Nous avons réalisé la synthèse de précurseurs d'analogues sulfures de facteurs NOD, messagers chimiques intervenant lors du phénomène de nodulation rencontré dans l'association symbiotique entre certaines plantes légumineuses et des bactéries de la famille rhizobium. Cette association permet à la plante de fixer l'azote atmosphérique préalablement métabolisé par les bactéries. Ces analogues devraient permettre de mieux comprendre les différents processus intervenant au cours de la symbiose plante/ bactérie ainsi qu'étudier l'hydrolyse des facteurs NOD par des enzymes, les chitinases. Nous avons choisi de préparer des analogues fonctionnalisés pour lersquels seule la liaison O-glycosidique entre deux unités serait remplacée par une liaison thioglycosidique. Grâce à l'utilisation de donneurs de glycosyle sous la forme de trichloroacétimidate, nous avons réalisé la synthèse d'un thiotrisaccharide ainsi que celle d'un thiotétrasaccharide, précurseur d'analogues de facteurs NOD, dont les unités réductrices et non réductrices sont potentiellement différenciées en vue de leur fonctionnalisation. Par ailleurs, le transfert d'une unité de glucosamine sur un thiodisaccharide, à l'aide de la bétâ-1,4-galactosyltranférase, a conduit à la préparation d'un thiotrisaccharide. Cette dernière étape a permis d'envisager la synthèse d'un thiotétrasaccharide par voie chimio-enzymatique. Ces précurseurs devraient conduire à de nouveaux analogues sulfures de facteurs NOD sur lesquels des tests biologiques pourraient être réalisés afin d'évaluer l'activité de nodulation ainsi que la résistance aux chitinases

<p>Examensarbetet besvarar hur en Science Park-nod bör göra sig synlig på glesbygden. Arbetet har uträttats för Näringlivsbolaget i Eksjö kommun under perioden mars 2009- september 2009. Det har besvarat frågor rörande marknadsföring av Science Park-noder med ett konkret exempel i samhället Mariannelund. Noden i Mariannelund har funnits sedan hösten 2008, men har ännu inte marknadsförts någonting. Rapporten påvisar hur marknadsföringen kan göras för att tjänsten ska efterfrågas av fler kunder. En Science Park-nod erbjuder kontorsplats att hyra, kopieringsmöjligheter, möjlighet till företagsrådgivning och arbetskamrater. Målgruppen är nystartade företag, mindre än tre år gamla.</p><p>För att kunna besvara frågeställningen krävdes insamling av tidigare forskning. För att veta vilka marknadsföringskanaler som var mest sedda och använda av målgruppen skickades en postenkät ut till 162 företag i målgruppen omkring samhället Mariannelund. Postenkäten gav aktuell information angående målgruppens mediavanor. Postenkäten behandlade också frågor angående webbformgivning och Science Park-begrepp. Svarsfrekvensen var relativt låg, cirka 30% besvarade postenkäten. För att kontrollera vad målgruppen anser sig ha för behov som nyföretagare utfördes telefonsamtal till målgruppen för att ställa frågor om det. Svarsfrekvensen blev högre vid telefonsamtalen, hälften av dem som tilldelats postenkäten besvarade telefonsamtalen.</p><p>Telefonsamtal och e-postkontakt hölls även med branschaktörer såsom andra Science Park-noder i Jönköpings län samt grannkommunerna Hultsfred och Vimmerby. Anledningen till det var att få veta hur andra aktörer marknadsför sig mot nyföretagare.</p><p>Studien visar att en Science Park-nod på glesbygden bör locka nya företagare till sig genom att sprida publicitet om noden till både nya företagare och andra glesbygdsbor. Detta bör helst göras på ett sådant sätt att invånarna börjar prata om noden genom mun-till-munmetoden. Noden kan till exempel uppmärksammas i lokala dagstidningar, hålla events för allmänheten, göra postutskick om nodens tjänster till målgruppen samt skapa en egen hemsida.</p><p>Argumenten i kommunikationen bör handla om att Science Park-noden inte ligger långt från målgruppens bostad samt att nodens personal kan hjälpa kunderna att utveckla en affärsplan. Kommunikationen bör vara att noden löser ett uppkommet problem hos målgruppen. Om noden skaffar en grafisk profil kan element skapas som kan användas ofta för målgruppen, ju oftare desto bättre för att skapa större kännedom hos målgruppen.</p> / <p>This work treats the question of how a Science Park-node should get familiar at the countryside. The study has been made mostly through questionnairies from March 2009 until September 2009. The work has been answering how the Science Park-node in the little conurbation Mariannelund should be marketing their business. Although the business has been there since the fall 2008 it has not yet been marketed. This report shows how the marketing ideas possibly can make the Science Park-node to get more customers. A Science Park-node can offer customers a part of an office, copying-machine, businessconsulting and fellow workers. The target group are businesses that are at the most three years old.