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  • 301.
    Censin, J. C.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nowak, Christoph
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Cooper, Nicholas
    Univ Cambridge, Juvenile Diabet Res Fdn,Wellcome Trust Diabet & I, Dept Med Genet,Cambridge Inst Med Res, Natl Inst Hlth Res,Cambridge Biomed Res Ctr, Cambridge, England..
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Todd, John A.
    Univ Cambridge, Juvenile Diabet Res Fdn,Wellcome Trust Diabet & I, Dept Med Genet,Cambridge Inst Med Res, Natl Inst Hlth Res,Cambridge Biomed Res Ctr, Cambridge, England.;Univ Oxford, NIHR Oxford Biomed Res Ctr, Wellcome Trust Ctr Human Genet,Nuffield Dept Med, JDRF,Wellcome Trust Diabet & Inflammat Lab, Oxford, England..
    Fall, Tove
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Molekylär epidemiologi.
    Childhood adiposity and risk of type 1 diabetes: A Mendelian randomization study2017Inngår i: PLoS Medicine, ISSN 1549-1277, E-ISSN 1549-1676, Vol. 14, nr 8, artikkel-id e1002362Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background The incidence of type 1 diabetes (T1D) is increasing globally. One hypothesis is that increasing childhood obesity rates may explain part of this increase, but, as T1D is rare, intervention studies are challenging to perform. The aim of this study was to assess this hypothesis with a Mendelian randomization approach that uses genetic variants as instrumental variables to test for causal associations. Methods and findings We created a genetic instrument of 23 single nucleotide polymorphisms (SNPs) associated with childhood adiposity in children aged 2-10 years. Summary-level association results for these 23 SNPs with childhood-onset (<17 years) T1D were extracted from a meta-analysis of genome-wide association study with 5,913 T1D cases and 8,828 reference samples. Using inverse-variance weighted Mendelian randomization analysis, we found support for an effect of childhood adiposity on T1D risk (odds ratio 1.32, 95% CI 1.06-1.64 per standard deviation score in body mass index [SDS-BMI]). A sensitivity analysis provided evidence of horizontal pleiotropy bias (p = 0.04) diluting the estimates towards the null. We therefore applied Egger regression and multivariable Mendelian randomization methods to control for this type of bias and found evidence in support of a role of childhood adiposity in T1D (odds ratio in Egger regression, 2.76, 95% CI 1.40-5.44). Limitations of our study include that underlying genes and their mechanisms for most of the genetic variants included in the score are not known. Mendelian randomization requires large sample sizes, and power was limited to provide precise estimates. This research has been conducted using data from the Early Growth Genetics (EGG) Consortium, the Genetic Investigation of Anthropometric Traits (GIANT) Consortium, the Tobacco and Genetics (TAG) Consortium, and the Social Science Genetic Association Consortium (SSGAC), as well as meta-analysis results from a T1D genome-wide association study. Conclusions This study provides genetic support for a link between childhood adiposity and T1D risk. Together with evidence from observational studies, our findings further emphasize the importance of measures to reduce the global epidemic of childhood obesity and encourage mechanistic studies.

  • 302. Cervos-Navarro, J
    et al.
    Sharma, H S
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Boncam-Rudloff, E
    Westma, J
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Glial cell reactions in the central nervous system following heat stress.1998Inngår i: Prog Brain Res, Vol. 115, s. 241-Artikkel i tidsskrift (Fagfellevurdert)
  • 303. Chen, Meng-Chi
    et al.
    Paez-Espinosa, Veronica
    Welsh, Nils
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Eizirik, Décio L
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Interleukin-1b regulates phospholipase D-1 expression in rat pancreatic b-cells.2000Inngår i: Endocrinology, Vol. 141, s. 2822-Artikkel i tidsskrift (Fagfellevurdert)
  • 304.
    Chenxiao, Liu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    A flow cytometry method for Vγ9Vδ2 T cell cytotoxicity towards adherent cells and potentiating Vγ9Vδ2 T cell proliferation and cytotoxicityInngår i: Artikkel i tidsskrift (Annet vitenskapelig)
  • 305.
    Chenxiao, Liu
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Characteristics of Vg9Vd2 T cell in colon cancer progressionManuskript (preprint) (Annet vitenskapelig)
  • 306. Chow, R H
    et al.
    Lund, P-E
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Löser, S
    Panten, U
    Gylfe, Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Coincidence of early glucose-induced depolarization with lowering of cytoplasmic Ca2+ in mouse pancreatic beta-cells1995Inngår i: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 485, nr 3, s. 607-617Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    1. The temporal relationship between the early glucose-induced changes of membrane potential and cytoplasmic Ca2+ concentration ([Ca2+]i) was studied in insulin-releasing pancreatic beta-cells. 2. The mean resting membrane potential and [Ca2+]i were about -70 mV and 60 nM, respectively, in 3 mM glucose. 3. Elevating the glucose concentration to 8-23 mM typically elicited a slow depolarization, which was paralleled by a lowering of [Ca2+]i. When the slow depolarization had reached a threshold of -55 to -40 mV, there was rapid further depolarization to a plateau with superimposed action potentials, and [Ca2+]i increased dramatically. 4. Imposing hyperpolarizations and depolarizations of 10 mV from a holding potential of -70 mV had no detectable effect on [Ca2+]i. Furthermore, glucose elevation elicited a decrease in [Ca2+]i even at a holding potential of -70 mV. 5. Step depolarizations induced [Ca2+]i transients, which decayed with time courses well fitted by double exponentials. The slower component became faster by a factor of about 4 upon elevation of glucose, suggesting involvement of ATP-dependent Ca2+ sequestration or extrusion of [Ca2+]i. 6. Glucose stimulation increased the size and accelerated the recovery of carbachol-triggered [Ca2+]i transients, and thapsigargin, an intracellular Ca(2+)-ATPase inhibitor, counteracted the glucose-induced lowering of [Ca2+]i, indicating that calcium transport into intracellular stores is involved in glucose-induced lowering of [Ca2+]i. 7. The results support the notion that in beta-cells, nutrient-induced elevation of ATP leads initially to ATP-dependent removal of Ca2+ from the cytoplasm, paralleled by a slow depolarization due to inhibition of ATP-sensitive K+ channels. Only after depolarization has reached a threshold do action potentials occur, inducing a sharp elevation in [Ca2+]i.

  • 307.
    Chowdhury, Azazul Islam
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Role of Cell-cell Interactions and Palmitate on β-cells Function2014Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    The islets of Langerhans secrets insulin in response to fluctuations of blood glucose level and efficient secretion requires extensive intra-islet communication. Secretory failure from islets is one of the hallmark in progression of type 2 diabetes.  Changes in islet structure and high levels of saturated free fatty acids may contribute to this failure. The aim of this thesis is to study the role of cell-cell interactions and palmitate on β-cells functions.

    To address the role of cell-cell interactions on β-cells functions MIN6 cells were cultured as monolayers and as pseudoislets. Glucose stimulated insulin secretion was higher in pseudoislets compared to monolayers. Transcript levels of mitochondrial metabolism as well glucose oxidation rate was higher in pseudoislets. Insulin receptor substrate-1 (IRS-1) phosphorylation was altered when cells were grown as pseudoislets. Proteins expression levels related to glycolysis, cellular connections and translational regulations were up-regulated in pseudoislets. We propose the superior capacity of pseudoislets compared to monolayers depend on metabolism, cell coupling, gene translation, protein turnover and differential IRS-1 phosphorylation.

    To address the role of palmitate on β-cells human islets were cultured in palmitate. Long term palmitate treatment decreased insulin secretion which is associated with up-regulation of suppressor of cytokine signaling-2 (SOCS2) and protein inhibitor of activated STAT-1 (PIAS1). Up-regulation of SOCS2 decreased phosphorylation of Akt at site T308, whereas PIAS1 decreased protein level of ATP- citrate lyase (ACLY) and ATP synthase subunit B (ATP5B). We propose long term palmitate treatment reduces phosphatidylinositol 3-kinase (PI3K) activity, attenuates formation of acetyl-CoA and decreases ATP synthesis which may aggravate β-cells dysfunction.  

