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Phosphoinositide 3-kinase is a family of lipid kinases that function by phosphorylating the D3 position of phosphoinositide (PI) lipids generating PI(3)P, PI(3,4)P2 and PI(3,4,5)P3. These D3 phosphoinositides regulate various cellular processes through the recruitment of effector proteins containing lipid specific pleckstrin homology (PH) domains. PI phosphatases such as PTEN and SHIP function to restrain PI3K signaling by limiting the amount of D3 PI available for binding. Deletion of either PTEN or SHIP significantly alters B cell function and humoral immune responses. TAPP1 and TAPP2 are dual PH domain containing adaptors which selectively bind the phosphoinositide PI(3,4)P2 via their C-terminal PH domains. PI(3,4)P2 is a lipid messenger generated by PI3K and through the inositol phosphatase activity of SHIP. The function of PI(3,4)P2 remains incompletely understood. To identify the functional role of TAPP-PI(3,4)P2 interactions, we utilized a knock-in (KI) mouse bearing mutations within the PI-binding pocket of both TAPPs. Our study assessed the effect of PI3K dependent KI mutation on B lymphocyte development, activation and antibody production. Flow cytometry analyses of lymphoid tissues found that TAPP KI mice develop relatively normal frequencies of mature B cell populations with the exception of peritoneal B1 cells, which are increased by approximately 50%. Strikingly, TAPP KI mice developed substantially elevated serum antibody levels. TAPP KI mice were able to generate high affinity antigen-binding antibodies upon immunization with NP-OVA in alum adjuvant; however, total immunoglobulin production was markedly increased under this immunization condition. We further assessed the germinal centre (GC) response, which are known to require PI3K signaling and a hallmark of T cell dependent (TD) antibody responses. TAPP KI mice generated larger germinal centers (GC) upon immunization, which was associated with increased GC B cell survival. We further assessed whether uncoupling of TAPPs from PI(3,4)P2 alters B cell signaling and functional responses in vitro. B cells purified from TAPP KI mice were found to have altered functional responses in vitro, with significantly increased survival and cell division following antigen receptor cross-linking. Consistent with increased cell survival, TAPP KI B cells show increased Akt phosphorylation on Ser473 and Thr308 after antigen receptor cross-linking. However, reconstitution of B cell deficient mice with either WT or TAPP KI B cells was found to generate similar GC responses, suggesting that activation of other cells may contribute to the enhanced in vivo responses. Consistently, when we examined the CD4+ T follicular helper cells, a subset providing critical cues to GC responses, we found increased expression of ICOS activation marker. Our results indicate the interactions of TAPP adapters with PI(3,4)P2 serve to restrain lymphocyte activation and limit antibody production, providing the first in vivo evidence that this interaction is important for immune function.

