The recent emergence of a number of new viral diseases as well as the re-emergence of tuberculosis (TB), indicate an urgent need for new drugs against viral and bacterial infections. Coronavirus nsp1 has been shown to induce suppression of host gene expression and interfere with host immune response. However, the mechanism behind this is currently unknown. Here we present the first nsp1 structure from an alphacoronavirus, Transmissible gastroenteritis virus (TGEV) nsp1. Contrary to previous speculation, the TGEV nsp1 structure clearly shows that alpha- and betacoronavirus nsp1s have a common evolutionary origin. However, differences in conservation, shape and surface electrostatics indicate that the mechanism for nsp1-induced suppression of host mRNA translation is likely to be different in the alpha- and betacoronavirus genera. The Modoc virus is a neuroinvasive rodent virus with similar pathology as flavivirus encephalitis in humans. The flaviviral methyltransferase catalyses the two methylations required to complete 5´ mRNA capping, essential for mRNA stability and translation. The structure of the Modoc NS5 methyltransferase domain was determined in complex with its cofactor S-adenosyl-L-methionine. The observed methyltransferase conservation between Modoc and other flaviviral branches, indicates that it may be possible to identify drugs that target a range of flaviviruses and supports the use of Modoc virus as a model for general flaviviral studies. 1-deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is part of the methylerythritol phosphate (MEP) pathway that produces essential precursors for isoprenoid biosynthesis. This pathway is used by a number of pathogens, including Mycobacterium tuberculosis and Plasmodium falciparum, but it is not present in humans. Using a structure-based approach, we designed a number of MtDXR inhibitors, including a novel fosmidomycin-analogue that exhibited improved activity against P.falciparum in an in vitro blood cell growth assay. The approach also allowed the first design of an inhibitor that bridge both DXR substrate and co-factor binding sites, providing a stepping-stone for further optimization.

O objetivo deste estudo in vitro foi avaliar e comparar a microestrutura e a composição mineral do esmalte e da dentina de dentes decíduos e permanentes. Terceiros molares hígidos e segundos molares decíduos foram selecionados e distribuídos aleatoriamente em grupos, de acordo com o método de análise dos substratos utilizado: Microscopia Eletrônica de Varredura (MEV), Espectroscopia de Energia Dispersiva de Raio X (EDX), Difração de Raio X (DRX) e Microscopia Óptica (MO). Foi realizada comparação qualitativa e quantitativa da estrutura dental. As medidas de densidade numérica e diâmetro dos prismas de esmalte/túbulos dentinários e, de espessura do esmalte, dentina e dentina peritubular foram realizadas por meio de fotomicrografias obtidas pela MEV. Os resultados obtidos por meio da SEM foram analisados estatisticamente pelo teste não-paramétrico de Kruskal-Wallis. A quantidade relativa de íons cálcio (Ca) e fósforo (P) foram determinadas por meio de EDX e as fases químicas presentes em ambos os substratos, por análise de DRX. O valor das medidas de espessura observado para o esmalte e dentina dos dentes decíduos foi de 1.14 mm e 3.02 mm, respectivamente. Para os dentes permanentes, obtiveram-se valores de 2.58 mm para o esmalte e 5.95 mm para a dentina. Com relação ao diâmetro da cabeça dos prismas de esmalte, os resultados foram estatisticamente semelhantes para os dentes decíduos e permanentes, demonstrando uma ligeira diminuição do diâmetro da superfície externa para a região próxima a junção amelodentinária (JAD). A densidade numérica dos prismas foi maior nos dentes decíduos, principalmente próximo à JAD, sendo estatisticamente diferente dos valores observados nos dentes permanentes, independente da região analisada. Na análise do diâmetro e densidade numérica dos túbulos dentinários verificou-se semelhança estatística entre os dentes decíduos e permanentes, havendo aumento gradativo do número de túbulos