</p><p>In the beginning of the project there had to be a theoretical research. Then I had to know which marketingchannels that are mostly used or seen by the target group, that is why a postal questionnaire was sent out to 162 new businesses in the area around Mariannelund. To remind the target group about the questionnaire telephone calls were made where I also asked them some new questions, this time about the needs a new company has got.</p><p>Phone calls were also made to other organizations, in the same type of business as the Science Park-node, to get to know how they marketed their businesses.</p><p>The study shows that a Science Park-node at the countryside should try to attract new customers by making publicity about the node to people in the countryside. This should be made in a way that makes people talk about it. Some ideas are that the node can try to be seen in the local newspapers, make events for the citizens of Mariannelund, mail information about the node to the target group and make an own website.</p><p>The communication of the node should be that it solves problems for the target group. One idea is that it can focus on telling the target group that it is situated nearby home and that the target group can get personal assistance with the development of their business plan. If the Science Park-node also makes a graphic profile with lots of elements which is shown for the target group the popularity will come sooner.</p>

Type 1 diabetes is an autoimmune disorder determined both by genetic and environmental factors. The Non-obese diabetic (NOD) mouse is one of the best animal models of this disease. It spontaneously develops diabetes through a process resembling the human pathogenesis. The strong association of NOD Type 1 diabetes to the MHC region and the existence of other diabetes susceptibility loci are also in parallel with the human disease. The identity of the genetic factors and biological function mediated by these loci remain, however, largely unknown. Like in other autoimmune diseases, defects in tolerance mechanisms are thought to be at the origin of type 1 diabetes. Accordingly, defects in both central and peripheral tolerance mechanisms have been reported in the NOD mouse model. Using a subphenotype approach that aimed to dissect the disease into more simple phenotypes, we have addressed this issue. In paper I, we analyzed resistance to dexamethasone-induced apoptosis in NOD immature thymocytes previously mapped to the Idd6 locus. Using a set of congenic mice carrying B6-derived Idd6 regions on a NOD background and vice-versa we could restrict the Idd6 locus to an 8cM region on the telomeric end of chromosome 6 and the control of apoptosis resistance to a 3cM region within this area. In paper II, further analysis of diabetes incidence in these congenic mice separated the genes controlling these two traits, excluding the region controlling the resistance to apoptosis as directly mediating susceptibility to diabetes. These results also allowed us to further restrict the Idd6 locus to a 3Mb region. Expression analysis of genes in this chromosomal region highlighted the Lrmp/Jaw1 gene as a prime candidate for Idd6. Lrmp encodes an endoplasmatic reticulum resident protein. Papers III and IV relate to peripheral tolerance mechanisms. Several T cell populations with regulatory functions have been implicated in type 1 diabetes. In paper III, we analyzed NOD transgenic mice carrying a diverse CD1d-restricted TCR αVa3.2b9), named 24abNOD mice. The number of nonclassical NKT cells was found to be increased in these mice and almost complete protection from diabetes was observed. These results indicate a role for nonclassical NKT cells in the regulation of autoimmune diabetes. In paper IV, we studied the effects of introducing the diverse CD1d-restricted TCR (Va3.2b9) in immunodeficient NOD Rag-/- mice (24abNODRag-/- mice). This resulted in a surprising phenotype with inflammation of the ears and augmented presence of mast cells as well as spleenomegaly and hepatomegaly associated with extended fibrosis and increased numbers of mast cells and eosinophils in the tissues. These observations supported the notion that NKT cells constitute an “intermediary” cell type, not only able to elicit the innate immune system to mount an inflammatory response, but also able to interact with the adaptive immune system affecting the action of effector T cells in an autoimmune situation. In this context the 24abNODRag-/- mice provide an appropriate animal model for studying the interaction of NKT cells with both innate and adaptive components of the immune systemα.

