Polariserade politiska debatter om migration : positioneringar och attityder i tv-sända valdebatter

Frågor om rasism och flyktingpolitik är vanligt förekommande i politiska debatter, inte minst sedan Sverigedemokraterna 2010 tog plats i riksdagen och driver begränsad migration till Sverige som sin huvudfråga. Föreliggande studie undersöker hur politiker talar om flyktingpolitik och migration till Sverige i de tv-sända partiledardebatterna inför valet 2014. Syftet är att undersöka hur positioneringar och attityder till migration formas genom interaktionen mellan deltagarna och av debatterna som medieproduktion. Analysunderlaget utgörs av de sekvenser där ämnena flyktingpolitik, migration och integration diskuteras. Sammanlagt handlar det om åtta sekvenser från åtta olika debatter. Med aktör-nätverksteori (Latour 2007) som teoretiskt ramverk studerar jag hur partiledarna, tv-kamerorna, programledarna, bildskärmarna i studion och publiken blir till aktörer som i samspel med varandra skapar den bild av debatten som når tittarna. Jag använder verktyg från appraisal (Martin & White 2005) och multimodal diskursanalys (van Leeuwen 2005, 2008) för att studera hur aktörerna översätts och positioneras. Jag tittar bland annat på hur partiledarna citerar, förnekar och motsäger varandras yttranden och hur de formulerar egna åsikter genom att ta avstånd från någon annan. Analysen visar hur debatten polariseras då samtliga partiledare tar avstånd från Sverigedemokraternas partiledare Åkesson och han från dem, men också hur Åkesson görs till en central aktör då kameran filmar honom i betydligt större utsträckning än de andra partiledarna. Analysen visar också hur Åkesson gör negativa bedömningar både av migration och av de andra partiernas politik i frågan. Den dominerande attityden bland övriga partiledare är att Sverige är ett demokratiskt och öppet land som bör ta emot flyktingar och immigranter. Denna ”toleransdiskurs” skapar en positiv självbild som upprätthålls av att det finns ”andra” att tolerera och hjälpa (Blommaert & Verschueren 1998). Immigranter och flyktingar bedöms också utifrån ett nyttoperspektiv (jfr Boréus 2006b) där de välkomnas till Sverige med argumentet att de bidrar till Sveriges ekonomi. En analys av de bilder som visas på bildskärmarna i en tv-studio ger resultatet att debattämnet illustreras av negativa skildringar av människor som flyr. Individerna på bilderna avbildas med dunkla färger och på distans, vilket bidrar till att konstruera dem som främmande och hotfulla. Detta ligger i linje med den attityd till migration som Sverigedemokraterna ger uttryck för. En slutsats är att den polariserade debatten upprätthålls både av partiledarna, av kamerans val av fokus och av programledarna. Attityderna till migration skapas i interaktionen där de också blir ett sätt att positionera sig politiskt och upprätthålla bilden av Sverige – antingen som ett tolerant och godhjärtat land eller som ett land under hot från det som betraktas som icke-svenskt

Metabolic stress-induced human beta-cell death is mediated by increased intracellular levels of adenosine

