Design and synthesis of soluble and cell-permeable PI3Kδ inhibitors for long-acting inhaled administration

PI3Kδ is a lipid kinase that is believed to be important in the migration and activation of cells of the immune system. Inhibition is hypothesised to provide a powerful yet selective immunomodulatory effect that may be beneficial for the treatment of conditions such as asthma or rheumatoid arthritis. In this work we describe the identification of inhibitors based on a thiazolopyridone core structure and their subsequent optimisation for inhalation. The initially identified compound (13) had good potency and isoform selectivity but was not suitable for inhalation. Addition of basic substituents to a region of the molecule pointing to solvent was tolerated (enzyme inhibition pIC50 >9) and by careful manipulation of the pKa and lipophilicity we were able to discover compounds (20b, 20f) with good lung retention and cell potency that could be taken forward to in-vivo studies where significant target engagement could be demonstrated

Developing the anaerobic digestion process through technology integration

Process optimization is needed for the development and expansion of the biogas industry and to meet the ever growing demand for methane. This thesis explores process technologies for the development of the anaerobic digestion process and includes pre-treatments, studies on the effects of different mixing modes and evaluation of a water treatment technology. Two pre-treatments were evaluated, mechanical and electroporation, for treatment of ley crop silage. Mechanical treatment included two milling machines designed for recycling of paper, Grubben deflaker and Krima disperser, and showed an increased biogas production of 59 % and 43 % respectively as well as a positive energy balance and economic results.. Electroporation increased the biogas production with 16 %, however, development is needed to increase its energy efficiency. Digester mixing has an effect on the digestion result. The performed review and experiments show that the mixing demand increases with organic loading. Excessive mixing during process start up, instabilities and shock loads leads to increased volatile fatty acid concentrations and process inhibition. Reduction of mixing reduces the effects of process instabilities and periodical mixing with mixing breaks has been shown to be beneficial for biogas production. A high temperature membrane filtration unit was evaluated at 70 °C, 90 °C and 110 °C to determine separation efficiencies, permeation speed when treating process water at a biogas plant.  Improved separation can increase the capacity of the substrate pre-processing and reduce process related problems. The results show a total solids separation of 60 %, and an increasing filtration speed with temperature with fluxes of between 113 and 464 L/ h m2. The substrate pre-processing could theoretically handle up to 29 % more substrate as a result. Integration of these technologies in a biogas plant show that the pre-treatments studied exhibits a good performance when integrated and that mixing reduction has the potential to lower the process electricity demand by 23 % in the performed case study. However, even though the membrane filtration unit shows promising results it would demand a relatively high energy consumption and lead to limited benefits to a process already at it maximum organic loading

The wet fermentation biogas process : Limitations and possibilities for efficiency improvements

The biogas process is known as an environmental friendly and sustainable way of producing energy and fuel but to be fully commercially competitive with other types of processes, efficiency improvements are needed. By doing a case study at the Växtkraft biogas plant in Västerås, Sweden, three specific limitations were identified and studied. Firstly, to improve the capacity of the plant, pre-treatments of the different substrates are needed to disintegrate the substrate and by doing so increasing the gas yield and the speed in which it is produced. Secondly, to improve the fermentation process itself more knowledge is needed around the mixing inside the digester. To be able to create an optimal and stable environment for the microorganisms the mixing is the key, because the mixing affects the mass transfer of all solids, nutrients, gases and other substances in the digester. Thirdly, the water treatment of the recirculated process water cannot reach the desired separation of dry matter (DM) and this is affecting the capacity of the plant negatively. The feed for the digester is produced by mixing the process water and the substrate to get a pumpable slurry with a DM content of 8-10 %. When there is too much DM in the process water to begin with, the mixing ratio between the substrate and the liquid changes, decreasing the amount of substrate that can be added to the mixture and later on fed to the digester.   The full biogas potential of most organic materials cannot be extracted during the relatively short retention time of most digesters because of their complex structures. The organic materials are broken down too slowly and the nutrients cannot become biologically available in that time span. This means that a lot of the bound energy in the organic material leaves the biogas plant with the liquid digestate. The efficiency of the process can be improved by pre-treating the material before digestion. Pre-treatment experiments to disintegrate ley crop silage using electroporation, a treatment using electrical fields, were conducted to study its effect on the biogas yield. The experiments resulted in up to twice the amount of biogas being produced from the pre-treated material compared to untreated material.   Numerical simulations of the mixing inside a digester were carried out to understand the effect that a gas lift mixing configuration has on the mass transfer in the system. The mixing dynamics were evaluated by testing five different flow rates of the injected gas and the effect that the liquid recirculation system has. The results indicate that there are large unmixed zones and that changing the gas flow rate only has a marginal effect on these areas. The simulation also suggests that the outlet of the liquid recirculation system is situated too close to the gas injectors, resulting in energy losses in form of diminished mixing of the digester.   Experiments to reduce the DM content of the recirculated process water were carried out using a ceramic ultrafiltration membrane. The flux through the membrane and the separation efficiency were investigated at different operation temperatures, 70°C, 90°C and 110°C. The results show that 59-63 % of the DM was separated in this temperature interval and that the flux/flow through the membrane increased with the temperature. These results correspond to a 29 % increase in the capacity to add new substrate. The energy required to heat the membrane, if heat recovery is used, is small in comparison to the increased methane yield.   In the best case scenario these above identified improvements could increase the methane yield by up to 40%.Biogasop