    Delarbeid
    1. Functional differences between aggregated and dispersed insulin-producing cells
    Åpne denne publikasjonen i ny fane eller vindu >>Functional differences between aggregated and dispersed insulin-producing cells
    Vise andre…
    2013 (engelsk)Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, nr 7, s. 1557-1568Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Beta cells situated in the islet of Langerhans respond more vigorously to glucose than do dissociated beta cells. Mechanisms for this discrepancy were studied by comparing insulin-producing MIN6 cells aggregated into pseudoislets with MIN6 monolayer cells and mouse and human islets. MIN6 monolayers, pseudoislets and mouse and human islets were exposed to glucose, alpha-ketoisocaproic acid (KIC), pyruvate, KIC plus glutamine and the phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 or wortmannin. Insulin secretion (ELISA), cytoplasmic Ca2+ concentration ([Ca2+](c); microfluorometry), glucose oxidation (radiolabelling), the expression of genes involved in mitochondrial metabolism (PCR) and the phosphorylation of insulin receptor signalling proteins (western blotting) were measured. Insulin secretory responses to glucose, pyruvate, KIC and glutamine were higher in pseudoislets than monolayers and comparable to those of human islets. Glucose oxidation and genes for mitochondrial metabolism were upregulated in pseudoislets compared with single cells and monolayers, respectively. Phosphorylation at the inhibitory S636/639 site of IRS-1 was significantly higher in monolayers and dispersed human and mouse cells than pseudoislets and intact human and mouse islets. PI3K inhibition only slightly attenuated glucose-stimulated insulin secretion from monolayers, but substantially reduced that from pseudoislets and human and mouse islets without suppressing the glucose-induced [Ca2+](c) response. We propose that islet architecture is critical for proper beta cell mitochondrial metabolism and IRS-1 signalling, and that PI3K regulates insulin secretion at a step distal to the elevation of [Ca2+](c).

    Emneord
    Beta cell, Ca2+, Insulin secretion, IRS-1, Islets, Mitochondrial metabolism, PI3-kinase
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-203520 (URN)10.1007/s00125-013-2903-3 (DOI)000319881300013 ()
    Tilgjengelig fra: 2013-07-16 Laget: 2013-07-15 Sist oppdatert: 2017-12-06bibliografisk kontrollert
    2. Signaling in Insulin-Secreting MIN6 Pseudoislets and Monolayer Cells
    Åpne denne publikasjonen i ny fane eller vindu >>Signaling in Insulin-Secreting MIN6 Pseudoislets and Monolayer Cells
    Vise andre…
    2013 (engelsk)Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 12, nr 12, s. 5954-5962Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Cell cell interactions are of fundamental importance for cellular function. In islets of Langerhans, which control blood glucose levels by secreting insulin in response to the blood . glucose concentration, the secretory response of intact islets is c higher than that of insulin-producing beta-cells not arranged in the islet architecture. The objective was to define mechanisms by which cellular performance is enhanced when cells are arranged in a) three-dimensional space. The task was addressed by making a c comprehensive analysis based on protein expression patterns " generated from insulin-secreting MIN6 cells grown as islet-like c clusters, so-called pseudoislets, and in monolayers. After culture, glucose-stimulated insulin secretion (GSIS) was measured from monolayers and pseudoislets. GSIS rose 6-fold in pseudoislets but only 3-fold in monolayers when the glucose concentration was increased from 2 to 20 mmol/L. Proteins from pseudoislets and monolayers were extracted and analyzed by liquid-chromatography mass spectrometry, and differentially expressed proteins were mapped onto KEGG pathways. Protein profiling identified 1576 proteins, which were common to pseudoislets and monolayers. When mapped onto KEGG pathways, 11 highly enriched pathways were identified. On the basis of differences in expression of proteins belonging to the pathways in pseudoislets and monolayers, predictions of differential pathway activation were performed. Mechanisms enhancing insulin secretory capacity of the beta-cell, when situated in the islet, include pathways regulating glucose metabolism, cell interaction, and translational regulation.

    Emneord
    glucose-stimulated insulin secretion (GSIS), beta-cells, MIN6 cells, pseudoislets
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-215288 (URN)10.1021/pr400864w (DOI)000328231300053 ()
    Tilgjengelig fra: 2014-01-13 Laget: 2014-01-13 Sist oppdatert: 2017-12-06bibliografisk kontrollert
    3. GLP-1 recovers impaired insulin secretion from human islets treated with palmitate via down-regulation of SOCS2
    Åpne denne publikasjonen i ny fane eller vindu >>GLP-1 recovers impaired insulin secretion from human islets treated with palmitate via down-regulation of SOCS2
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-230839 (URN)
    Tilgjengelig fra: 2014-08-30 Laget: 2014-08-30 Sist oppdatert: 2018-01-11
    4. Role of PIAS1 in palmitate-mediated beta-cell dysfunction
    Åpne denne publikasjonen i ny fane eller vindu >>Role of PIAS1 in palmitate-mediated beta-cell dysfunction
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-230840 (URN)
    Tilgjengelig fra: 2014-08-30 Laget: 2014-08-30 Sist oppdatert: 2018-01-11
  • 308.
    Chowdhury, Azazul Islam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    GLP-1 analogue recovers impaired insulin secretion from human islets treated with palmitate via down-regulation of SOCS22017Inngår i: Molecular and Cellular Endocrinology, ISSN 0303-7207, E-ISSN 1872-8057, Vol. 439, nr C, s. 194-202Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Elevated circulating palmitate levels have been connected with type 2 diabetes mellitus. GLP-1 has favorable effects on beta-cells function. The aim was to identify mechanisms for decreased GSIS after long-term palmitate exposure and restoration by GLP-1 by analyzing changes in G-protein coupled receptor (GPCR) pathway signaling. Insulin secretory response to 20 mM glucose was attenuated after 7 days in islets exposed to palmitate but inclusion of exendin-4 restored secretion. Palmitate treatment altered genes of several GPCR signaling pathways including inflammatory pathways with up-regulated IL-1B, SOCS1 and SOCS2 transcript levels. Protein level of SOCS2 was also up-regulated by palmitate and accompanied by down-regulation of pAkt(T308), which was restored by exendin-4 treatment. When SOCS2 was knocked down, palmitate-induced clown-regulation of IRS-1 and pAkt(T308) was prevented and GSIS, proinsulin to insulin ratio and apoptosis was restored. Long-term palmitate treatment up regulates SOCS2 and reduces PI3K activity, thereby impairing GSIS. GLP-1 reverts the palmitate-induced effects.

  • 309.
    Chowdhury, Azazul Islam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    GLP-1 recovers impaired insulin secretion from human islets treated with palmitate via down-regulation of SOCS2Manuskript (preprint) (Annet vitenskapelig)
  • 310.
    Chowdhury, Azazul Islam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Dyachok, Oleg
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tengholm, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandler, Stellan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Functional differences between aggregated and dispersed insulin-producing cells2013Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, nr 7, s. 1557-1568Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Beta cells situated in the islet of Langerhans respond more vigorously to glucose than do dissociated beta cells. Mechanisms for this discrepancy were studied by comparing insulin-producing MIN6 cells aggregated into pseudoislets with MIN6 monolayer cells and mouse and human islets. MIN6 monolayers, pseudoislets and mouse and human islets were exposed to glucose, alpha-ketoisocaproic acid (KIC), pyruvate, KIC plus glutamine and the phosphatidylinositol 3-kinase (PI3K) inhibitors LY294002 or wortmannin. Insulin secretion (ELISA), cytoplasmic Ca2+ concentration ([Ca2+](c); microfluorometry), glucose oxidation (radiolabelling), the expression of genes involved in mitochondrial metabolism (PCR) and the phosphorylation of insulin receptor signalling proteins (western blotting) were measured. Insulin secretory responses to glucose, pyruvate, KIC and glutamine were higher in pseudoislets than monolayers and comparable to those of human islets. Glucose oxidation and genes for mitochondrial metabolism were upregulated in pseudoislets compared with single cells and monolayers, respectively. Phosphorylation at the inhibitory S636/639 site of IRS-1 was significantly higher in monolayers and dispersed human and mouse cells than pseudoislets and intact human and mouse islets. PI3K inhibition only slightly attenuated glucose-stimulated insulin secretion from monolayers, but substantially reduced that from pseudoislets and human and mouse islets without suppressing the glucose-induced [Ca2+](c) response. We propose that islet architecture is critical for proper beta cell mitochondrial metabolism and IRS-1 signalling, and that PI3K regulates insulin secretion at a step distal to the elevation of [Ca2+](c).