a partir da JAD em direção a região próxima a polpa. A espessura da dentina peritubular, na região próxima a JAD e central foi, respectivamente, 0.91 e 0.59 mm nos dentes decíduos 1.16 e 0.98 mm nos dentes permanentes. A porcentagem de Ca e P foi maior nos dentes permanentes. Observou-se ainda, que a quantidade de colágeno nos dentes decíduos foi aparentemente menor quando analisados por meio da MO. De acordo com os resultados obtidos neste estudo, pode-se concluir que, de maneira geral, os dentes decíduos apresentam menor porcentagem de Ca e P, menor espessura de esmalte e dentina, maior densidade numérica de prismas e dentina peritubular mais delgada quando comparada aos dentes permanentes. / This study evaluated in vitro the microstructure and mineral composition of dental enamel and dentin comparing the permanent teeth with the deciduous teeth. Sound third molars and second primary molars were selected and randomly assigned to the following groups, according to the analysis methods of the substrates performed: Scanning Electron Microscopy (SEM), X-Ray diffraction (XRD), Energy dispersive X-ray spectrometer (EDS) and Optical Microscopy (OP). A qualitative and quantitative comparison of the dental structure was done. The measurements of the number and diameter of prisms/tubules, thickness of enamel, dentin and peritubular dentin were done in SEM photomicrographs. The microscopic findings were analyzed statistically by a non-parametric test (Kruskal- Wallis). The relative amounts of calcium (Ca) and phosphorus (P) were determined by EDS investigation. Phase present in both types of teeth were observed by the XRD analysis. The mean thickness measurements observed in the deciduous teeth enamel and dentin was, respectively, 1.14 mm and 3.02 mm and in the permanent teeth, 2.58 mm and 5.95 mm. The mean rod head diameter in deciduous teeth was statistically similar to that of permanent teeth enamel, and a slightly decrease from the outer enamel surface to the region next to the enameldentine junction was assessed. The numerical density of enamel rods was higher in the deciduous teeth, mainly near EDJ, that showed statistically significant difference. The mean tubules number and diameter in deciduous teeth were statistically similar to that of permanent teeth, and this numerical density increased from the EDJ to the region near the pulp. The mean thickness measurements of peritubular dentin observed in the regions near EDJ and central were, respectively, 0.91 and 0.59 mm for the primary teeth / 1.16 and 0.98 mm for the permanent teeth. The percentage of Ca and P was higher in the permanent teeth. The collagen level was apparently lower in deciduous teeth when analyzed by OP. The primary teeth structure showed a lower level of Ca and P and a thinner enamel and dentin thickness. The deciduous enamel presented higher numerical density of rods. The peritubular dentin was thicker in the permanent teeth.

Detta arbete beskriver en examensuppsats i datateknik på Linnéuniversitetet. Röntgenavdelningen på SUS, Skånes Universitetssjukhus i Lund, använder en lättviktig flyttbar röntgenmaskin som väger endast cirka 90 kg, för röntgenundersökningar ute på äldreboenden. Bilderna överförs till sjukhusets PACS när maskinen är tillbaka på sjukhuset, genom att man kopplar in Dragon via kabel till sjukhusets nätverk. Målsättningen är att förbättra den trådlösa kommunikationen som för närvarande är för långsam och opålitlig, så att bilderna kan överföras till sjukhusets PACS direkt efter undersökningen. I detta arbete beskrivs vilka alternativ som kan användas. Samt om de mobila bredbandstjänster som finns tillgängliga i Region Skåne är bra nog för att kunna användas för uppgiften. Slutsatsen är att ett 3G HSDPA/HSUPA abonnemang kan vara tillförlitligt nog. Framför allt om extra redundans tillförs med dubbla SIM-kort som använder separata nät och att signalen förstärks med antenn placerad utomhus på transportfordonet. Transportfordonet används som brygga mellan Wifi och mobilt nätverk. Röntgenmaskinen kommunicerar med transportfordonet via Wifi. För de fall Wifi inte fungerar