Phosphoinositide 3-kinase is a family of lipid kinases that function by phosphorylating the D3 position of phosphoinositide (PI) lipids generating PI(3)P, PI(3,4)P2 and PI(3,4,5)P3. These D3 phosphoinositides regulate various cellular processes through the recruitment of effector proteins containing lipid specific pleckstrin homology (PH) domains. PI phosphatases such as PTEN and SHIP function to restrain PI3K signaling by limiting the amount of D3 PI available for binding. Deletion of either PTEN or SHIP significantly alters B cell function and humoral immune responses. TAPP1 and TAPP2 are dual PH domain containing adaptors which selectively bind the phosphoinositide PI(3,4)P2 via their C-terminal PH domains. PI(3,4)P2 is a lipid messenger generated by PI3K and through the inositol phosphatase activity of SHIP. The function of PI(3,4)P2 remains incompletely understood. To identify the functional role of TAPP-PI(3,4)P2 interactions, we utilized a knock-in (KI) mouse bearing mutations within the PI-binding pocket of both TAPPs. Our study assessed the effect of PI3K dependent KI mutation on B lymphocyte development, activation and antibody production. Flow cytometry analyses of lymphoid tissues found that TAPP KI mice develop relatively normal frequencies of mature B cell populations with the exception of peritoneal B1 cells, which are increased by approximately 50%. Strikingly, TAPP KI mice developed substantially elevated serum antibody levels. TAPP KI mice were able to generate high affinity antigen-binding antibodies upon immunization with NP-OVA in alum adjuvant; however, total immunoglobulin production was markedly increased under this immunization condition. We further assessed the germinal centre (GC) response, which are known to require PI3K signaling and a hallmark of T cell dependent (TD) antibody responses. TAPP KI mice generated larger germinal centers (GC) upon immunization, which was associated with increased GC B cell survival. We further assessed whether uncoupling of TAPPs from PI(3,4)P2 alters B cell signaling and functional responses in vitro. B cells purified from TAPP KI mice were found to have altered functional responses in vitro, with significantly increased survival and cell division following antigen receptor cross-linking. Consistent with increased cell survival, TAPP KI B cells show increased Akt phosphorylation on Ser473 and Thr308 after antigen receptor cross-linking. However, reconstitution of B cell deficient mice with either WT or TAPP KI B cells was found to generate similar GC responses, suggesting that activation of other cells may contribute to the enhanced in vivo responses. Consistently, when we examined the CD4+ T follicular helper cells, a subset providing critical cues to GC responses, we found increased expression of ICOS activation marker. Our results indicate the interactions of TAPP adapters with PI(3,4)P2 serve to restrain lymphocyte activation and limit antibody production, providing the first in vivo evidence that this interaction is important for immune function.

I mitt examensarbete jämför jag styrkan för sammanfogningar i trämöbler med fasta tappar och centrumtappar utifrån fem parametrar: tappens dimensioner, tappens inpassning, tappens komprimering, tappens antal och tappens limning. Den övergripande frågan har varit, ”är fasta tappar eller centrumtappar starkast?” Målet har varit att sålla i olika teorier rörande dessa två typer av sammanfogningar och skapa ett underlag i syfte att hjälpa möbelsnickare och formgivare att kunna ta medvetna beslut vad gäller sina val av dessa typer av sammanfogningar. Genom litteraturstudier och verkstads besök har jag samlat kunskap som ligger till grund för det hållfasthets test jag sedan gjort i materiallabbet på Linköpings universitet. Testet har utgått från ett scenario där en stols bakben ska fogas samman med en sarg. Testet visar, utifrån ett antal angivna avgränsningar, att fasta tappar utan undantag är starkare än centrumtappar.Det visar också att en dubbel fast tapp fördelar belastningen bättre än en enkel fast tapp och bidrar till en betydligt starkare fog. För c-tappar gäller generellt att ökat antal tappar ökar fogens seghet men inte nödvändigtvis maxbelastningen. Inpassning och komprimering har betydelse för hur seg en fog är. / I have in my thesis compared the strength of mortise and tenon joints and dowel joints in wooden furniture. I´ve made the comparison based on five parameters: the dimensions of the tenon or dowel, the fit of the tenon or dowel, the compression of the tenon or dowel, the number of tenons or dowels and the gluing of the tenon or dowel. The bigger question has been, “is the mortise and tenon joint or the dowel joint the strongest?” The goal has been to go through different theories regarding these two types of joinery and making a foundation to help cabinet makers and designers to make conscious decisions regarding their choices of these two types of joinery. Through studies of literature and visiting workshops I´ve gathered knowledge that lies as a foundation for a test of strength of different joinery made in the material testing facility of Linköping University. The test was based on a scenario of joining the back leg and side rim of a chair. The test shows, from the given definitions, that mortise and tenon joints are without exceptions stronger than dowel joints. It also shows that double tenons better will distribute the load and make for a stronger and tougher joint. Dowel joints will get tougher with an increased number of dowels but it will not necessarily make for a stronger joint. The fit and compression of the tenon or dowel will affect the joints strength.