Examensarbetet besvarar hur en Science Park-nod bör göra sig synlig på glesbygden. Arbetet har uträttats för Näringlivsbolaget i Eksjö kommun under perioden mars 2009- september 2009. Det har besvarat frågor rörande marknadsföring av Science Park-noder med ett konkret exempel i samhället Mariannelund. Noden i Mariannelund har funnits sedan hösten 2008, men har ännu inte marknadsförts någonting. Rapporten påvisar hur marknadsföringen kan göras för att tjänsten ska efterfrågas av fler kunder. En Science Park-nod erbjuder kontorsplats att hyra, kopieringsmöjligheter, möjlighet till företagsrådgivning och arbetskamrater. Målgruppen är nystartade företag, mindre än tre år gamla. För att kunna besvara frågeställningen krävdes insamling av tidigare forskning. För att veta vilka marknadsföringskanaler som var mest sedda och använda av målgruppen skickades en postenkät ut till 162 företag i målgruppen omkring samhället Mariannelund. Postenkäten gav aktuell information angående målgruppens mediavanor. Postenkäten behandlade också frågor angående webbformgivning och Science Park-begrepp. Svarsfrekvensen var relativt låg, cirka 30% besvarade postenkäten. För att kontrollera vad målgruppen anser sig ha för behov som nyföretagare utfördes telefonsamtal till målgruppen för att ställa frågor om det. Svarsfrekvensen blev högre vid telefonsamtalen, hälften av dem som tilldelats postenkäten besvarade telefonsamtalen. Telefonsamtal och e-postkontakt hölls även med branschaktörer såsom andra Science Park-noder i Jönköpings län samt grannkommunerna Hultsfred och Vimmerby. Anledningen till det var att få veta hur andra aktörer marknadsför sig mot nyföretagare. Studien visar att en Science Park-nod på glesbygden bör locka nya företagare till sig genom att sprida publicitet om noden till både nya företagare och andra glesbygdsbor. Detta bör helst göras på ett sådant sätt att invånarna börjar prata om noden genom mun-till-munmetoden. Noden kan till exempel uppmärksammas i lokala dagstidningar, hålla events för allmänheten, göra postutskick om nodens tjänster till målgruppen samt skapa en egen hemsida. Argumenten i kommunikationen bör handla om att Science Park-noden inte ligger långt från målgruppens bostad samt att nodens personal kan hjälpa kunderna att utveckla en affärsplan. Kommunikationen bör vara att noden löser ett uppkommet problem hos målgruppen. Om noden skaffar en grafisk profil kan element skapas som kan användas ofta för målgruppen, ju oftare desto bättre för att skapa större kännedom hos målgruppen. / This work treats the question of how a Science Park-node should get familiar at the countryside. The study has been made mostly through questionnairies from March 2009 until September 2009. The work has been answering how the Science Park-node in the little conurbation Mariannelund should be marketing their business. Although the business has been there since the fall 2008 it has not yet been marketed. This report shows how the marketing ideas possibly can make the Science Park-node to get more customers. A Science Park-node can offer customers a part of an office, copying-machine, businessconsulting and fellow workers. The target group are businesses that are at the most three years old. In the beginning of the project there had to be a theoretical research. Then I had to know which marketingchannels that are mostly used or seen by the target group, that is why a postal questionnaire was sent out to 162 new businesses in the area around Mariannelund. To remind the target group about the questionnaire telephone calls were made where I also asked them some new questions, this time about the needs a new company has got. Phone calls were also made to other organizations, in the same type of business as the Science Park-node, to get to know how they marketed their businesses. The study shows that a Science Park-node at the countryside should try to attract new customers by making publicity about the node to people in the countryside. This should be made in a way that makes people talk about it. Some ideas are that the node can try to be seen in the local newspapers, make events for the citizens of Mariannelund, mail information about the node to the target group and make an own website. The communication of the node should be that it solves problems for the target group. One idea is that it can focus on telling the target group that it is situated nearby home and that the target group can get personal assistance with the development of their business plan. If the Science Park-node also makes a graphic profile with lots of elements which is shown for the target group the popularity will come sooner.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 4 uppsatser.