på grund av byggnader och omgivande miljö arbetades ett reservalternativ fram. Jag har också undersökt och jämfört DICOM protokollet mot FTP. Detta för att se om DICOM har en overhead som skulle motivera användet av FTP istället för sändning av bilder. Resultatet av jämförelsen visade att DICOM har 5-10 % overhead jämfört med FTP. / This abstract describes a degree project in computer engineering at Linnaeus University. The Department of Radiology at SUS, Skåne University Hospital in Lund, is using a lightweight portable x-ray machine that weights about 90 kg, for radiography services in nursing homes for elders. The images are transferred to hospital PACS when the machine returns to the hospital, this is done with Dragon connecting to hospital network via wire. The goal is to improve the currently too slow and unreliable wireless communication, so the images can be transferred to hospital PACS directly after examination. This report describes what alternatives can be used and investigates whether the mobile broadband services currently available in Skåne County are good enough to be relied on for the task. The conclusion is that a 3G HSDPA/HSUPA subscription can be used reliably enough, if extra redundancy is added via dual SIM cards using separate mobile networks and the signal is strengthen by an antenna placed outdoors on the transport vehicle. The transport vehicle is used as a bridge between Wifi and mobile networks. The mobile x-ray machine communicates with the transport vehicle via Wifi. In those cases Wifi does not work due to difficult building environments, a backup solution was worked out to be used. I also investigated and compared the DICOM protocol against FTP. This was to find out if DICOM has an overhead that would motivate using FTP instead for the transmission of the images, the result of the comparison showed that DICOM has an 5-10 % overhead compared with FTP. / Mobil röntgen Skånes Universitetssjukhus Lund

Introduktion: Uppskattningsvis 40% av alla magnetresonanstomografiska (MRT) undersökningar som görs i Europa och USA utförs med gadoliniumbaserade kontrastmedel. Under det senaste decenniet har det i flera studier uppmärksammats att ansamling av gadolinium sker i olika strukturer i hjärnan. Patienter med multipel skleros följs regelbundet upp med MRT undersökningar och MRT med kontrastförstärkning är den vanligaste metoden för att urskilja nytillkomna patologiska förändringar. Utveckling inom teknologi och metoder inom artificiell intelligens har visat att det finns anledning att kartlägga om röntgensjuksköterskans arbete med undersökningar och läkemedel som administreras till patienter kan förändras så att det förebygger ansamling av gadolinium. Syfte: Syftet med denna litteraturöversikt var att kartlägga ansamlingen av gadoliniumkontrastmedel hos patienter med multipel skleros och hur artificiell intelligens kan tillämpas vid MRT för att minska användning av gadoliniumkontrast. Metod: Allmän litteraturöversikt där vetenskapliga artiklar av kvantitativ studiedesign har sökts fram genom databaserna CINAHL och PubMed. Resultat: Både makrocykliska och linjära gadoliniumbaserade kontrastmedel ansamlas i de basala ganglierna. Genom tillämpning av AI och CAD går det att framställa bilder med fullgod bildkvalitet och samtidigt reducera mängden kontrastmedel som administreras till patienten. Slutsats: Det behövs mer forskning om gadoliniumansamling för att nya rutiner och metoder ska kunna implementeras. Ansamling av gadolinium visar att det finns skäl att fortsätta utveckla nya metoder för uppföljning av sjukdomsförloppet hos MS-patienter. När det gäller AI inom medicinsk bilddiagnostik och magnetresonanstomografi finns många utvecklingsmöjligheter som kan bidra till minskning av gadoliniumbaserad kontrast i framtiden. Fortsatt forskning inom deep learning och CAD kan i framtiden utvecklas så att röntgensjuksköterskan får en mer självbestämmande funktion i bildframställning vid MRT, men även ett mer självständigt arbete i hanteringen av farmaka. Dessutom kan denna utveckling bidra till att röntgensjuksköterskans multidiciplinära