Introduction: Transabdominal laparoscopic (TAPP) approach in the therapy of inguinal hernia is a suitable alternative to classical open inguinal hernia repair mainly in the hands of an experienced surgeon. TAPP repair offers the possibility of gentle dissection with implantation of the mesh from posterior approach. Hypothesis and objectives of the work: The fixation of mesh through penetrating techniques using staples, clips or screws is associated with a significantly increased risk of developing a post-herniotomy inguinal pain syndrome (CPIP). The aim of the thesis is to review options of self-fixating meshes in laparoscopic TAPP procedure without additional fixation. Furthermore to evaluate effect of this technique on development of the chronic postoperative groin pain and also on frequency of hernia recurrence and mesh migration. Patients and methods: Data analysis included all patients, who underwent inguinal hernia surgery at our Surgical Department within the period from 1.10.12 to 31.12.14 and fulfilled the inclusion criteria. Standard surgical technique was used. Data were entered and subsequently analyzed on Herniamed platform. Results: There were 241 patients enrolled to the group of which 396 inguinal hernias were repaired. The minimal follow up was at 12 months. At the assessment in one...

Introduction: Transabdominal laparoscopic (TAPP) approach in the therapy of inguinal hernia is a suitable alternative to classical open inguinal hernia repair mainly in the hands of an experienced surgeon. TAPP repair offers the possibility of gentle dissection with implantation of the mesh from posterior approach. Hypothesis and objectives of the work: The fixation of mesh through penetrating techniques using staples, clips or screws is associated with a significantly increased risk of developing a post-herniotomy inguinal pain syndrome (CPIP). The aim of the thesis is to review options of self-fixating meshes in laparoscopic TAPP procedure without additional fixation. Furthermore to evaluate effect of this technique on development of the chronic postoperative groin pain and also on frequency of hernia recurrence and mesh migration. Patients and methods: Data analysis included all patients, who underwent inguinal hernia surgery at our Surgical Department within the period from 1.10.12 to 31.12.14 and fulfilled the inclusion criteria. Standard surgical technique was used. Data were entered and subsequently analyzed on Herniamed platform. Results: There were 241 patients enrolled to the group of which 396 inguinal hernias were repaired. The minimal follow up was at 12 months. At the assessment in one...

Samhället efterfrågar idag i allt högre grad miljövänlig och hållbar byggnation. Ett sätt möta dessa nya krav på miljövänlig byggnation är att använda mer trä då detta minskar koldioxidutsläpp genom substitutionseffekten. Syftet att undersöka huruvida traditionella fogningstekniker som helt utförs i trä kan ersätta samtida fogar i framtida byggnation. Målet är att visa att detta är möjligt ur hållfasthetssynpunkt. Undersökningen kommer att begränsas till att undersöka en pelar-balk-anslutning där den traditionella fogen representeras av tre olika varianter tapp i tapphålsfog och den samtida av balksko. Fogarna undersöks beräkningsmässigt samt genom försök där belastningsfallet ämnar ge en hög tvärkraft. Resultaten pekar på att det är möjligt att introducera den undersökta traditionella träfogningstekniken vid samtida byggnation. / Societies demand for environmentally friendly and sustainable construction is ever increasing. One way to meet these new demands on environmentally friendly construction is to use more wood which decreases carbon emissions through the substitution effect. This report aims to research whether traditional joinery techniques entirely executed in wood can replace contemporary joinery techniques in future construction. The goal is to show whether this is possible from a strength standpoint. The research will be limited in that it will strictly seek to study a pillar-beamconnection where the traditional joint researched will be three varying mortise and tenon joints and the contemporary joint is a joist hanger. The joints will be analyzed with calculation and experimentation where the load case aims to produce mainly shear in the joint. The results point towards it being possible to introduce this traditional joint in contemporary construction.