Anaerob nedbrytning av TNT : Ett bioreaktorförsök på Vingåkersverken

A bioslurry reactor was built for the bioremediation of TNT contaminated waste from the demilitarization industry. The field test was conducted at Vingåkersverken in Vingåker, Sweden, to see if results from laboratory studies could be repeated in a full scale reactor. The goal of the project was to optimize the reactor to such a degree that it could be used to handle the waste produced at Vingåkersverken and also that this technique could be applied for remediation of contaminated soils. Unfortunately the samples taken during the full scale field test were destroyed by the shipping company and no analysis was possible. A later attempt by the Biorex research group has also been unsuccessful to reduce the amount of TNT using the bioreactor. How are we going to reach the results from the laboratory studies? The work continues

“VI BRÅKAR FORTFARANDE... JAG VILL BARA LYSSNA OM VI ÄR BÄSTA KOMPISAR” : En kvalitativ studie om förskollärare och barns beskrivning av konflikter och konflikthantering

Att ha en god social kompetens är något som är viktigt för att skapa och upprätthålla relationer samt för att kunna hantera olika situationer och eventuella konflikter som uppstår i mötet med andra människor. Social kompetens är också något som ingår i förskolans uppdrag och som är beskrivet i läroplanen för förskolan. Syftet med denna studie har varit att undersöka hur barn respektive förskollärare beskriver vardagliga konflikter och vad det är som skiljer sig eller överensstämmer mellan barn och förskollärares beskrivningar. I studien har vi använt oss av en kvalitativ metod med intervjuer av förskollärare samt gruppsamtal med barn. Resultatet visar att de främsta orsakerna som beskrivs av både barn och förskollärare kring varför konflikter uppstår är svårigheter i kommunikationen och det språkliga men också att barn vill ha samma sak som någon annan. Den främsta lösningen för konflikter som uppstår i förskolan, som både barn och förskollärare framhöll var att prata med varandra och att pedagoger är närvarande

Working with alcohol and drug addiction treatment of clients with adhd : A qualitative study of socialworkers experiences

Syftet med studien är att undersöka hur socialsekreterare ser på förutsättningar för klienter som har adhd och en missbruksproblematik till att genomgå och bibehålla kontinuitet i utredning och behandling. Studien belyser hur socialsekreterarna anser att samverkan fungerar med andra aktörer inom missbruksvården och betydelsen av förhållningssätt och relation till klienten. Studien skildrar både möjligheter och svårigheter i behandlingsarbetet. Till vår studie har vi använt oss av fyra socialsekreterare inom Norr- och Västerbotten som arbetar med vår målgrupp av individer som har missbruk och en samtidig adhd diagnos. Resultatet i vår studie visar att en prioriterad samverkan finns, men att komplexiteten med olika regelverk och syn på samsjuklighet gör att samverkan brister och inte kan möta dessa individers behov. Socialsekreterarna upplever de interna riktlinjerna inom kommun och landsting som ett hinder då dessa bland annat kräver att individerna ska vara fria från missbruk eller diagnostiserade för att få anpassad vård. Socialsekreterarna beskriver en gemensam bild över att vården till dessa klienter måste ges under samma huvudman för att det ska fungera