samverkan med radiologer stärks och bidrar till en positiv utveckling med kortare granskningstider, bättre hantering av patienter, optimerade undersökningar, minskning av undersökningstider och kortare vårdköer. / Introduction: Approximately 40% of all magnetic resonance imaging (MRI) scans performed in Europe and the United States are performed with gadolinium based contrast agents. Over the past decade, several studies have shown a gadolinium deposition in various structures in the brain. Patients with multiple sclerosis are regularly followed up with MRI with contrast enhancement is the most common method for distinguishing new pathological changes. Developments in technology and methods in artificial intelligence have shown that there is reason to map out whether the radiographers work with examinations and drugs administered to patients can be changed so that the accumulation of gadolinium is prevented. Aim: The purpose of this literature review was to examine the accumulation of gadolinium contrast agents in patients with multiple sclerosis of gadolinium contrast agents in patients with multiple sclerosis and how artificial intelligence can be applied in MRI to reduce the use of gadolinium based contrast agents. Methods: General literature review where scientific articles of a quantitative nature have been searched through the databases CINAHL and PubMed. Results: Both macrocyclic and linear gadolinium based contrast agents are retained in the basal ganglia. With artificial intelligence and CAD, it is possible to obtain data with good quality and at the same time reduce the amount of gadolinium based contrasts to patients. Conclusions: More research on gadolinium accumulation is needed for new routines and methods to be implemented. Accumulation of gadolinium shows that there is reason to continue to develop new methods for monitoring the course of the disease in MS patients. Concerning AI in medical imaging and magnetic resonance imaging, there are many development opportunities that can contribute to the reduction of gadolinium contrast in the future. Continued research in deep learning and CAD can be developed in the future so that the X-ray nurse has a more self-determining function in image production in MRI, but also a more independent work in the management of pharmacies. In addition, this development can contribute to the X - ray nurse's multidisciplinary collaboration with radiologists is strengthened and contributes to a positive development in shorter examination times, better management of patients, optimized examinations, reduction of examination times and shorter care queues.

In dieser Arbeit, wurden Endozytose und intrazellulären Transportwegen für zwei verschiedene biologisch relevante Nanopartikel (dendritisch Polyglycerolsulfat (dPGS-np) und Polyethylenimin beschichtete Goldnanopartikel (PEI-np)) mit Kryo-Röntgentomographie untersucht. Diese Untersuchungen zeigten, beide Nanopartikeln über Makropinozytose endozytiert werden und dass die meisten Nanopartikel in Endosomen, multivesikulären Körpern und Lysosomen lokalisiert sind. Trotz dieser Ähnlichkeiten im Verhalten beider Partikel gab es auch Unterschiede die zeigten. Im Gegensatz zu PEI-np, wurden einige dPGS-np in Lipidtröpfchen gefunden. Weiterhin verursachen die PEI-np bei einer Konzentration von 0,13 nM ein Zerplatzen von Lysosomen in erheblichem Ausmaß wodurch die Nanopartikel in das Zytoplasma entweichen und teilweise in den Zellkern eindringen. Im Unterschied dazu konnte kein Nachweis für ein Zerplatzen von Lysosomen durch dPGS-np erbracht werde. Interessanterweise wurde ein Wechsel des Endocytose-Weges von der Makropinozytose zu einer mutmaßlichen Caveolae-vermittelten Endozytose beobachtet, wenn die PEI-np-Konzentration um das Zehnfache reduziert wurde. Unter diesen Bedingungen induzierten PEI-np kein Zerplatzen von Lysosomen mehr. Das Ausbleiben von zerplatzten Lysosomen bei dieser niedrigeren Konzentration korreliert mit einer verringerten Zellschädigung und hat somit wichtige Auswirkungen auf die Verwendung von PEI beim Gentransfer. Überraschenderweise stellte sich