  • 311.
    Chowdhury, Azazul Islam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hörnaeus, Katarina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi.
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala Univ, Med Cell Biol, Uppsala, Sweden..
    Role of PIAS1 in palmitate mediated beta cell dysfunction2015Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, nr Suppl. 1, s. S230-S230Artikkel i tidsskrift (Annet vitenskapelig)
  • 312.
    Chowdhury, Azazul Islam
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Hörnaeus, Katarina
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Role of PIAS1 in palmitate-mediated beta-cell dysfunctionManuskript (preprint) (Annet vitenskapelig)
  • 313.
    Chowdhury, Azazul
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Satagopam, Venkata P.
    Manukyan, Levon
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Artemenko, Konstantin A.
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fung, Yi Man Eva
    Schneider, Reinhard
    Bergquist, Jonas
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Kemiska sektionen, Institutionen för kemi - BMC, Analytisk kemi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Signaling in Insulin-Secreting MIN6 Pseudoislets and Monolayer Cells2013Inngår i: Journal of Proteome Research, ISSN 1535-3893, E-ISSN 1535-3907, Vol. 12, nr 12, s. 5954-5962Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Cell cell interactions are of fundamental importance for cellular function. In islets of Langerhans, which control blood glucose levels by secreting insulin in response to the blood . glucose concentration, the secretory response of intact islets is c higher than that of insulin-producing beta-cells not arranged in the islet architecture. The objective was to define mechanisms by which cellular performance is enhanced when cells are arranged in a) three-dimensional space. The task was addressed by making a c comprehensive analysis based on protein expression patterns " generated from insulin-secreting MIN6 cells grown as islet-like c clusters, so-called pseudoislets, and in monolayers. After culture, glucose-stimulated insulin secretion (GSIS) was measured from monolayers and pseudoislets. GSIS rose 6-fold in pseudoislets but only 3-fold in monolayers when the glucose concentration was increased from 2 to 20 mmol/L. Proteins from pseudoislets and monolayers were extracted and analyzed by liquid-chromatography mass spectrometry, and differentially expressed proteins were mapped onto KEGG pathways. Protein profiling identified 1576 proteins, which were common to pseudoislets and monolayers. When mapped onto KEGG pathways, 11 highly enriched pathways were identified. On the basis of differences in expression of proteins belonging to the pathways in pseudoislets and monolayers, predictions of differential pathway activation were performed. Mechanisms enhancing insulin secretory capacity of the beta-cell, when situated in the islet, include pathways regulating glucose metabolism, cell interaction, and translational regulation.

  • 314.
    Christensen, Michael
    et al.
    Aarhus Univ, Dept Clin Med, Aarhus, Denmark.
    Schiffer, Tomas A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Gustafsson, Håkan
    Linkoping Univ, Dept Radiol Norrkoping, Linkoping, Sweden;Linkoping Univ, Dept Med & Hlth Sci, Linkoping, Sweden.
    Krag, Sören Palmelund
    Aarhus Univ Hosp, Dept Pathol, Aarhus, Denmark.
    Nörregaard, Rikke
    Aarhus Univ, Dept Clin Med, Aarhus, Denmark.
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Metformin attenuates renal medullary hypoxia in diabetic nephropathy through inhibition uncoupling protein-22019Inngår i: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 35, nr 2, artikkel-id e3091Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: The purpose of the study is to examine the effect of metformin on oxygen metabolism and mitochondrial function in the kidney of an animal model of insulinopenic diabetes in order to isolate any renoprotective effect from any concomitant effect on blood glucose homeostasis.

    Methods: Sprague-Dawley rats were injected with streptozotocin (STZ) (50 mg kg(-1)) and when stable started on metformin treatment (250 mg kg(-1)) in the drinking water. Rats were prepared for in vivo measurements 25 to 30 days after STZ injection, where renal function, including glomerular filtration rate and sodium transport, was estimated in anesthetized rats. Intrarenal oxygen tension was measured using oxygen sensors. Furthermore, mitochondrial function was assessed in mitochondria isolated from kidney cortex and medulla analysed by high-resolution respirometry, and superoxide production was evaluated using electron paramagnetic resonance.

    Results: Insulinopenic rats chronically treated with metformin for 4 weeks displayed improved medullary tissue oxygen tension despite of no effect of metformin on blood glucose homeostasis. Metformin reduced UCP2-dependent LEAK and differentially affected medullary mitochondrial superoxide radical production in control and diabetic rats.

    Conclusions: Metformin attenuates diabetes-induced renal medullary tissue hypoxia in an animal model of insulinopenic type 1 diabetes. The results suggest that the mechanistic pathway to attenuate the diabetes-induced medullary hypoxia is independent of blood glucose homeostasis and includes reduced UCP2-mediated mitochondrial proton LEAK.

  • 315.
    Christensen, Michael
    et al.
    Aarhus Univ, Aarhus N, Denmark..
    Schiffer, Tomas A.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Norregaard, Rikke
    Aarhus Univ, Aarhus N, Denmark..
    Palm, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Metformin Normalises Medullary Hypoxia in The Diabetic Rat Kidney2017Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 31Artikkel i tidsskrift (Annet vitenskapelig)
  • 316.
    Christoffersson, Gustaf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Leukocytes in Angiogenesis: Learning from Transplanted Pancreatic Islets2013Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Angiogenesis, the growth of new blood vessels, is a complex process involving several cell types and molecular signals. Excessive vascular growth is a problem in tumors, and insufficient vascularization hampers the function of transplanted insulin-producing pancreatic islets. Understanding the mechanisms behind blood vessel growth generates increased means to control angiogenesis. In this thesis a model of pancreatic islet transplantation to muscle has been used to study the involvement of leukocytes in the development of new vasculature.

    Transplantation of isolated islets of Langerhans into mouse muscle promoted revascularization of the grafts to a level comparable to native islets in the pancreas. The complete and functional vascular restoration resulted in improved blood glucose control compared to the clinical standard implantation site, the liver. This proved muscle as a transplantation site to be a clinically relevant option for the treatment of type 1 diabetes.

    The rapid islet revascularization process was found to be dependent on a distinct subset of neutrophils characterized by high expression of the chemokine receptor CXCR4 and the enzyme matrix metalloproteinase 9 (MMP-9). These cells were recruited to recently transplanted and hypoxic grafts by islet-secreted vascular endothelial growth factor A (VEGF-A). Leukocyte migration and interactions in the engraftment area were monitored using a high-speed confocal microscope followed by software tracking. New software was developed to visualize migration statistics. This tool revealed areas around the islet graft where neutrophil gathering coincided with sites of angiogenesis. Macrophages in the engraftment area positioned themselves close to the newly formed vasculature and were shown to have a stabilizing effect on the vessels. When macrophages were removed, no pericytes were recruited to the forming vasculature. The perivascular macrophages also began to express a pericyte marker when in the graft, suggesting a close relationship between these cell types or macrophage plasticity.

    In conclusion, this thesis presents muscle as a proangiogenic transplantation site for pancreatic islets for the treatment of type 1 diabetes, where the revascularization of the grafts was dependent on the recruitment and actions of specialized immune cells.

    Delarbeid
    1. Clinical and Experimental Pancreatic Islet Transplantation to Striated Muscle: Establishment of a Vascular System Similar to that in Native Islets
    Åpne denne publikasjonen i ny fane eller vindu >>Clinical and Experimental Pancreatic Islet Transplantation to Striated Muscle: Establishment of a Vascular System Similar to that in Native Islets
    Vise andre…
    2010 (engelsk)Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, nr 10, s. 2569-2578Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Objective: Curing type 1 diabetes by transplanting pancreatic islets into the liver is associated with poor long-term outcome and graft failure at least partly due to inadequate graft revascularization. The aim of the current study was to evaluate striated muscle as a potential angiogenic site for islet transplantation. Research Design and Methods: The current study presents a new experimental model which is found applicable to clinical islet transplantation. Islets were implanted into striated muscle where after intra-islet vascular density and blood flow were visualized with intravital and confocal microscopy in mice, and by magnetic resonance imaging in three auto-transplanted pancreatectomized patients. Mice were rendered neutropenic by repeated injections of Gr-1 antibody and diabetes was induced by alloxan treatment. Results: Contrary to liver-engrafted islets, islets transplanted to mouse muscle were revascularized with vessel densities and blood flow entirely comparable to islets within intact pancreas. Initiation of islet revascularization at the muscular site was dependent on neutrophils, and the function of islets transplanted to muscle was proven by curing diabetic mice. The experimental data were confirmed in auto-transplanted patients where higher plasma volumes were measured in islets engrafted in forearm muscle compared to adjacent muscle tissue through high-resolution magnetic resonance imaging. Conclusions: This study presents a novel paradigm in islet transplantation whereby recruited neutrophils are crucial for the functionally restored intra-islet blood perfusion following transplantation to striated muscle under experimental and clinical situations.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-130874 (URN)10.2337/db10-0205 (DOI)000283205700030 ()20651296 (PubMedID)
    Forskningsfinansiär
    Swedish Research Council, 57p-20680, 57x-20675
    Tilgjengelig fra: 2010-09-15 Laget: 2010-09-15 Sist oppdatert: 2017-12-12bibliografisk kontrollert
    2. VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue
    Åpne denne publikasjonen i ny fane eller vindu >>VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue
    Vise andre…
    2012 (engelsk)Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, nr 23, s. 4653-4662Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [sv]