Tramway constructions : To help with the choice of tramway construction

Stockholms spårvägar växer i allt snabbare fart, och det är allt fler kommuner som är intresserade av den typen av transportmedel. Något som idag är en brist inom spårvägsindustrin i Stockholm är kunskap och erfarenhet om spårvägsämnet. Drift och underhåll har varit minimal eftersom det inte har prioriterats sedan Tvärbanan öppnades. Detta har lett till för tidig reinvestering av gatuspår i mångmiljonbelopp. Då det förekommer olika förutsättningar som måste tas hänsyn till i form av buller, mån om plats och geoteknik finns det många konstruktioner att välja mellan när en spårväg ska byggas. Denna rapport har som syfte att underlätta val av spårvägsinvesteringar i framtiden. Det har också som mål att bidra med kunskap om hur viktigt det är med drift- och underhåll och att det inte bör snålas in på den aspekten. En begränsning har gjorts till fem spårvägskonstruktioner som förekommer i Stockholm och vanligtvis i Göteborg och Norrköping. För att få en förståelse för hur konstruktionerna är uppbyggda redogörs en beskrivning av dem i rapporten.  Rapporten inleds med hur det historiskt har sett ut med spårvägar, nedläggning av dem och återinvestering i Stockholm. Dessa år av glapp mellan nedläggning och återinvestering i Stockholm visar på hur mycket kunskap som har glömts bort och som måste fås tillbaka för framtida investeringar. En analys kring placering av de olika konstruktionerna, hur varierande för- och nackdelarna och kostnaderna är avslutar rapporten. Mycket av rapporten bygger på litteraturstudier på tidigare rapporter som har kompletterats med kontinuerliga möten med handledare och kontakt med personer från olika kommuner och företag i Sverige för att inhämta trovärdig information.  The tramways of Stockholm are growing at an increasing rate and so is the number of municipals interested in that type of transportation.  In Stockholm’s tramway industry there is currently a lack of knowledge and experience on the subject of tramways. Drift and maintenance has been minimal due to lack of prioritization since Tvärbanan was opened. This has led to a premature reinvestment of millions of SEK for road tracks. Due to different presumptions that have to be taken into account such as noise, considerations of room and geoscience, there are many different constructions to choose from when a tramway is to be built. This report’s purpose serves to facilitate choice of tramway investments in the future. Another goal of the report is to contribute with knowledge of how important service and maintenance of tramways is and why shying away from spending money on these matters is bad. For the purpose of this report a restriction has been made, five tramway constructions will be looked at, these are present in Stockholm but also in Göteborg and Norrköping. To acquire an understanding of how the constructions are built, a description of these is accounted for in the report. The report starts off with a historical perspective on tramways, closure of them and reinvestment of them in Stockholm. The years of gaps between closure and reinvestment in Stockholm shows how much knowledge has been forgotten and has to be reacquired for future investments. In the end of the report an analysis, about placement of the different constructions, how varied the pros and cons are and the costs of these, is presented. Much of the report is based on literature studies of earlier reports and has been complemented with continuous meetings with tutors and contact with people from different municipals and companies in Sweden to obtain trustworthy information

Det trengs mange og handlekraftige (første)hjelpere!

Verdens Helseorganisasjon og norske myndigheter har satt som mål at selvmordsforsøk og selvmord skal reduseres. Dette kan oppnås via forskjellige former for opplæring. Kunnskap om selvmordsforebygging må derfor formidles til store befolkningsgrupper. I Norge har Vivat Selvmordsforebygging en viktig rolle i dette undervisningsarbeidet. Kurset «Førstehjelp ved selvmordsfare» er nylig revidert i tråd med tilgjengelig kunnskap. De bærende elementer i kurset er beholdt, men viktig ny forståelse er lagt til. Hjelperens vilje og evne til å ta ledelse i førstehjelpsinnsatsen er tydeliggjort. Et annet og sentralt element er brakt inn; sammen med personen i fare leter man etter hva som kan utgjøre vendepunktet bort fra selvmord og mot fortsatt liv. Både nasjonale og internasjonale studier tyder på at deltakerne på kurset opplever at de er bedre i stand til å yte nødvendig førstehjelp etter gjennomført opplæring