljø hvor den enkelte mann kan fremtre slik han vil og klarer til en hver tid, skaper trivsel og opplevelse av sammenheng og mening som gir egenopplevd god helse. Undersøkelsen viser hvordan sammenhenger mellom helse, aktivitet og nettverk kan være mulig å forklare ved at enkeltindividet internaliserer nettverkets verdier og omdanner dem til positiv helseeffekt gjennom en følelse av velvære og fellesskap. / Internationally several studies have focused on men’s health connected to masculinity ideology. In Norway there is a lack of knowledge about men’s health related to gender. This study aimed at exploring retired men’s experiences of health, activities and social network. Data were collected by 10 group interviews with participants in an informal social network, established for and by men inhabiting a medium-sized Norwegian town. The men gathered at a cabin in the town woods about 15 minutes walking distance from the nearest road and parking lot. This social network consisted of 25 retired males, aged from 60 to well past 80 years. This group of men was meeting on a regular basis nearly every day all year connected to daytime hiking activities. Comparative analysis inspired by Grounded Theory was conducted to extract relevant categories from the interview data. The results showed that the social network and the cabin in the woods had become the men’s ‘own room’ combining friendship with conscious and active caring for ones own health and coping. Participation in an accepting environment allowed every man to appear as he wanted. The companionship at the cabin in beautiful surroundings created a feeling of wellbeing and a sense of coherence supporting the men’s experiences of having good health in spite of their relative high age and, for some, severe medical diagnosis. The study showed how connections between health, activity and social network in terms of individuals internalizing the values of the network can be transformed into personal health and feeling of wellbeing.

Ifølge observationer af Grønnum og Basbøll er der sket en ekspansion af stødets forekomst, hvor ord som ikke tidligere har haft stød er begyndt at få det. Disse nye stød forekommer både under kendte betingelser og nye betingelser. Formålet med denne opgave er at undersøge om stødforekomsten i københavnsk rigsmål er blevet forandret i retning mod flere stød. Dette undersøges gennem at analysere forekomsten af nye stød i et materiale bestående af indspil- ninger fra otte forskellige talere, hentede fra radioprogrammer og podcasts udgivet mellem 2018 og 2020. Konklusionen er at der ses en tendens til en forandring i stødets forekomst i retning mod flere stød, men ud fra dette materiale er denne forandring stadig i et tidligt stadie. Der ses en forandring mod flere stød i forhold til at ord som ikke tidligere havde stød fore- kommer med stød, men i forhold til andelen ord med stød generelt kan der ikke drages nogle konklusioner. Mængden materiale i denne undersøgelse er for begrænset til at der kan gives et ordentligt billede af forandringen.

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Le cancer de la prostate est le cancer le plus diagnostiqué et représente la troisième cause de mort par cancer chez les hommes au Canada. Environ un quart des patients auront une récidive biochimique suite aux traitements de première ligne (chirurgie ou radiation). Le traitement systématique subséquent est la thérapie de déprivation à l’androgène qui permettra, dans un premier temps, un ralentissement de la croissance de la tumeur dite hormonosensible. Puis, dans un second temps, cette thérapie mènera à une progression vers un stade résistant à la castration avec ou sans métastases. De plus, environ 10% des patients recevront un diagnostic de cancer de la prostate métastatique. Cette forme du cancer de la prostate est une des formes les plus agressives et, à ce jour, il n’existe aucun traitement curatif. C’est pourquoi il est important de mieux déterminer les facteurs impliqués dans la progression du cancer de la prostate. De nombreuses études menées par le laboratoire ont permis d’identifier la kinase IKKe comme un facteur impliqué dans la progression du cancer de la prostate. Ainsi, il a été montré que les lignées résistantes à la castration expriment constitutivement IKKe sécrètent IL-6 et IL-8, cytokines impliquées dans la transactivation du récepteur à l’androgène, un des mécanismes de progression de ce cancer. Pour permettre cette sécrétion, IKKe phosphoryle C/EBP-b, facteur de transcription, ce qui conduit à l’activation de la transcription des gènes IL-6 et IL-8. Par ailleurs, C/EBP-b joue un rôle dans le contrôle de la sénescence induite par la thérapie de déprivation à l’androgène. Nous émettons donc l’hypothèse que IKKe interfère avec les mécanismes de sénescence induit par la thérapie de déprivation à l’androgène et que cibler IKKe permettrait de contrôler la croissance du cancer de la prostate résistant à la castration. Le premier objectif fut d’évaluer l’impact de l’inhibition de IKKe sur le destin cellulaire lors de la progression du cancer de la prostate. La déplétion de IKKe induit un phénotype de sénescence dans la lignée PC-3. L’utilisation d’inhibiteurs de IKKe, le BX795 et l’Amlexanox, induit un phénotype de sénescence dans les cellules