Försvarsmakten är under en återuppbyggnad och står inför en stor nyanskaffning av materiel till samtliga delar av organisationen. 161. Stridsledning- och luftbevakningsbataljonen skall utöka och ersätta delar av den befintliga sensorkedjan med nya system där det finns utrymme för anskaffning av rörliga markbaserade radarsystem.  Tidigare forskning och rapporter från bland annat FOI och Försvarsmakten kopplat mot framtidens radarsensorer tyder på att AESA-radarer är väl lämpliga vid en framtida anskaffning. Arbetet är av tekniskt beskrivande karaktär och använder teorin om militär nytta samt analysverktyget multimålmetoden. Arbetets syfte är att undersöka om de framtagna värderingskriterierna kostnad, rörlighet, masthöjd och målupptäckt skulle kunna användas vid en svensk anskaffning av ett rörligt markbaserat radarsystem. Slutsatsen är att värderingskriterierna som tagits fram i arbetet kan och bör användas vid en anskaffning av ett rörligt markbaserat radarsystem. Dock behöver värderingskriterierna fördjupas ytterligare för att i framtida användning få fram ett mer precist resultat. / The Swedish Armed Forces are undergoing a re-establishment and are facing a major new acquisition of equipment for all parts of the organization. 161. Combat Control and Air Surveillance Battalion will increase and replace parts of the existing sensor chain with new systems where there is room for the acquisition of mobile ground-based radar systems.  Previous research and reports from, among others, FOI and the Swedish Armed Forces related to future radar sensors indicate that AESA radars are well suited for in a future acquisition. This report is of a technical descriptive type and uses the theory of military utility and the analysis tool multi-criteria decision. The purpose of the report is to investigate whether the valuation criteria’s cost, mobility, mast height and target detection should be used as criteria in a Swedish acquisition of a mobile ground-based radar system. The conclusion is that the evaluation criteria concluded in the report can and should be used in the acquisition of a mobile ground-based radar system. However, the evaluation criteria need to be further deepened to obtain a more precise result in future use.

Developing new membrane morphologies and modifying the existing membrane materials are required to obtain membranes with improved gas separation performances. The incorporation of zeolites and low molecular-weight additives (LMWA) into polymers are investigated as alternatives to modify the permselective properties of polymer membranes. In this study, these two alternatives were applied together to improve the separation performance of a polymeric membrane. The polycarbonate (PC) chain characteristics was altered by incorporating p-nitroaniline (pNA) as a LMWA and the PC membrane morphology was modified by introducing zeolite 4A particles as fillers. For this purpose, pure PC and PC/pNA dense homogenous membranes, and PC/zeolite 4A and PC/pNA/zeolite 4A mixed matrix membranes (MMM) were prepared by solvent-evaporation method using dichloromethane as the solvent. The pNA and zeolite 4A concentrations in the casting solutions were changed between 1-5% (w/w) and 5-30% (w/w), respectively. Membranes were characterized by SEM, DSC, and single gas permeability measurements of N2, H2, O2, CH4 and CO2. They were also tested for their binary gas separation performances with CO2/CH4, CO2/N2 and H2/CH4 mixtures at different feed gas compositions. DSC analysis of the membranes showed that, incorporation of zeolite 4A particles into PC/pNA increased the glass transition temperatures, Tg, but incorporation of them to pure PC had no effect on the Tg, suggesting that pNA was a necessary agent for interaction between zeolite 4A and PC matrix. The ideal selectivities increased in the order of pure PC, PC/zeolite 4A MMMs and PC/pNA/zeolite 4A MMMs despite a loss in the permeabilities with respect to pure PC. A significant improvement was achieved in selectivities when the PC/pNA/zeolite 4A MMMs were prepared with pNA concentrations of 1 % and 2 % (w/w) and with a zeolite loading of 20 % (w/w). The H2/CH4 and CO2/CH4 selectivities of PC/pNA (1%)/zeolite 4A (20%) membrane were 121.3 and 51.8, respectively, which were three times higher than those of pure PC membrane. Binary gas separation performance of the membranes showed that separation selectivities of pure PC and PC/pNA homogenous membranes were nearly the same as the ideal selectivities regardless of the feed gas composition. On the other hand, for PC/zeolite 4A and PC/pNA/zeolite 4A MMMs, the separation selectivities were always lower than the respective ideal selectivities for all binary gas mixtures, and demonstrated a strong feed composition dependency indicating the importance of gas-membrane matrix interactions in MMMs. For CO2/CH4 binary gas mixture, when the CO2 concentration in the feed increased to 50 %, the selectivities decreased from 31.9 to 23.2 and 48.5 to 22.2 for PC/zeolite 4A (20%) and PC/pNA (2%)/zeolite 4A (20%) MMMs, respectively. In conclusion, high performance PC based MMMs were prepared by blending PC with small amounts of pNA and introducing zeolite 4A particles. The prepared membranes showed promising results to separate industrially important gas mixtures depending on the feed gas compositions.