    Recruitment and retention of leukocytes at a site of blood vessel growth are crucial for proper angiogenesis and subsequent tissue perfusion. Although critical for many aspects of regenerative medicine, the mechanisms of leukocyte recruitment to and actions at sites of angiogenesis are not fully understood. In this study, we investigated the signals attracting leukocytes to avascular transplanted pancreatic islets and leukocyte actions at the engraftment site. Expression of the angiogenic stimulus VEGF-A by mouse pancreatic islets was elevated shortly after syngeneic transplantation to muscle. High levels of leukocytes, predominantly CD11b+/Gr-1+/CXCR4hi neutrophils, were observed at the site of engraftment, whereas VEGF-A–deficient islets recruited only half of the amount of leukocytes when transplanted. Acute VEGF-A exposure of muscle increased leukocyte extravasation but not the levels of SDF-1α. VEGF-A–recruited neutrophils expressed 10 times higher amounts of MMP-9 than neutrophils recruited to an inflammatory stimulus. Revascularization of islets transplanted to MMP-9–deficient mice was impaired because blood vessels initially failed to penetrate grafts, and after 2 weeks vascularity was still disturbed. This study demonstrates that VEGF-A recruits a proangiogenic circulating subset of CD11b+/Gr-1+ neutrophils that are CXCR4hi and deliver large amounts of the effector protein MMP-9, required for islet revascularization and functional integration after transplantation.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-188352 (URN)10.1182/blood-2012-04-421040 (DOI)000313113300031 ()
    Tilgjengelig fra: 2012-12-16 Laget: 2012-12-16 Sist oppdatert: 2018-01-11bibliografisk kontrollert
    3. Vascular sprouts induce local attraction of proangiogenic neutrophils
    Åpne denne publikasjonen i ny fane eller vindu >>Vascular sprouts induce local attraction of proangiogenic neutrophils
    Vise andre…
    2017 (engelsk)Inngår i: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 102, s. 741-751Artikkel i tidsskrift (Fagfellevurdert) Published
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-196483 (URN)10.1189/jlb.1MA0117-018R (DOI)000413395700019 ()
    Prosjekter
    eSSENCE
    Tilgjengelig fra: 2017-06-05 Laget: 2013-03-10 Sist oppdatert: 2018-11-12bibliografisk kontrollert
    4. Pericyte repopulation of transplanted pancreatic islets is macrophage dependent
    Åpne denne publikasjonen i ny fane eller vindu >>Pericyte repopulation of transplanted pancreatic islets is macrophage dependent
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-196485 (URN)
    Tilgjengelig fra: 2013-03-10 Laget: 2013-03-10 Sist oppdatert: 2018-01-11
  • 317.
    Christoffersson, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Intramuscular islet transplantation promotes restored islet vascularity2011Inngår i: Islets, ISSN 1938-2014, E-ISSN 1938-2022, Vol. 3, nr 2, s. 69-71Artikkel i tidsskrift (Annet vitenskapelig)
    Abstract [en]

    In a recent publication, we reported that islets transplanted to mouse striated muscle became revascularized with intra-islet vessel densities comparable to native islets. Revascularization of islet grafts was completely dependent on recruited Gr-1+ leukocytes. Diabetic mice cured by transplantation of 300 islets into muscle handled glucose tolerance tests as healthy controls, whereas mice cured by intraportal islet transplantation into the liver had increased blood glucose values during the load. The translational impact of these observations were confirmed by magnetic resonance imaging of autotransplanted islets in the forearm muscle of pancreactomized patients, and higher blood perfusion of the grafts compared to adjacent muscle were found. In summary, the striated muscle is a promising site for islet transplantation which promotes full revascularization of implanted grafts. The proangiogenic role of recruited leukocytes during engraftment needs to be further characterized, and considered for immune suppression treatments.

  • 318.
    Christoffersson, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Henriksnäs, Johanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Johansson, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för radiologi.
    Rolny, Charlotte
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi, Enheten för radiologi.
    Caballero-Corbalán, José
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Segersvärd, Ralf
    Permert, Johan
    Korsgren, Olle
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för onkologi, radiologi och klinisk immunologi.
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Clinical and Experimental Pancreatic Islet Transplantation to Striated Muscle: Establishment of a Vascular System Similar to that in Native Islets2010Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 59, nr 10, s. 2569-2578Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Objective: Curing type 1 diabetes by transplanting pancreatic islets into the liver is associated with poor long-term outcome and graft failure at least partly due to inadequate graft revascularization. The aim of the current study was to evaluate striated muscle as a potential angiogenic site for islet transplantation. Research Design and Methods: The current study presents a new experimental model which is found applicable to clinical islet transplantation. Islets were implanted into striated muscle where after intra-islet vascular density and blood flow were visualized with intravital and confocal microscopy in mice, and by magnetic resonance imaging in three auto-transplanted pancreatectomized patients. Mice were rendered neutropenic by repeated injections of Gr-1 antibody and diabetes was induced by alloxan treatment. Results: Contrary to liver-engrafted islets, islets transplanted to mouse muscle were revascularized with vessel densities and blood flow entirely comparable to islets within intact pancreas. Initiation of islet revascularization at the muscular site was dependent on neutrophils, and the function of islets transplanted to muscle was proven by curing diabetic mice. The experimental data were confirmed in auto-transplanted patients where higher plasma volumes were measured in islets engrafted in forearm muscle compared to adjacent muscle tissue through high-resolution magnetic resonance imaging. Conclusions: This study presents a novel paradigm in islet transplantation whereby recruited neutrophils are crucial for the functionally restored intra-islet blood perfusion following transplantation to striated muscle under experimental and clinical situations.

  • 319.
    Christoffersson, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Lomei, Jalal
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    O'Callaghan, Paul
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Kreuger, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Engblom, Stefan
    Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Avdelningen för beräkningsvetenskap. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Matematisk-datavetenskapliga sektionen, Institutionen för informationsteknologi, Tillämpad beräkningsvetenskap.
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Vascular sprouts induce local attraction of proangiogenic neutrophils2017Inngår i: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 102, s. 741-751Artikkel i tidsskrift (Fagfellevurdert)
  • 320.
    Christoffersson, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Olsen, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Pericyte repopulation of transplanted pancreatic islets is macrophage dependentManuskript (preprint) (Annet vitenskapelig)
  • 321.
    Christoffersson, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    The neutrophil: one cell on many missions or many cells with different agendas?2018Inngår i: Cell and Tissue Research, ISSN 0302-766X, E-ISSN 1432-0878, Vol. 371, nr 3, s. 415-423Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The unique role of neutrophils in host defense is not only based on their abilities to kill bacteria but is also due to their abundance in circulation and their ability to quickly migrate and accumulate in great numbers at afflicted sites. The high number of circulating neutrophils is the result of regulated release of new neutrophils from bone marrow as well as from marginated pools to balance their recruitment to tissue. Marginated pools, such as the spleen and lung, have previously been attributed to passively delay neutrophil transit time due to their large capillary network, but recent reports demonstrate that they are comprised of neutrophils with specific functions. The spleen, for instance, holds neutrophil subpopulations at different anatomical locations with distinct functions important for, e.g., bacterial eradication, and the lung was recently shown to re-educate neutrophils that had trafficked from a site of sterile injury to home back to bone marrow for elimination. Further, recent reports demonstrate subpopulations of neutrophils with different actions during homeostasis, infection, tissue restitution and cancer. It is becoming increasingly clear that this cannot be due to different stages of neutrophil activation during their life span but instead points towards distinct subpopulations of neutrophils with different effector functions. Whether these cellular distinctions are due to different education or origin is, however, not yet known. Together, the accumulating information about the heterogeneous neutrophils presents important insights into their role in development of pathologies, as well as revealing novel targets in the form of certain subpopulations to treat disease.