résistantes à la castration, où IKKe a une expression constitutive, accompagnée d’une forte induction de dommages à l’ADN et d’une instabilité génomique, de façon dose-dépendent. Dans les iii cellules hormonosensibles, les inhibiteurs n’ont que très peu d’effet puisque l’expression de IKKe n’est pas constitutive. De plus, les inhibiteurs de IKKe ralentit la croissance tumorale des xénogreffes PC-3 et DU145, alors qu’ils n’ont aucun effet sur la croissance tumorale de la xénogreffe hormonosensible 22Rv1. Le deuxième objectif avait pour but de caractériser le rôle de IKKe dans l’échappement de la sénescence induite par la thérapie de déprivation à l’androgène. Nos travaux de recherche montrent que la déplétion ou l’utilisation de l’Amlexanox induit une diminution du recrutement de C/EBP-b au niveau du promoteur du gène de Rad51, protéine indispensable pour l’efficacité des mécanismes de réparation des dommages à l’ADN. De plus, bloquer la voie de réparation médiée par Rad51 par l’intermédiaire de l’Amlexanox améliore la sensibilité à l’Olaparib des cellules résistantes à la castration in vitro. De même, dans un modèle de xénogreffes résistantes à la castration, la combinaison Amlexanox – Olaparib montre un meilleur effet sur le ralentissement de la croissance tumorale. En conclusion, ce projet de doctorat aura permis de préciser les mécanismes impliquant IKKe dans la progression du cancer de la prostate. Les résultats apportent un nouvel éclairage sur le rôle de IKKe dans la régulation des dommages à l’ADN, particulièrement sur la transcription du gène Rad51 via C/EBP-b. De plus, les expériences in vivo montrent le potentiel thérapeutique de l’Amlexanox, notamment en le combinant avec l’Olaparib, afin de contrôler la croissance des tumeurs résistantes à la castration. / Prostate cancer is the most frequently diagnosed cancer and is the third leading cause of cancer death in men in Canada. About a quarter of patients will have a biochemical recurrence following first-line treatments (surgery or radiation). The subsequent systematic treatment is androgen deprivation therapy which will initially slow the growth of hormone- sensitive tumors. Almost inevitably this therapy will lead to progression towards castrate resistance with or without metastases. In addition, approximately 10% of patients will be initially diagnosed with metastatic prostate cancer. This form of prostate cancer is one of the most aggressive forms and, to date, there is no curative treatment. This underscores the important of better understanding the factors involved in the progression of prostate cancer. Numerous studies conducted by our laboratory have identified IKKe kinase as a factor involved in the progression of prostate cancer. It has been shown that castrate resistant cell lines that constitutively express IKKe secrete IL-6 and IL-8, cytokines involved in the transactivation of the androgen receptor, one of the mechanisms leading to cancer progression. IKKe contributes to this through the phosphorylation of C/EBP-b, a transcription factor, which leads to the activation of the transcription of the IL-6 and IL-8 genes. Furthermore, C/EBP-b plays a role in the control of senescence induced by androgen deprivation therapy. We therefore hypothesized that IKKe interferes with the mechanisms of senescence induced by androgen deprivation therapy and that targeting IKKe would control the growth of castration-resistant prostate cancer. The first objective was to assess the impact of IKKe inhibition on cell fate during prostate cancer progression. Depletion of IKKe induces a senescence phenotype in the PC- 3 cell line. The use of the IKKe inhibitors, BX795 and Amlexanox, induces a senescence phenotype in castrate resistant cell lines, where IKKe is constitutively expressed, accompanied by a strong induction of DNA damage and genomic instability in a dose- dependent manner. Since IKKe expression is not constitutive in hormone-sensitive cell lines, IKKe inhibitors have very little effect in these. In addition, IKKe inhibitors slow the growth of the PC-3 and DU145 xenografts, while they have no effect on the growth of hormone-sensitive 22Rv1 xenografts. v The second objective was to study the role of IKKe in the senescence escape induced by androgen deprivation therapy. Our research shows that the IKKe depletion or the use of Amlexanox induces a decrease in the C/EBP-b recruitment on the promoter of the Rad51 gene, a protein essential for the efficiency of the mechanisms of DNA damage repair. In addition, blocking the Rad51-mediated repair pathway through Amlexanox enhances susceptibility to Olaparib in castrate resistant cell lines in vitro. Likewise, in a castrate resistant xenograft model, the combination Amlexanox - Olaparib has a stronger effect on tumor growth as compared to a control or each treatment individually. In conclusion, this doctoral research has made it possible to identify a new mechanism implicating IKKe in the progression of prostate cancer. The results show the role of IKKe in the regulation of DNA damage, particularly on the transcription of the Rad51 gene via C/EBP-b. In addition, in vivo experiments show the therapeutic potential of Amlexanox, particularly in combination with Olaparib, to control the growth of castrate resistant tumors.