During the pressing of powder mixtures to make cemented carbide tools, the degree to which the powder spreads to fill the die and to which it compacts is uncertain. This leads to inconsistent dimensions and densities in the finished product. This performance changes with the composition of the powder, including the amount of pressing agent in the mixture, the particle size distribution and particle shape. One way to quantify the degree to which powder will spread to fill the mold evenly is using the property called 'flowability'. There are several techniques by which flowability can be measured, and each technique does not always give results that are consistent with other techniques. It is, therefore, important to know what technique(s) predict(s) the final behavior of the powder in this application before it is used in quality assurance or to design a process. Additionally, powder size distribution and shape metrics are measured using dynamic image analysis to investigate if there is any relationship between key values of these properties and compaction behavior. In this study, static Angle of repose, Tap Density, Hall flow time and Powder rheometry were benchmarked against each other and against the dimensions of presses and liquid phase sintered tool inserts to understand which technique had the strongest dependence on the compactability, which was defined as the ratio of the tallest dimension in the insert to the smallest. After the study, the results showed that a more extensive particle size distribution improves the compaction properties and that the powders with a higher resistance to a rotating blade tend to have better compaction properties. On the other hand, a clear pattern for the results of all measurement methods and the correlation between the compaction behavior of the carbide tools could not be discerned. In conclusion, the study showed that it is possible to determine a relationship between the results of measurement methods and the compaction behavior of powders. By using simple tests to predict the compactability properties, both money and time can be saved on the research of new, improved powder. Furthermore, the implementation of this study can lead to even better pressing and compactibility properties in the future for cemented carbide tools. / Vid pressning av pulverblandningar för tillverkning av hårdmetallverktyg är det osäkert i vilken grad pulvret sprider sig för att fylla matrisen och i vilken grad det komprimeras. Detta leder till inkonsekventa dimensioner och densitet i den färdiga produkten. Denna prestanda förändras med pulvrets sammansättning, inklusive mängden bindemedel som finns i blandningen, partikelstorleksfördelningen och partikelformen. Ett sätt att kvantifiera i vilken grad pulvret sprids för att fylla formen jämnt är att använda den egenskap som kallas "flytbarhet". Det finns flera tekniker för att mäta flytbarhet, och varje teknik ger inte alltid resultat som överensstämmer med andra tekniker. Det är därför viktigt att veta vilken eller vilka tekniker som förutsäger pulvrets slutliga beteende i denna tillämpning innan den används i kvalitetssäkring eller för att utforma en process. Vidare mäts pulvrets partikelstorleksfördelning och form med dynamisk bildanalys för att undersöka om det finns något samband mellan nyckelvärden för dessa egenskaper och komprimeringsbeteendet. I den här studien jämfördes statisk rasvinkel, tappdensitet, hallflödestid och pulverreometri samt med dimensionerna på pressar och sintrade verktygsinsatser i vätskefas för att förstå vilken teknik som hade det starkaste beroendet på kompatibiliteten, vilket definieras som förhållandet mellan den högsta dimensionen i insatsen och den minsta. Efter studien visade resultaten att en mer omfattande partikelstorleksfördelning förbättrar komprimeringsegenskaperna och att pulver med högre motståndskraft mot ett roterande blad tenderar att ha bättre komprimeringsegenskaper. Vidare kunde inte ett tydligt mönster för resultaten för alla mätmetoder och sambandet på komprimeringbeteendet för hårmetallverktygen urskiljas. Sammanfattningsvis visade studien på att det går att använda sig av mätmetoder för att kunna urskilja ett samband mellan resultaten på mätmetoderna och pulvers kompaktibillitetsegenskaper. Genom att använda sig av enkla mätningar för att kunna förutsäga kompaktibilitetsegenskaper samt komprimeringsbeteende kan både pengar respektive tid sparas. Vidare kan genomförandet av denna studie i framtiden leda till ännu bättre pressnings- samt kompaktibilitetsegenskaper för hårdmetallverktyg.