  • 322.
    Christoffersson, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    von Herrath, Matthias
    La Jolla Inst Allergy & Immunol, Type Diabet Ctr 1, La Jolla, CA 92037 USA;Novo Nordisk Res Ctr, Seattle, WA 98109 USA.
    Regulatory Immune Mechanisms beyond Regulatory T Cells2019Inngår i: Trends in immunology, ISSN 1471-4906, E-ISSN 1471-4981, Vol. 40, nr 6, s. 482-491Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    In autoimmunity, aggressive immune responses are counteracted by suppressive rejoinders. For instance, FOXP3-expressing regulatory T cells (Tregs), have shown remarkable effects in limiting autoimmunity in preclinical models. However, early results from human Treg trials have not been as positive. Here, we highlight questions surrounding Treg transfers as putative treatments for autoimmunity. We discuss whether lack of antigenic recognition might be key to shifting cells from contributing to an aggressive autoresponse, to being part of a regulatory network. Moreover, we argue that identifying the physiological range of immunosuppression of Tregs might help potentiate their efficacy. We propose widening the view on immunoregulation by considering the participation of CD8(+) Tregs in this process, which could have major implications in autoimmunity.

  • 323.
    Christoffersson, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Vågesjö, Evalina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Giraud, Antoine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Massena, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Powers, A. C.
    Opdenakker, G.
    Phillipson, M.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    A distinct subset of proangiogenic CD11b(+)/Gr-1(+)/CXCR4(+)/MMP-9(hi) neutrophils are recruited by VEGF-A to transplanted hypoxic tissue2013Inngår i: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 43, nr SI, s. 9-9Artikkel i tidsskrift (Annet vitenskapelig)
  • 324.
    Christoffersson, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Vågesjö, Evelina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Pettersson, Ulrika S.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Massena, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Nilsson, Emil K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Broman, Jan-Erik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Psykiatri, Akademiska sjukhuset.
    Schiöth, Helgi B.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Benedict, Christian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Funktionell farmakologi.
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Acute sleep deprivation in healthy young men: Impact on population diversity and function of circulating neutrophils2014Inngår i: Brain, behavior, and immunity, ISSN 0889-1591, E-ISSN 1090-2139, Vol. 41, s. 162-172Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Lack of sleep greatly affects our immune system. The present study investigates the acute effects of total sleep deprivation on blood neutrophils, the most abundant immune cell in our circulation and the first cell type recruited to sites of infection. Thus, the population diversity and function of circulating neutrophils were compared in healthy young men following one night of total sleep deprivation (TSD) or after 8 h regular sleep. We found that neutrophil counts were elevated after nocturnal wakefulness (2.0 +/- 0.2 x 10(9)/l vs. 2.6 +/- 0.2 x 10(9)/l, sleep vs. TSD, respectively) and the population contained more immature CD16(dim)/CD62L(bright) cells (0.11 +/- 0.040 x 10(9)/l [5.5 +/- 1.1%] vs. 0.26 +/- 0.020 x 10(9)/l [9.9 +/- 1.4%]). As the rise in numbers of circulating mature CD16(bright)/CD62L(bright) neutrophils was less pronounced, the fraction of this subpopulation showed a significant decrease (1.8 +/- 0.15 x 10(9)/l [88 +/- 1.8%] vs. 2.1 +/- 0.12 x 10(9)/l [82 +/- 2.8%]). The surface expression of receptors regulating mobilization of neutrophils from bone marrow was decreased (CXCR4 and CD49d on immature neutrophils; CXCR2 on mature neutrophils). The receptor CXCR2 is also involved in the production of reactive oxygen species (ROS), and in line with this, total neutrophils produced less ROS. In addition, following sleep loss, circulating neutrophils exhibited enhanced surface levels of CD11b, which indicates enhanced granular fusion and concomitant protein translocation to the membrane. Our findings demonstrate that sleep loss exerts significant effects on population diversity and function of circulating neutrophils in healthy men. To which extent these changes could explain as to why people with poor sleep patterns are more susceptible to infections warrants further investigation.  

  • 325.
    Christoffersson, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Vågesjö, Evelina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Vandooren, Jennifer
    Liden, Majken
    Massena, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Reinert, RB
    Brissova, M
    Powers, AC
    Opdenakker, Ghislain
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    VEGF-A recruits a proangiogenic MMP-9-delivering neutrophil subset that induces angiogenesis in transplanted hypoxic tissue2012Inngår i: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 120, nr 23, s. 4653-4662Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [sv]

    Recruitment and retention of leukocytes at a site of blood vessel growth are crucial for proper angiogenesis and subsequent tissue perfusion. Although critical for many aspects of regenerative medicine, the mechanisms of leukocyte recruitment to and actions at sites of angiogenesis are not fully understood. In this study, we investigated the signals attracting leukocytes to avascular transplanted pancreatic islets and leukocyte actions at the engraftment site. Expression of the angiogenic stimulus VEGF-A by mouse pancreatic islets was elevated shortly after syngeneic transplantation to muscle. High levels of leukocytes, predominantly CD11b+/Gr-1+/CXCR4hi neutrophils, were observed at the site of engraftment, whereas VEGF-A–deficient islets recruited only half of the amount of leukocytes when transplanted. Acute VEGF-A exposure of muscle increased leukocyte extravasation but not the levels of SDF-1α. VEGF-A–recruited neutrophils expressed 10 times higher amounts of MMP-9 than neutrophils recruited to an inflammatory stimulus. Revascularization of islets transplanted to MMP-9–deficient mice was impaired because blood vessels initially failed to penetrate grafts, and after 2 weeks vascularity was still disturbed. This study demonstrates that VEGF-A recruits a proangiogenic circulating subset of CD11b+/Gr-1+ neutrophils that are CXCR4hi and deliver large amounts of the effector protein MMP-9, required for islet revascularization and functional integration after transplantation.

  • 326.
    Christoffersson, Gustaf
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Waldén, Tomas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Sandberg, Monica
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Opdenakker, Ghislain
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Matrix Metalloproteinase-9 Is Essential for Physiological Beta Cell Function and Islet Vascularization in Adult Mice2015Inngår i: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 185, nr 4, s. 1094-1103Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The availability of paracrine factors in the islets of Langerhans, and the constitution of the beta cell basement membrane can both be affected by proteolytic enzymes. This study aimed to investigate the effects of the extraceaular matrix-degrading enzyme gelatinase B/matrix metalloproteinase-9 (Mmp-9) on islet function in mice. Islet function of Mmp9-deficient (Mmp9(-/-)) mice and their wild-type Littermates was evaluated both in vivo and in vitro. The pancreata of Mmp9(-/-) mice did not differ from wild type in islet mass or distribution. However, Mmp9(-/-) mice had an impaired response to a glucose toad in vivo, with lower serum insulin levels. The glucose-stimulated insulin secretion was reduced also in vitro in isolated Mmp9(-/-) islets. The vascular density of Mmp9(-/-) islets was lower, and the capillaries had fewer fenestrations, whereas the islet blood flow was threefold higher. These alterations could partly be explained by compensatory changes in the expression of matrix-related proteins. This in-depth investigation of the effects of the loss of MMP9(-/-) function on pancreatic islets uncovers a deteriorated beta cell function that is primarily due to a shift in the beta cell phenotype, but also due to islet vascular aberrations. This likely reflects the importance of a normal islet matrix turnover exerted by MMP-9, and concomitant release of paracrine factors sequestered on the matrix.