IntroductionHigh intracellular concentrations of adenosine and 2’-deoxyadenosine have been suggested to be an important mediator of cell death. The aim of the present study was to characterize adenosine-induced death in insulin-producing beta-cells, at control and high glucose + palmitate-induced stress conditions.MethodsHuman insulin-producing EndoC-betaH1 cells were treated with adenosine, 2’-deoxyadenosine, inosine and high glucose + sodium palmitate, and death rates using flow cytometry were studied.ResultsWe observed that adenosine and the non-receptor-activating analogue 2-deoxyadenosine, but not the adenosine deamination product inosine, promoted beta-cell apoptosis at concentrations exceeding maximal adenosine-receptor stimulating concentrations. Both adenosine and inosine were efficiently taken up by EndoC-betaH1 cells, and inosine counteracted the cell death promoting effect of adenosine by competing with adenosine for uptake. Both adenosine and 2’-deoxyadenosine promptly reduced insulin-stimulated production of plasma membrane PI(3,4,5)P3, an effect that was reversed upon wash out of adenosine. In line with this, adenosine, but not inosine, rapidly diminished Akt phosphorylation. Both pharmacological Bax inhibition and Akt activation blocked adenosine-induced beta-cell apoptosis, indicating that adenosine/2’-deoxyadenosine inhibits the PI3K/Akt/BAD anti-apoptotic pathway. High glucose + palmitate-induced cell death was paralleled by increased intracellular adenosine and inosine levels. Overexpression of adenosine deaminase-1 (ADA1) in EndoC-betaH1 cells, which increased Akt phosphorylation, prevented both adenosine-induced apoptosis and high glucose + palmitate-induced necrosis. ADA2 overexpression not only failed to protect against adenosine and high glucose + palmitate-activated cell death, but instead potentiated the apoptosis-stimulating effect of adenosine. In line with this, ADA1 overexpression increased inosine production from adenosine-exposed cells, whereas ADA2 did not. Knockdown of ADA1 resulted in increased cell death rates in response to both adenosine and high glucose + palmitate. Inhibition of miR-30e-3p binding to the ADA1 mRNA 3’-UTR promoted the opposite effects on cell death rates and reduced intracellular adenosine contents.DiscussionIt is concluded that intracellular adenosine/2’-deoxyadenosine regulates negatively the PI3K pathway and is therefore an important mediator of beta-cell apoptosis. Adenosine levels are controlled, at least in part, by ADA1, and strategies to upregulate ADA1 activity, during conditions of metabolic stress, could be useful in attempts to preserve beta-cell mass in diabetes

Inhibition of Y1 receptor signaling improves islet transplant outcome

Failure to secrete sufficient quantities of insulin is a pathological feature of type-1 and type-2 diabetes, and also reduces the success of islet cell transplantation. Here we demonstrate that Y1 receptor signaling inhibits insulin release in β-cells, and show that this can be pharmacologically exploited to boost insulin secretion. Transplanting islets with Y1 receptor deficiency accelerates the normalization of hyperglycemia in chemically induced diabetic recipient mice, which can also be achieved by short-term pharmacological blockade of Y1 receptors in transplanted mouse and human islets. Furthermore, treatment of non-obese diabetic mice with a Y1 receptor antagonist delays the onset of diabetes. Mechanistically, Y1 receptor signaling inhibits the production of cAMP in islets, which via CREB mediated pathways results in the down-regulation of several key enzymes in glycolysis and ATP production. Thus, manipulating Y1 receptor signaling in β-cells offers a unique therapeutic opportunity for correcting insulin deficiency as it occurs in the pathological state of type-1 diabetes as well as during islet transplantation.Islet transplantation is considered one of the potential treatments for T1DM but limited islet survival and their impaired function pose limitations to this approach. Here Loh et al. show that the Y1 receptor is expressed in β- cells and inhibition of its signalling, both genetic and pharmacological, improves mouse and human islet function.info:eu-repo/semantics/publishe

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We recently reported that the C2AB portion of Synaptotagmin 1 (Syt1) could self-assemble into Ca(2+)-sensitive ring-like oligomers on membranes, which could potentially regulate neurotransmitter release. Here we report that analogous ring-like oligomers assemble from the C2AB domains of other Syt isoforms (Syt2, Syt7, Syt9) as well as related C2 domain containing protein, Doc2B and extended Synaptotagmins (E-Syts). Evidently, circular oligomerization is a general and conserved structural aspect of many C2 domain proteins, including Synaptotagmins. Further, using electron microscopy combined with targeted mutations, we show that under physiologically relevant conditions, both the Syt1 ring assembly and its rapid disruption by Ca(2+) involve the well-established functional surfaces on the C2B domain that are important for synaptic transmission. Our data suggests that ring formation may be triggered at an early step in synaptic vesicle docking and positions Syt1 to synchronize neurotransmitter release to Ca(2+) influx. DOI: http://dx.doi.org/10.7554/eLife.17262.00

PIP5KIβ Selectively Modulates Apical Endocytosis in Polarized Renal Epithelial Cells