heraus, dass beide Nanopartikelarten eine bisher nicht beobachtete umfassende zytoplasmatische Veränderungen in den Zellen induzierten. Insbesondere wurden nach der Inkubation mit beiden Diese zytoplasmatischen Veränderungen könnten wichtige physiologische Veränderungen widerspiegeln, jedoch ist hierzu zusätzliche Forschung erforderlich. Diese Beobachtungen deuten darauf hin, dass das Verhalten biologisch relevanter Nanopartikel in Zukunft vorhersehbarer werden kann durch weitere systematische Studien. / In this thesis, the endocytosis and trafficking pathways of two different biologically relevant nanoparticles, namely dendritic polyglycerol sulfate coated gold nanoparticles (dPGS-np) and polyethyleneimine coated gold nanoparticles (PEI-np) were investigated via cryo soft X-ray tomography. Both nanoparticles were found to be endocytosed predominantly via macropinocytosis, and most nanoparticles became localized to endosomes, multivesicular bodies and lysosomes. Despite these similarities in trafficking, there were also key differences. Some dPGS-np were found in lipid droplets but no PEI nanoparticles were found in this compartment. At a concentration of 0.13 nM, PEI-np were observed to induce extensive rupture of lysosomes, leading to significant levels of cytoplasmic escape and nuclear entry. In contrast, no evidence for lysosomal rupture with dPGS-np was detected, and concomitantly very low levels of cytoplasmic escape and no nuclear entry were found. Interestingly, when the PEI-np concentration was reduced by ten-fold, a switch in the endocytosis pathway from macropinocytosis to a putative caveolae-mediated endocytosis was observed. Importantly, under these conditions, PEI nanoparticles no longer induced lysosomal rupture. This lack of lysosomal rupture at the lower concentration was correlated with reduced cellular damage, and so has important implications for use of PEI in gene delivery. Most surprisingly, both nanoparticle types were found to induce similar global cytoplasmic alterations in the cells. These cytoplasmic alterations could reflect important physiological changes, but further work is required to determine this. Our observations suggest that the behavior of biologically relevant nanoparticles might become more predictable in the future by further application of systematic studies.

Ce travail de thèse présente l’étude du diagramme de phase des oxydes lamellaires NaxMoO2dans le cadre de la recherche de nouveaux matériaux. L’identification des transitionsstructurales au cours de l’intercalation et désintercalation électrochimique du sodium dans lesdomaines de composition ½ ≤ x ≤ 1 et ¼ < x ≤ ½ a été faite par électrochimie combinée à ladiffraction des rayons X in situ. Il a été montré que le profil très accidenté de la courbegalvanostatique résulte de multiples réarrangements structuraux au cours du cyclage.Notamment l’existence de nombreuses phases NaxMoO2 particulières a été mise en évidence,pour lesquelles des mises en ordre des ions sodium et des atomes de molybdène sont attendues.Des composés Na~1/2MoO2, Na~2/3MoO2 et NaMoO2 ont été synthétisés ex situ par voieélectrochimique ou chimique et leur caractérisation révèle des arrangements structurauxcomplexes, tel que des chaînes de clusters de molybdène dans les feuillets [MoO2] de NaMoO2. / This work concerns the investigation of the phase diagram of sodium layered oxides NaxMoO2in the search of new materials. Structural transitions upon sodium electrochemical(de)intercalation were studied by electrochemistry combined with in situ X-ray diffraction forcompositions ½ ≤ x ≤ 1 et ¼ < x ≤ ½. It was shown that the very undulating aspect of theelectrochemical curve results from multiple structural rerarrangements upon cycling. Especiallynumerous NaxMoO2 specific phases have been evidenced, for which sodium/vacancy orderingsas well as the formation of Mo-Mo bonds are expected. Na~1/2MoO2, Na~2/3MoO2 et NaMoO2compounds have been (electro)chemically synthesized and their structural characterizationreveals complex structures, such as chains of diamond-like molybdenum clusters in NaMoO2.