  • 327.
    Christoffersson, Gustav
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Zang, Guangxiang
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Zhuang, Zhen W.
    Vågesjö, Evelina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Simons, Michael
    Phillipson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi, Integrativ Fysiologi.
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Vascular adaptation to a dysfunctional endothelium as a consequence of Shb deficiency2012Inngår i: Angiogenesis, ISSN 0969-6970, E-ISSN 1573-7209, Vol. 15, nr 3, s. 469-480Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Vascular endothelial growth factor (VEGF)-A regulates angiogenesis, vascular morphology and permeability by signaling through its receptor VEGFR-2. The Shb adapter protein has previously been found to relay certain VEGFR-2 dependent signals and consequently vascular physiology and structure was assessed in Shb knockout mice. X-ray computed tomography of vessels larger than 24 mm diameter (micro-CT) after contrast injection revealed an increased frequency of 48-96 µm arterioles in the hindlimb calf muscle in Shb knockout mice. Intravital microscopy of the cremaster muscle demonstrated a less regular vasculature with fewer branch points and increased vessel tortuosity, changes that led to an increased blood flow velocity. Reduced in vivo angiogenesis was observed in Shb knockout MatrigelTM plugs. Unlike the wild-type situation, VEGF-A did not provoke a dissociation of VE-cadherin from adherens junctions in Shb knockout venules. The reduced angiogenesis and altered properties of junctions had consequences for two patho-physiological responses to arterial occlusion: vascular permeability was reduced in the Shb knockout cremaster muscle after ligation of one supplying artery and heat-induced blood flow determined by Laser-Doppler measurements was decreased in the hindlimb after ligation of the femoral artery. Consequently, the Shb knockout mouse exhibited structural and functional (angiogenesis and vascular permeability) vascular abnormalities that have implications for understanding the function of VEGF-A under physiological conditions.

  • 328. Chu, Kwan Yi
    et al.
    Lau, Tung
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin diabetes och metabolism.
    Leung, Po Sing
    Angiotensin II type 1 receptor blockade improves beta-cell function and glucose tolerance in a mouse model of type 2 diabetes2006Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 55, nr 2, s. 367-374Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We identified an angiotensin-generating system in pancreatic islets and found that exogenously administered angiotensin II, after binding to its receptors (angiotensin II type 1 receptor [AT1R]), inhibits insulin release in a manner associated with decreased islet blood flow and (pro)insulin biosynthesis. The present study tested the hypothesis that there is a change in AT1R expression in the pancreatic islets of the obesity-induced type 2 diabetes model, the db/db mouse, which enables endogenous levels of angiotensin II to impair islet function. Islets from 10-week-old db/db and control mice were isolated and investigated. In addition, the AT1R antagonist losartan was administered orally to 4-week-old db/db mice for an 8-week period. We found that AT1R mRNA was upregulated markedly in db/db islets and double immunolabeling confirmed that the AT1R was localized to beta-cells. Losartan selectively improved glucose-induced insulin release and (pro)insulin biosynthesis in db/db islets. Oral losartan treatment delayed the onset of diabetes, and reduced hyperglycemia and glucose intolerance in db/db mice, but did not affect the insulin sensitivity of peripheral tissues. The present findings indicate that AT1R antagonism improves beta-cell function and glucose tolerance in young type 2 diabetic mice. Whether islet AT1R activation plays a role in the pathogenesis of human type 2 diabetes remains to be determined.

  • 329.
    Chu, Xia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Gao, Xiang
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jansson, Leif
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Quach, My
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Skogseid, Britt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Barbu, Andreea
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Endokrin tumörbiologi.
    Multiple Microvascular Alterations in Pancreatic Islets and Neuroendocrine Tumors of a Men1 Mouse Model2013Inngår i: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 182, nr 6, s. 2355-2367Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Vascular therapeutic targeting requires thorough evaluation of the mechanisms activated in the specific context of each particular tumor type. We highlight structural, molecular, and functional microvascular aberrations contributing to development and maintenance of pancreatic neuroendocrine tumors (NETs), with special reference to multiple endocrine neoplasia 1 (MEN1) syndrome, using a Men1 mouse model. Tissue samples were analyzed by immunofluorescence to detect vessel density and pericyte distribution within the endocrine pancreas; expression of angiogenic factors was assessed by immunohistochemistry and quantitative real-time PCR in isolated islets and adenomas cultured under normoxic or hypoxic conditions. The increased vascular density of pancreatic NETs developed in Men1 mice was paralleled by an early and extensive redistribution of pericytes within endocrine tissue. These morphological alterations are supported by, and in some cases preceded by, fine-tuned variations in expression of several angiogenic regulators and are further potentiated by hypoxia. By combining two novel ex vivo and in vivo single-islet and tumor perfusion techniques, we demonstrated that both vascular reactivity and blood perfusion of tumor arterioles are significantly altered in response to glucose and L-nitro-arginine methyl ester. Our findings unravel multiple potential molecular and physiological targets differentially activated in the endocrine pancreas of Men1 mice and highlight the need for in-depth functional studies to fully understand the contribution of each component to development of pancreatic NETs in MEN1 syndrome.

  • 330.
    Ciba, Iris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Eriksson, J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Ardelt-Gattinger, E.
    Obes Acad Austria, Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.;Salzburg Univ, Dept Psychol, A-5020 Salzburg, Austria..
    Hofmann, J.
    Obes Acad Austria, Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.;Salzburg Univ, Dept Psychol, A-5020 Salzburg, Austria.;Paracelsus Med Univ, Dept Paediat, Salzburg, Austria..
    Weghuber, D.
    Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria.;Paracelsus Med Univ, Dept Paediat, Salzburg, Austria..
    Dahlbom, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Forslund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Eating Behavior In Swedish And Austrian Children And Adolescents With Obesity2016Inngår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 106, s. 30-31Artikkel i tidsskrift (Fagfellevurdert)
  • 331.
    Ciba, Iris
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Weghuber, D.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria..
    Manell, Hannes
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Staaf, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Dahlbom, Marie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Paulmichl, K.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria..
    Zsoldos, F.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria.;Paracelsus Med Univ, Obes Res Unit, Salzburg, Austria..
    Widhalm, K.
    Paracelsus Med Univ, Dept Paediat, Salzburg, Austria.;Acad Inst Clin Nutr, Vienna, Austria..
    Bergsten, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Forslund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa, Pediatrik.
    Development of Glucose Intolerance in Obese Children Studied in the Beta-Judo Cohort2015Inngår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 104, nr S466, s. 12-12Artikkel i tidsskrift (Annet vitenskapelig)
  • 332.
    Ciray, N H
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Backstrom, T
    Ulmsten, U
    Institutionen för kvinnors och barns hälsa.
    Roomans, G M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Steroid hormone effects on intracellular communication between term pregnant human myome cells before labor1.1996Inngår i: Biol of Reprod, Vol. 55, s. 379-Artikkel i tidsskrift (Fagfellevurdert)
  • 333.
    Ciray, NH
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Backstrom, T
    Ulmsten, U
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Roomans, GM
    Institutionen för medicinsk cellbiologi.
    Steroid hormone effects on intercellular communication between term pregnant human myometrial cells before labor11996Inngår i: Biology of Reproduction, Vol. 55, s. 379-Artikkel i tidsskrift (Fagfellevurdert)
  • 334. Ciray, NH
    et al.
    Guner, H
    Hakansson, H
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tekilioglu, M
    Roomans, G M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ulmsten, U
    Institutionen för kvinnors och barns hälsa.
    Morphometric analysis of gap junctions in nonpregnant and term pregnant human myometrium.1995Inngår i: Acta Obstet. Gynecol. Scand., Vol. 74, s. 497-Artikkel i tidsskrift (Fagfellevurdert)
  • 335.
    Ciray, NH
    et al.
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Persson, B E
    Institutionen för kirurgiska vetenskaper.
    Backstrom, T
    Institutionen för kvinnors och barns hälsa.
    Roomans, G M
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ulmsten, U
    Institutionen för kvinnors och barns hälsa.
    Dye-coupling between term pregnant human myometrial cells before labour: carboxfluorescein versus lucifer yellow.1995Inngår i: Cell Biol Int, Vol. 19, s. 609-Artikkel i tidsskrift (Fagfellevurdert)
  • 336.
    Claesson-Welsh, Lena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Cancer och vaskulärbiologi.
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    VEGFA and tumour angiogenesis2013Inngår i: Journal of Internal Medicine, ISSN 0954-6820, E-ISSN 1365-2796, Vol. 273, nr 2, s. 114-127Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    In this review we summarize the current understanding of signal transduction downstream of vascular endothelial growth factor A (VEGFA) and its receptor VEGFR2, and the relationship between these signal transduction pathways and the hallmark responses of VEGFA, angiogenesis and vascular permeability. These physiological responses involve a number of effectors, including extracellular signal-regulated kinases (ERKs), Src, phosphoinositide 3 kinase (PI3K)/Akt, focal adhesion kinase (FAK), Rho family GTPases, endothelial NO and p38 mitogen-activated protein kinase (MAPK). Several of these factors are involved in the regulation of both angiogenesis and vascular permeability. Tumour angiogenesis primarily relies on VEGFA-driven responses, which to a large extent result in a dysfunctional vasculature. The reason for this remains unclear, although it appears that certain aspects of the VEGFA-stimulated angiogenic milieu (high level of microvascular density and permeability) promote tumour expansion. The high degree of redundancy and complexity of VEGFA-driven tumour angiogenesis may explain why tumours commonly develop resistance to anti-angiogenic therapy targeting VEGFA signal transduction.