Localized synthesis of phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2] at clathrin coated pits (CCPs) is crucial for the recruitment of adaptors and other components of the internalization machinery, as well as for regulating actin dynamics during endocytosis. PtdIns(4,5)P2 is synthesized from phosphatidylinositol 4-phosphate by any of three phosphatidylinositol 5-kinase type I (PIP5KI) isoforms (α, β or γ). PIP5KIβ localizes almost exclusively to the apical surface in polarized mouse cortical collecting duct cells, whereas the other isoforms have a less polarized membrane distribution. We therefore investigated the role of PIP5KI isoforms in endocytosis at the apical and basolateral domains. Endocytosis at the apical surface is known to occur more slowly than at the basolateral surface. Apical endocytosis was selectively stimulated by overexpression of PIP5KIβ whereas the other isoforms had no effect on either apical or basolateral internalization. We found no difference in the affinity for PtdIns(4,5)P2-containing liposomes of the PtdIns(4,5)P2 binding domains of epsin and Dab2, consistent with a generic effect of elevated PtdIns(4,5)P2 on apical endocytosis. Additionally, using apical total internal reflection fluorescence imaging and electron microscopy we found that cells overexpressing PIP5KIβ have fewer apical CCPs but more internalized coated structures than control cells, consistent with enhanced maturation of apical CCPs. Together, our results suggest that synthesis of PtdIns(4,5)P2 mediated by PIP5KIβ is rate limiting for apical but not basolateral endocytosis in polarized kidney cells. PtdIns(4,5)P2 may be required to overcome specific structural constraints that limit the efficiency of apical endocytosis. © 2013 Szalinski et al

Subcellular optogenetic inhibition of G proteins generates signaling gradients and cell migration

Cells sense gradients of extracellular cues and generate polarized responses such as cell migration and neurite initiation. There is static information on the intracellular signaling molecules involved in these responses, but how they dynamically orchestrate polarized cell behaviors is not well understood. A limitation has been the lack of methods to exert spatial and temporal control over specific signaling molecules inside a living cell. Here we introduce optogenetic tools that act downstream of native G protein–coupled receptor (GPCRs) and provide direct control over the activity of endogenous heterotrimeric G protein subunits. Light-triggered recruitment of a truncated regulator of G protein signaling (RGS) protein or a Gβγ-sequestering domain to a selected region on the plasma membrane results in localized inhibition of G protein signaling. In immune cells exposed to spatially uniform chemoattractants, these optogenetic tools allow us to create reversible gradients of signaling activity. Migratory responses generated by this approach show that a gradient of active G protein αi and βγ subunits is sufficient to generate directed cell migration. They also provide the most direct evidence so for a global inhibition pathway triggered by Gi signaling in directional sensing and adaptation. These optogenetic tools can be applied to interrogate the mechanistic basis of other GPCR-modulated cellular functions

Pulsatility of insulin release – a clinically important phenomenon

The mechanisms and clinical importance of pulsatile insulin release are presented against the background of more than half a century of companionship with the islets of Langerhans. The insulin-secreting β-cells are oscillators with intrinsic variations of cytoplasmic ATP and Ca2+. Within the islets the β-cells are mutually entrained into a common rhythm by gap junctions and diffusible factors (ATP). Synchronization of the different islets in the pancreas is supposed to be due to adjustment of the oscillations to the same phase by neural output of acetylcholine and ATP. Studies of hormone secretion from the perfused pancreas of rats and mice revealed that glucose induces pulses of glucagon anti-synchronous with pulses of insulin and somatostatin. The anti-synchrony may result from a paracrine action of somatostatin on the glucagon-producing α-cells. Purinoceptors have a key function for pulsatile release of islet hormones. It was possible to remove the glucagon and somatostatin pulses with maintenance of those of insulin with an inhibitor of the P2Y1 receptors. Knock-out of the adenosine A1 receptor prolonged the pulses of glucagon and somatostatin without affecting the duration of the insulin pulses. Studies of isolated human islets indicate similar relations between pulses of insulin, glucagon, and somatostatin as found during perfusion of the rodent pancreas. The observation of reversed cycles of insulin and glucagon adds to the understanding how the islets regulate hepatic glucose production. Current protocols for pulsatile intravenous infusion therapy (PIVIT) should be modified to mimic the anti-synchrony between insulin and glucagon normally seen in the portal blood