This master's thesis analyzes annotation server algorithms for searching and updating annotation fragments. The annotation server is a part of the project Decipher. Analyzed algorithms are improved and replaced by newly designed algorithms in this project. A part of this project also designs a new algorithm for measuring how much is an annotation affected after updating the document.

The Hepatitis C virus (HCV) NS3/4A protease inhibitors (PIs) have become a mainstay of newer all-oral combination therapies. Despite improvements in potency of this inhibitor class, drug resistance remains a problem with the rapid emergence of resistance-associated substitutions (RASs). In this thesis I elucidate the molecular mechanisms of drug resistance for PIs against a resistant variant and apply insights toward the design of inhibitors with improved resistance profiles using structural, biochemical and computational techniques. Newer generation PIs retain high potency against most single substitutions in the protease active site by stacking on the catalytic triad. I investigated the molecular mechanisms of resistance against the Y56H/D168A variant. My analysis revealed that the Y56H substitution disrupts these inhibitors’ favorable stacking interactions with the catalytic residue His57. To further address the impact of drug resistance, I designed new inhibitors that minimize contact with known drug resistance residues that are unessential in substrate recognition. The initially designed inhibitors exhibited flatter resistance profiles than the newer generation PIs but lost potency against the D168A variant. Finally, I designed inhibitors to extend into the substrate envelope (SE) and successfully regained potency against RAS variants maintaining a flat profile. These inhibitors both pack well in the enzyme and fit within the SE. Together these studies elucidate the molecular mechanisms of PI resistance and highlight the importance of substrate recognition in inhibitor design. The insights from this thesis provide strategies toward the development of diverse NS3/4A PIs that may one day lead to the eradication of HCV.

No description available.

This master's thesis describes Semantic Enrichment Component (SEC), that searches entities (e.g., persons or places) in the input text document and returns information about them. The goals of this component are to create a single interface for named entity recognition tools, to enable parallel document processing, to save memory while using the knowledge base, and to speed up access to its content. To achieve these goals, the output of the named entity recognition tools in the text was specified, the tool for storing the preprocessed knowledge base into the shared memory was implemented, and the client-server scheme was used to create the component.

Thesis (MPhil (Ancient Studies. Centre for Bible Interpretation and Translation in Africa))--University of Stellenbosch, 2007. / Reading the creation narratives in Genesis 1 and 2, one encounters two totally different renditions. The two creation narratives agree that God created the universe and that God blesses his creation in abundance. But why did the Hebrews need two creation stories so different in style? Gen. 1-2:4a seized my interest and I wanted to explore not only the milieu in which it was written, but also to read it against the creation narratives of the ancient Near East. The research was done religioushistorically. An insight had to be gained in the function and role of mythology within a cultural system and after distinguishing between folk sagas, legends and myths, different types of myths, as well as some perspectives on myths had to be investigated. Creation themes such as creation by birth, by struggle or victory, by action or activity as well as creation through the spoken word were encountered in the various creation narratives studied. Ancient Near East cosmogonies such as the variety of Egyptian cosmogonies, as well as Mesopotamian creation epics have been considered. Hittite myths were also considered, but here the result was the discovery of an extended pantheon with virtually no creation references. Thereafter I have concentrated on the cosmogony of the Hebrew Bible and the position, structure and understanding of Gen. 1-2:4a. Most creation stories revert to bloody violence between the gods. The God of the Hebrews is a God of order – from chaos he creates more than order, he creates beauty. The subsequent survey of the conception of humankind in the near Ancient East, proved to be varied as well as interesting, some with remarkable parallels. My interest was extended to placing the creation narrative of Gen. 1-2:4a in the modern era, by attempting to gain insight into the “Big Bang” theory, as well as Creationism and Evolution movements. Many motives were deducted by the research, but the idea of God creating in a “Godly” manner (bārā') and not merely give order to pre-created creations through struggle was unique. Human beings were created as the pinnacle of creation, and made to live in a relationship with their Creator.