  • 337.
    Claesson-Welsh, Lena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Ito, Nobuyuki
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Anand-Apte, Bela
    Soker, Shay
    Setter, Bruce
    O´Reilly, Michael
    Folkman, Judah
    Angiostatin induces endothelial cell apoptosis and activation of focal adhesion kinase independently of the integrin-binding motif RGD1998Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 95, nr 10, s. 5579-5583Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Angiostatin, a fragment of plasminogen, has been identified and characterized as an endogenous inhibitor of neovascularization. We show that angiostatin treatment of endothelial cells in the absence of growth factors results in an increased apoptotic index whereas the proliferation index is unchanged. Angiostatin also inhibits migration and tube formation of endothelial cells. Angiostatin treatment has no effect on growth factor-induced signal transduction but leads to an RGD-independent induction of the kinase activity of focal adhesion kinase, suggesting that the biological effects of angiostatin relate to subversion of adhesion plaque formation in endothelial cells.

  • 338. Cnop, Miriam
    et al.
    Welsh, Nils
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Jonas, Jean-Christophe
    Jörns, Anne
    Lenzen, Sigurd
    Eizirik, Decio L
    Mechanisms of Pancreatic {beta}-Cell Death in Type 1 and Type 2 Diabetes: Many Differences, Few Similarities.2005Inngår i: Diabetes, ISSN 0012-1797, Vol. 54 Suppl 2, s. S97-S107Artikkel i tidsskrift (Fagfellevurdert)
  • 339.
    Comasco, Erika
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Rangmar, J
    Univ Gothenburg, Dept Psychol, Gothenburg, Sweden.
    Eriksson, Ulf J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Oreland, Lars
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Neurological and neuropsychological effects of low and moderate prenatal alcohol exposure2018Inngår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 222, nr 1, artikkel-id e12892Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Several explanations for the diverse results in research on foetal alcohol spectrum disorders or alcohol-related neurodevelopmental disorder might be at hand: timing, amount and patterns of alcohol exposure, as well as complex epigenetic responses. The genetic background of the offspring and its interaction with other prenatal and post-natal environmental cues are likely also of importance. In the present report, key findings about the possible effects of low and moderate doses of maternal alcohol intake on the neuropsychological development of the offspring are reviewed and plausible mechanisms discussed. Special focus is put on the serotonergic system within developmental and gene-environment frameworks. The review also suggests guidelines for future studies and also summarizes some of to-be-answered questions of relevance to clinical practice. Contradictory findings and paucity of studies on the effects of exposure to low alcohol levels during foetal life for the offspring's neuropsychological development call for large prospective studies, as well as for studies including neuroimaging and multi-omics analyses to dissect the neurobiological underpinnings of alcohol exposure-related phenotypes and to identify biomarkers. Finally, it remains to be investigated whether any safe threshold of alcohol drinking during pregnancy can be identified.

  • 340. Conget, I
    et al.
    Zhang, T-M
    Eizirik, D L
    Uppsala universitet, Medicinska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Malaisse, W J
    SAM prevents impairment of glucose-stimulated insulin secretion caused by hexose deprivation or starvation.1995Inngår i: Am J Physiol, Vol. 268, s. 580-Artikkel i tidsskrift (Fagfellevurdert)
  • 341.
    Cortese, Giuliana
    et al.
    Univ Padua, Dept Stat Sci, Padua, Italy.
    Gandasi, Nikhil R.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Barg, Sebastian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Pedersen, Morten Gram
    Univ Padua, Dept Informat Engn, Padua, Italy.
    Statistical Frailty Modeling for Quantitative Analysis of Exocytotic Events Recorded by Live Cell Imaging: Rapid Release of Insulin-Containing Granules Is Impaired in Human Diabetic beta-cells2016Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 11, nr 12, artikkel-id e0167282Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Hormones and neurotransmitters are released when secretory granules or synaptic vesicles fuse with the cell membrane, a process denoted exocytosis. Modern imaging techniques, in particular total internal reflection fluorescence (TIRF) microscopy, allow the investigator to monitor secretory granules at the plasma membrane before and when they undergo exocytosis. However, rigorous statistical approaches for temporal analysis of such exocytosis data are still lacking. We propose here that statistical methods from time-to-event (also known as survival) analysis are well suited for the problem. These methods are typically used in clinical settings when individuals are followed over time to the occurrence of an event such as death, remission or conception. We model the rate of exocytosis in response to pulses of stimuli in insulin-secreting pancreatic beta-cell from healthy and diabetic human donors using piecewise-constant hazard modeling. To study heterogeneity in the granule population we exploit frailty modeling, which describe unobserved differences in the propensity to exocytosis. In particular, we insert a discrete frailty in our statistical model to account for the higher rate of exocytosis in an immediately releasable pool (IRP) of insulin-containing granules. Estimates of parameters are obtained from maximum-likelihood methods. Since granules within the same cell are correlated, i.e., the data are clustered, a modified likelihood function is used for log-likelihood ratio tests in order to perform valid inference. Our approach allows us for example to estimate the size of the IRP in the cells, and we find that the IRP is deficient in diabetic cells. This novel application of time-to-event analysis and frailty modeling should be useful also for the study of other well-defined temporal events at the cellular level.

  • 342.
    Cross, Michael J
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Lu, Lingge
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Magnusson, Peetra
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Nyqvist, Daniel
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    Holmqvist, Kristina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Welsh, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Claesson-Welsh, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för genetik och patologi.
    The Shb Adaptor Protein Binds to Tyrosine 766 in the FGFR-1 and Regulatesthe Ras/MEK/MAPK Pathway via FRS2 Phosphorylation in Endothelial Cells2002Inngår i: Molecular Biology of the Cell, ISSN 1059-1524, E-ISSN 1939-4586, Vol. 13, nr 8, s. 2881-2893Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Stimulation of fibroblast growth factor receptor-1 (FGFR-1) is known to result in phosphorylation of tyrosine 766 and the recruitment and subsequent activation of phospholipase C-γ (PLC-γ). To assess the role of tyrosine 766 in endothelial cell function, we generated endothelial cells expressing a chimeric receptor, composed of the extracellular domain of the PDGF receptor-α and the intracellular domain of FGFR-1. Mutation of tyrosine 766 to phenylalanine prevented PLC-γ activation and resulted in a reduced phosphorylation of FRS2 and reduced activation of the Ras/MEK/MAPK pathway relative to the wild-type chimeric receptor. However, FGFR-1–mediated MAPK activation was not dependent on PKC activation or intracellular calcium, both downstream mediators of PLC-γ activation. We report that the adaptor protein Shb is also able to bind tyrosine 766 in the FGFR-1, via its SH2 domain, resulting in its subsequent phosphorylation. Overexpression of an SH2 domain mutant Shb caused a dramatic reduction in FGFR-1–mediated FRS2 phosphorylation with concomitant perturbment of the Ras/MEK/MAPK pathway. Expression of the chimeric receptor mutant and the Shb SH2 domain mutant resulted in a similar reduction in FGFR-1–mediated mitogenicity. We conclude, that Shb binds to tyrosine 766 in the FGFR-1 and regulates FGF-mediated mitogenicity via FRS2 phosphorylation and the subsequent activation of the Ras/MEK/MAPK pathway.