O Brasil é o segundo maior produtor mundial de soja. Novas tecnologias que possibilitem um aumento na produção desse grão, sem causar impactos no ecossistema, são de grande interesse ambiental, social e econômico. Com objetivo de desenvolver um pacote biotecnológico foram realizados quatro grupos de estudos. Em ensaios in vitro e in vivo foram selecionados, um rizóbio (Ensifer fredii) e duas bactérias promotoras de crescimento vegetal (Pseudomonas fluorescens e Paenibacillus edaphicus) para serem co-inoculadas em sementes de soja. Por meio de estudos em casa-de-vegetação foram desenvolvidas duas tecnologias aplicadas ao inoculante contendo o rizóbio ( fatores Nod e cobamamida), que foram avaliados em conjunto (pacote biotecnológico) em campo de cultivo de soja, que mostrou-se capaz de aumentar a nodulação, o desenvolvimento da planta e rendimento dos grãos dessa leguminosa. / Brazil is the worlds second largest producer of soybean. New technologies that increase the production of this grain, without causing environmental impacts, they are of great enviromental, social and economic importance. In order to develop a biotechnological package it was conducted four study groups. Using in vitro and in vivo assays were selected, one rhizobium (Ensifer fredii) and two plant growth promoters bacterias (Pseudomonas fluorescens e Paenibacillus edaphicus) to b eco-inoculated in soybean seeds. Through studies in greenhouses, two technologies applied to agricultural inoculant have been developed (Nod factors and cobamamide), which were evaluated together (biotecnhological package) in soybean crop field, wich proved capable to increase nodulation, plant growth and yield grain of this legume.

Final publication is available at http://www.bloodjournal.org/ / 京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19614号 / 医博第4121号 / 新制||医||1015(附属図書館) / 32650 / 京都大学大学院医学研究科医学専攻 / (主査)教授 髙折 晃史, 教授 山田 亮, 教授 三森 経世 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Due to heavy nutrient load and adverse climate change the occurrence of toxic cyanobacterial blooms have significantly increased during the last decades. Nodularia spumigena is one of the dominant toxic cyanobacteria which produces massive and inherent blooms in brackish water body, the Baltic Sea, particularly in late summer. Nodularia spp. are known to produce nodularins (NOD) and a range of other bioactive peptides such as spumigins and nodulopeptins, all of which have unclear function. In a recent study, three new nodulopeptins with molecular weight of 899, 901 and 917 were characterised from N. spumigena KAC 66. In the present study, N. spumigena KAC 66 was fractionated by reversed phase flash chromatography and their toxicity was determined by their lethality to Daphnia pulex and D. magna along with inhibition of protein phosphatase 1 assay (PP1). All fractions showed lethality to Daphnids and inhibitory activity against PP1, the toxicity was due to additional compounds as NOD and nodulopeptin 901 were only detected in 7 fractions. Pure NOD was lethal to D. pulex and D. magna LC50= 8.4 μg/mL and 5.0 μg/mL, respectively. The newly characterised nodulopeptin 901 was also tested against D. magna (LC50=>100 μg/mL). NOD and nodulopeptin 901 inhibited PP1 with IC50 0.038 μg/mL and 25 μg/mL, respectively. In common with many studies, the maximum amount of NOD was retained within the cells during the seven week growth experiment. In contrast, as much as ~50% of nodulopeptin 901 was detected in the growth media throughout the duration of experiments. To gain further insight on the effects of environmental stress on growth and production of bioactive metabolites in N. spumigena KAC 66, a range of parameters were investigated which included; temperature, salinity, nitrate and phosphorus. In the present study it was investigated that extreme growth conditions have a considerable effect on biomass and toxin levels by N. spumigena KAC 66. The light intensity ranged from 17.35-17.47 μmol/s/m2, 22°C and 11-20 ‰ of salinity were the optimal growth conditions to obtain maximum biomasses, intra and extracellular peptide contents. At 6.5 mg/L nitrate the maximum growth, as indicated by Chl-a and maximum concentrations of intracellular NOD and nodulopeptin 901 were detected found in week 5 and 4, respectively. Temperature had the greatest effect on peptide production. Whilst growth was similar at 22°C, 25°C and 30°C, increase in temperature had a profound effect on NOD production in that an increase from 22°C to 25°C resulted in a 50% decrease in intracellular NOD levels. At 30°C little or no NOD was detected. In contrast, whilst concentrations of nodulopeptin 901 decreased with increasing temperature, they were still detected at consistent levels suggesting they play an important role. The results from phosphate experiment showed Chl-a, cell biomass and peptide production did not show clear dependency on availability of PO-3 4. This is the first study to evaluate the effects of selected environmental parameters on NOD/nodulopeptin 901 production which ultimately may be helpful to explain the distribution, control of natural blooms and toxin levels of N. spumigena in the Baltic Sea and as well as laboratory based experiments. In an attempt further exploit cyanobacterial diversity, 20 strains were isolated from the Dian Lake and 6 from the Dead Sea. The UPLC-PDA-MS analysis of isolates, Microcystis spp. from Dian Lake, China indicated the presence of several peptides namely MC-LR, cyanopeptolin A and aerucyclamides A-D. These new isolates will be examined for biological activity and chemical characterisation in future studies.