L'hépatite C pose un problème de santé publique majeur, dans la mesure où le risque de développer une infection chronique est relativement élevé (40 à 60%) et où la résistance au traitement de choix - l’interféron alpha pégylé et la ribavirine - touche près de la moitié des patients. Cette persistence virale repose avant tout sur de puissantes stratégies d’évasion du système immunitaire inné de l’hôte par le virus. Dans ce projet, nous nous sommes intéressés à la caractérisation de la réponse antivirale dans des hépatocytes primaires humains normaux et chroniquement infectés avec le VHC, un domaine encore largement inconnu dû à la difficulté d’obtenir ce type de matériel primaire. Nous avons étudié la fonctionnalité de deux voies majeures de détection des pathogènes viraux suite à l’exposition d’hépatocytes primaires humains à de l’ARNdb intracellulaire, via le récepteur et adaptateur RIG-I/MDA5-CARDIF, et extracellulaire via TLR3-TRIF, mimant ainsi les étapes précoces de la détection d’un virus par la cellule hôte. Nous avons établi par RT-PCR quantitatif et analyse transcriptomique par microarray, que ces deux voies de stimulation sont fonctionnelles dans des hépatocytes primaires normaux et que leur activation entraîne à la fois l’expression de gènes antiviraux communs (ISG56, ISG15, CXCL10, …) mais aussi spécifiques avec les gènes IL28A, IL28B et IL29 qui sont une signature de l’activation de la voie de détection de l’ARNdb intracellulaire. La protéine virale NS3/4A joue un rôle majeur à la fois dans le clivage de la polyprotéine virale initiale, mais aussi en interférant avec les cascades de signalisation engagées suite à la détection par la cellule hôte de l’ARN du VHC. Plus particulièrement, nous avons démontré que l’expression ectopique de NS3/4A dans des hépatocytes primaires humains normaux entraîne une diminution significative de l’induction des gènes antiviraux dûe au clivage de CARDIF au cours de l’activation de la voie de signalisation médiée par RIG-I. Nous avons également démontré que l’expression de la NS3/4A entraîne des modifications de l’expression de gènes-clé impliqués dans la régulation de l’apoptose et du programme de mort cellulaire, en particulier lorsque la voie TLR3 est induite. L’ensemble de ces effets sont abolis en présence de BILN2061, inhibiteur spécifique de NS3/4A. Malgré les stratégies de subversion de l’immunité innée par le VHC, nous avons démontré l’induction significative de plusieurs ISGs et chemokines dans des hepatocytes primaires provenant de patients chroniquement infectés avec le VHC, sans toutefois détecter d’interférons de type I, III ou certains gènes antiviraux précoces comme CCL5. Ces observations, concomitantes avec une diminution de l’expression de CARDIF et une correlation inverse entre les niveaux d’ARNm des ISGs et l’ARN viral révèlent une réponse antivirale partielle dûe à des mécanismes interférents sous-jacents. Cette réponse antivirale détectable mais inefficace est à mettre en lien avec l’échec du traitement classique PEG-IFN-ribavirine chez la moitié des patients traités, mais aussi en lien avec l’inflammation chronique et les dommages hépatiques qui mènent ultimement au développement d’une fibrose puis d’une cirrhose chez une grande proportion de patients chroniquement infectés. / Hepatitis C infection is a worldwide health problem since the risk to develop a persistent infection is relatively elevated (40 to 60%) and nearly half of the infected patients do not respond to the classical anti-HCV therapy based on a combination of PEG-IFNα and ribavirin. Viral persistence is based on powerful evasion strategies of the host’s innate immune system. In our study, we characterized antiviral response in primary human normal and chronically HCV-infected hepatocytes, a cutting-edge in our field due to the difficulty to isolate this particular cell type. In order to better define the antiviral response in freshly isolated human primary hepatocytes, we stimulated these cells with extracellular and intracellular dsRNA to trigger TLR3/TRIF and RIG-I-MDA5/CARDIF-mediated antiviral signaling pathways. By using qRT-PCR and microarray analysis, we report that both detection pathways are functional in normal human hepatocytes, their activation leading to the expression of both common (IFIT1, OASL, ISG15 and CXCL10) and specific genes (IL28A, IL28B and IL29), these last ones being a signature of the intracellular dsRNA-mediated pathway. HCV NS3/4A plays a key role in the viral polyprotein processing and upon viral RNA detection by interfering with the host’s antiviral signalling cascades. We report that major antiviral genes induction following activation of RIG-I mediated pathway are severely impaired in ectopically NS3/4A expressing normal hepatocytes due to CARDIF cleavage, but can be restored by specific NS3/4A inhibitor BILN2061. Our microarray analysis also revealed a role for NS3/4A following TRL3-mediated pathway activation on regulation of apoptosis and programmed cell death, which could be linked to strategies for the virus to persist in its host. Despite HCV strategies to circumvent the host’s immune defense system, we observed significant upregulation of ISGs and chemokines in liver biopsies and corresponding isolated hepatocytes from chronically HCV-infected patients. However, no type I and III interferon, neither key-antiviral genes (e.g., CCL5) were detected, underlying an ongoing –but inefficient- antiviral response unable to eradicate the virus. Moreover, we obtained significant inverse correlations between ISGs mRNAs and viral RNA in addition to CARDIF decrease, clearly unravelling efficient viral interfering strategies in a context of chronic HCV infection. This sustained -albeit incomplete- hepatic innate immune response is certainly associated to the failure of the classical IFN-based therapy in half of the infected patients and to the chronic inflammation causing liver damages and eventually leading to hepatocarcinoma which is often observed at late stage of the disease.