Ce manuscrit présente trois expériences menées dans le cadre de la fusion nucléaire par confinement inertiel. La première expérience porte sur l'étude la propagation d'un faisceau d'électrons rapides dans un plasma pré-comprimé dans le cadre du schémas d'allumage rapide. Deux expériences sur la génération d'onde de choc dans des plasmas ont été menées dans le cadre du schéma d'allumage par choc. La première expérience a été consacre à l'étude le la propagation d'un faisceau d'électrons rapides dans une cible comprimée. L'implosion de la cible avec une géométrie cylindrique a été menée avec l'installation laser GEKKO XII (ILE Osaka, Japon). Le faisceau d'électrons rapides a été injecté en utilisant l'installation laser LFEX (_1019W/cm2). et sa propagation à travers le cylindre comprimé a été observée avec plusieurs diagnostics X. Cette expérience a démontré l'effet d'un guidage du faisceau d'électrons rapides résultant du champ magnétique auto-généré. Par ailleurs, les résultats de cette expérience ont été en bon accord avec deux des simulation numériques. Cette étude a fait l'objet de la publication Approach to the study of fast electron transport in cylindrically imploded targets, Laser and particle Beams, 33, 525-534, (2015). Deux autres expériences ont été réalisées pour l’étude de la propagation de chocs forts créés par laser dans un plasma. Celles-ci ont été réalisées avec différentes installations laser.Dans la première expérience avec le laser Gekko Xll, nous avons observé la création et la propagation de deux ondes de choc successives dans des plasmas d’ablation de CH et de Be. L’objectif de caractériser l’amplification d’un choc transmis par la collision des deux chocscontre propagatifs a été partiellement réalisé. La comparaison des résultats expérimentauxà des simulations hydrodynamiques a permis d’établir une amplification du choc d’unfacteur 2 en pression pour les conditions expérimentales réalisées. Les tirs sur une cible deBe a permis de développer et valider les outils d’exploitation de la propagation de deuxchocs par radiographie X. La deuxième expérience a été réalisée avec laser PHELIX de GSI(Darmstadt, Allemagne). Le but de cette expérience était d’étudier la génération de chocsforts qui ont été utilisés pour étudier l’équations d’état du carbone dans le domaine WDMpertinent pour le planétologie. Les conditions de pression et de densité pour le carboneont été obtenues en déduisant la pression et la vitesse de l’onde de choc des diagnosticschronométriques employés dans cette expérience. Des états du diamant en phase liquidemétallique pour des pressions de l’ordre de 7 Mbar et des températures de 15,000 degrésont été obtenus. / This manuscript presents three experiments conducted as part of a nuclear fusion byinertial confinement. The first experiment is the study of the fast electron beam propagationin a pre-compressed plasma in the fast ignition scheme. Two other experiments about theshock wave generation in plasmas were conducted in the ignition shock pattern.The first experiment was devoted to the study of the fast electron beam transport in a compressed target. The implosion of the target with a cylindrical geometry was carriedout with the GEKKO XII laser facility (ILE Osaka, Japan). The fast electron beam wasgenerated by the LFEX laser ( 1019W/cm2) and its propagation through the compressedcylinder was observed with several X-ray diagnostics. This experiment showed the guidingeffect of the electron beam resulting from self-generated magnetic fields. Furthermore, theresults of this experiment were in good agreement with numerical simulations. This studywas the subject of the publication Approach to the study of fast electron transport incylindrically imploded targets, Laser and Particle Beams, 33,525-534,(2015). Two other experiments were performed to study the propagation of strong shockscreated by lasers in a plasma. These were carried out with different laser systems. In the firstexperiment with the Gekko XII laser, we observed the creation and the propagation of twosuccessive shock waves in an ablation plasma in CH and Be. The objective to characterizethe amplification of a transmitted shock by the collision of two counter propagatingshocks has been partially realized. The comparison of the experimental results with thehydrodynamic simulations enabled us to confirm an amplification of the shock by a factor2 in pressure in the condition of this experiment. The shot with a Be target allowed todevelop and to validate the diagnostic method of X-ray radiography for shock propagation.The second experiment was performed with laser PHELIX GSI (Darmstadt, Germany).The purpose of this experiment was to study the generation of strong shocks. They wereapplied to study the equation of state of carbone in WDM state for the planetology. Thecondition of pressure and density for the carbon were obtained by deducting the pressureand the velocity of the shock wave chronometric diagnostics employed in this experiment.In this experiment, diamond was at the metallic liquid phase with the pressure of 7 Mbarand the temperature of 15,000 degrees

The objective of my work was to develop HDPE clay nanocomposites for packaging with superior barrier (gas and water) properties by economical processing technique. This work also represents a comparative study of thermoplastic nanocomposites for packaging based on linear low density polyethylene (LLDPE), high density polyethylene (HDPE) and Nylon12. In this study properties and processing of a series of linear low density polyethylene (LLDPE), high density polyethylene (HDPE) and Nylon 12 nanocomposites based on Na-MMT clay and two different aspect ratio grades of kaolinite clay are discussed.