<p>The presence of protein amyloid in pancreas and its association to diabetes was first described 100 years ago in 1901, but was not identified as Islet Amyloid Polypeptide (IAPP) until 1986. The aim of the present work was to determine the role of the beta cell hormone, IAPP, in normal pancreatic islet physiology and during early disturbances of islet function.</p><p>Intra-islet peptides, i.e. chromogranin peptides and an extra-islet peptide, i.e. leptin, were studied to identify possible endogenous regulators of IAPP and insulin secretion. Chromogranin-B, but not chromogranin-A or pancreastatin, had the ability to inhibit islet IAPP and insulin release, suggesting that chromogranin-B may serve as an autocrine regulator of IAPP and insulin secretion. </p><p>Leptin had a more potent effect on IAPP secretion than on insulin secretion, which was dissociated from effects on islet glucose metabolism. Glucose oxidation rates were increased at physiological leptin concentrations, whereas higher leptin concentrations showed an inhibitory effect and chronically high leptin concentrations had no effect.</p><p>Female NOD mice were studied to investigate the release of IAPP in the progression to type 1 diabetes. The release of IAPP was lower than that of insulin from immune cell infiltrated islets, indicating preferential insulin release during the early course of the disease. </p><p>IAPP is expressed at an early embryonic stage. The effect of IAPP on cell proliferation in neonatal rat islets was studied in the search for a physiological role of IAPP. IAPP concentrations of (1-1000) nM stimulated neonatal islet cell proliferation mostly in beta cells and to a lesser extent in alpha cells. IAPP did not have any marked effect on the islet cell death frequency. These data indicate a role for IAPP as a potential regulator of beta cell proliferation in neonatal pancreatic islet.</p><p>It is concluded that IAPP may be involved in regulation of pancreatic beta cell function both in fetal and adult life.</p>

<p>Type 1 diabetes is resulting from the selective destruction of insulin-producing beta-cells within the pancreatic islets. Somatostatin acts as an inhibitor of hormone secretion through specific receptors (sst1-5).</p><p>All ssts were expressed in normal rat and mouse pancreatic islets, although the expression intensity and the co-expression pattern varied between ssts as well as between species. This may reflect a difference in response to somatostatin in islet cells of the two species.</p><p>The Non-Obese Diabetic (NOD) mouse model is an experimental model of type 1 diabetes, with insulitis accompanied by spontaneous hyperglycaemia. Pancreatic specimens from NOD mice at different age and stage of disease were stained for ssts. The islet cells of diabetic NOD mice showed increased islet expression of sst2-5 compared to normoglycemic NOD mice. The increase in sst2-5 expression in the islets cells may suggest either a contributing factor in the process leading to diabetes, or a defense response against ongoing beta-cell destruction.</p><p>Somatostatin analogues were tested on a human endocrine pancreatic tumour cell line and cultured pancreatic islets. Somatostatin analogues had an effect on cAMP accumulation, chromogranin A secretion and MAP kinase activity in the cell line. Treatment of rat pancreatic islets with somatostatin analogues with selective receptor affinity was not sufficient to induce an inhibition of insulin and glucagon secretion. However, a combination of selective analogues or non-selective analogues via co-stimulation of receptors can cause inhibition of hormone production. For insulin and glucagon, combinations of sst2 + sst5 and sst1 + sst2, respectively, showed a biological effect.</p><p>In summary, knowledge of islet cell ssts expression and the effect of somatostatin analogues with high affinity to ssts may be valuable in the future attempts to influence beta-cell function in type 1 diabetes mellitus, since down-regulation of beta-cell function may promote survival of these cells during the autoimmune attack. </p>