Percebendo no lentíssimo voo dos aeromodelos F1D um sublime que a aceleração contemporânea subtrai à vida, a presente pesquisa busca formular hipóteses em torno ao fenômeno desacelerante desse voo; para tal, entendese a \"dúvida\" enquanto potência e o \"desconhecido\" como instância de liberdade. / Observing the F1D\'s slow flight, we can realize a sublime feeling that contemporary acceleration subtracts from life. Our research looks for hypotheses about this deceleration generated by the F1D; besides that, we take the \"doubt\" as potency and the \"unknown\" as a field of freedom.

Il y a une dizaine d'années, de nouvelles flavoenzymes nommées hydroxylases flavine-dépendantes à deux composants ont été identifiées chez certains microorganismes. Le rôle physiologique de ces enzymes est maintenant bien connu. Elles sont impliquées dans les processus de biosynthèse et de biodégradation d'une multitude de molécules organiques. Ces hydroxylases sont composées de deux enzymes distinctes. La première est une flavine réductase qui catalyse la formation de flavine réduite nécessaire au fonctionnement de la seconde enzyme, une monooxygénase flavine-dépendante. Au début de notre projet, le mécanisme enzymatique de ces nouvelles hydroxylases était encore inconnu. Pour comprendre le détail de leur fonctionnement, nous avons choisi d'étudier le système ActVA-ActVB, un nouveau membre de la famille des hydroxylases flavine-dépendantes impliqué dans la dernière étape de biosynthèse de l'actinorhodine, un antibiotique naturel synthétisé par Streptomyces coelicolor. La caractérisation préalable de ActVB avait permis de montrer que cette enzyme était une NADH:FMN oxydoréductase capable de catalyser la réduction du FMN par le NADH selon un mécanisme de type séquentiel ordonné. Nos résultats ont permis d'identifier ActVA-Orf5, une monooxygénase flavine-dépendante capable d'utiliser la flavine réduite fournie par ActVB pour catalyser l'hydroxylation du précurseur de l'actinorhodine, la DHK. Le mécanisme de transfert de flavine entre les deux protéines a été étudié. Pour cela, les constantes de dissociation du FMNox et FMNred vis-à-vis de ActVA et ActVB ont été déterminées. Nos donnés montrent clairement qu'à l'état réduit, la flavine est bien plus affine pour la monooxygénase ActVA que pour la réductase ActVB alors qu'à l'état oxydé, elle possède une meilleure affinité pour la réductase que pour la monooxygénase. Cette différence d'affinité permet d'orienter le transfert de flavine d'une protéine à l'autre sans nécessiter d'interaction entre les deux protéines. Nous avons montré de plus que ActVA avait la capacité de stabiliser un intermédiaire activé de l'oxygène, une espèce électrophile nommée C(4a)-hydroperoxyflavine, au sein de son site actif. Cet intermédiaire réagit très rapidement avec la DHK nucléophile pour former son analogue hydroxylé : la DHK-OH. En accord avec ce mécanisme, il semble que le pouvoir nucléophile du substrat est très important pour cette réaction car seule la forme réduite à deux électrons de DHK (hydroquinone) est hydroxylée. D'autre part, ActVA ne semble pas être très spécifique car elle parvient également à catalyser l'hydroxylation de l'énantiomère de la DHK, la NNM-A et de l'analogue lactonique de la NNM-A, la NNM-D. Finalement le système ActVA-ActVB n'a pas la capacité de dimériser la DHK-OH pour former l'actinorhodine et l'enzyme intervenant dans la dernière étape de cette biosynthèse reste à identifier.