  • 343.
    Cunha, D. A.
    et al.
    Univ Libre Bruxelles, ULB Ctr Diabet Res, Brussels, Belgium..
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Molkentin, J. D.
    Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA..
    Bugliani, M.
    Univ Pisa, Dept Endocrinol & Metab, I-56100 Pisa, Italy..
    Marchetti, P.
    Univ Pisa, Dept Endocrinol & Metab, I-56100 Pisa, Italy..
    Eizirik, D. L.
    Univ Libre Bruxelles, ULB Ctr Diabet Res, Brussels, Belgium..
    Cnop, M.
    Univ Libre Bruxelles, ULB Ctr Diabet Res, Brussels, Belgium..
    Thrombospondin 1: a master regulator of the anti-oxidant defence in pancreatic beta cells2015Inngår i: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 58, nr Suppl. 1, s. S46-S46Artikkel i tidsskrift (Annet vitenskapelig)
  • 344.
    Cunha, Daniel A.
    et al.
    Univ Libre Bruxelles, ULB Ctr Diabet Res, CP-618,Route Lennik 808, B-1070 Brussels, Belgium..
    Cito, Monia
    Univ Libre Bruxelles, ULB Ctr Diabet Res, CP-618,Route Lennik 808, B-1070 Brussels, Belgium..
    Carlsson, Per-Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Vanderwinden, Jean-Marie
    Univ Libre Bruxelles, Light Microscopy Facil, B-1070 Brussels, Belgium..
    Molkentin, Jeffery D.
    Cincinnati Childrens Hosp Med Ctr, Dept Pediat, Cincinnati, OH 45229 USA..
    Bugliani, Marco
    Univ Pisa, Dept Endocrinol & Metab, Pisa, Italy..
    Marchetti, Piero
    Univ Pisa, Dept Endocrinol & Metab, Pisa, Italy..
    Eizirik, Decio L.
    Univ Libre Bruxelles, ULB Ctr Diabet Res, CP-618,Route Lennik 808, B-1070 Brussels, Belgium..
    Cnop, Miriam
    Univ Libre Bruxelles, ULB Ctr Diabet Res, CP-618,Route Lennik 808, B-1070 Brussels, Belgium.;Univ Libre Bruxelles, Erasmus Hosp, Div Endocrinol, B-1070 Brussels, Belgium..
    Thrombospondin 1 protects pancreatic beta-cells from lipotoxicity via the PERK-NRF2 pathway2016Inngår i: Cell Death and Differentiation, ISSN 1350-9047, E-ISSN 1476-5403, Vol. 23, nr 12, s. 1995-2006Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The failure of beta-cells has a central role in the pathogenesis of type 2 diabetes, and the identification of novel approaches to improve functional beta-cell mass is essential to prevent/revert the disease. Here we show a critical novel role for thrombospondin 1 (THBS1) in beta-cell survival during lipotoxic stress in rat, mouse and human models. THBS1 acts from within the endoplasmic reticulum to activate PERK and NRF2 and induce a protective antioxidant defense response against palmitate. Prolonged palmitate exposure causes THBS1 degradation, oxidative stress, activation of JNK and upregulation of PUMA, culminating in beta-cell death. These findings shed light on the mechanisms leading to beta-cell failure during metabolic stress and point to THBS1 as an interesting therapeutic target to prevent oxidative stress in type 2 diabetes.

  • 345. da Silva Xavier, Gabriela
    et al.
    Loder, Merewyn K
    McDonald, Angela
    Tarasov, Andrei I
    Carzaniga, Raffaella
    Kronenberger, Katrin
    Barg, Sebastian
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Rutter, Guy A
    TCF7L2 regulates late events in insulin secretion from pancreatic islet beta-cells2009Inngår i: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 58, nr 4, s. 894-905Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    OBJECTIVE:

    Polymorphisms in the human TCF7L2 gene are associated with reduced insulin secretion and an increased risk of type 2 diabetes. However, the mechanisms by which TCF7L2 affect insulin secretion are still unclear. We define the effects of TCF7L2 expression level on mature beta-cell function and suggest a potential mechanism for its actions.

    RESEARCH DESIGN AND METHODS:

    TCF7L2 expression in rodent islets and beta-cell lines was altered using RNAi or adenoviral transduction. Beta-cell gene profiles were measured by quantitative real-time PCR and the effects on intracellular signaling and exocytosis by live cell imaging, electron microscopy, and patch clamp electrophysiology.

    RESULTS:

    Reducing TCF7L2 expression levels by RNAi decreased glucose- but not KCl-induced insulin secretion. The glucose-induced increments in both ATP/ADP ratio and cytosolic free Ca2+ concentration ([Ca2+]i) were increased compared with controls. Overexpression of TCF7L2 exerted minor inhibitory effects on glucose-regulated changes in [Ca2+]i and insulin release. Gene expression profiling in TCF7L2-silenced cells revealed increased levels of mRNA encoding syntaxin 1A but decreased Munc18–1 and ZnT8 mRNA. Whereas the number of morphologically docked vesicles was unchanged by TCF7L2 suppression, secretory granule movement increased and capacitance changes decreased, indicative of defective vesicle fusion.

    CONCLUSION:

    TCF7L2 is involved in maintaining expression of beta-cell genes regulating secretory granule fusion. Defective insulin exocytosis may thus underlie increased diabetes incidence in carriers of the at-risk TCF7L2 alleles.

  • 346. Dahl, Tone Dolva
    et al.
    Skogstrand, Trude
    Helle, Frank
    Hultström, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Tenstad, Olav
    Iversen, Bjarne Magnus
    Attenuated contractility in afferent arterioles during development of proteinuria in two-kidney, one-clip hypertensive rats2013Inngår i: The FASEB Journal, ISSN 0892-6638, E-ISSN 1530-6860, Vol. 27, nr S1, s. 1110.15-Artikkel i tidsskrift (Annet vitenskapelig)
  • 347.
    Dahlbom, Ingrid
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa. Uppsala Univ, Childrens Hosp, Uppsala, Sweden.
    Lidström, M.
    Uppsala Univ, Childrens Hosp, Uppsala, Sweden.
    Vilen, H.
    Uppsala Univ, Childrens Hosp, Uppsala, Sweden.
    Andersson, K.
    Uppsala Univ, Childrens Hosp, Uppsala, Sweden.
    Ciba, Iris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa. Uppsala Univ, Childrens Hosp, Uppsala, Sweden.
    Kritikos, D.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa. Uppsala Univ, Childrens Hosp, Uppsala, Sweden.
    Forslund, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper. Uppsala Univ, Childrens Hosp, Uppsala, Sweden.
    Daily Assessments of Perceived Sensations in Obese and Non-Obese Children/Adolescents Using a New Mobile Application2017Inngår i: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 106, s. 14-14Artikkel i tidsskrift (Annet vitenskapelig)
  • 348.
    Dahlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Westermark, Gunilla T.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Vahlquist, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Ichthyin/NIPAL4 localizes to keratins and desmosomes in epidermis and Ichthyin mutations affect epidermal lipid metabolism2012Inngår i: Archives of Dermatological Research, ISSN 0340-3696, E-ISSN 1432-069X, Vol. 304, nr 5, s. 377-386Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Autosomal recessive congenital ichthyosis (ARCI) is a group of disorders characterized by abnormal desquamation of the skin and a disrupted epidermal water barrier. Ichthyin/NIPAL4 gene mutations have been identified in a subgroup of ARCI patients, but the role of ichthyin in epidermis remains elusive. In order to obtain new insights concerning the characteristics of ichthyin and the ARCI pathogenesis, we studied the expression and localization of ichthyin and related epidermal components in cultured keratinocytes and skin sections from patients with Ichthyin mutations and healthy controls. We observed an up-regulation of Ichthyin mRNA levels after in vitro differentiation of keratinocytes from both a patient with Ichthyin mutations and controls. Confocal and electron microscopy analyses of immunolabeled skin sections revealed that ichthyin localizes to desmosomes and keratins in both patients with mutant Ichthyin and controls, with an increased immunolabeling in patients. Nile red lipid analysis of skin sections exposed intra-cellular lipid accumulations in cells of the granular and cornified layers in patients but not in controls, consistent with the pathognomonic lipid membrane structures previously identified in epidermis from patients. Our combined findings indicate that ichthyin is associated with keratins and desmosomes in epidermis and is involved in lipid metabolism, possibly through processing of lamellar bodies. These results provide new clues to the understanding of the epidermal water barrier and the pathogenesis in ARCI.

  • 349.
    Dahlqvist, Johanna
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet.
    Westermark, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    Vahlquist, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Dermatologi och venereologi.
    Dahl, Niklas
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik.
    Ichthyin Localizes to Keratins and Desmosomes in Epidermis and is Involved in Lipid MetabolismManuskript (preprint) (Annet vitenskapelig)
  • 350. Daly, Craig J
    et al.
    Parmryd, Ingela
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk cellbiologi.
    McGrath, John C
    Visualization and analysis of vascular receptors using confocal laser scanning microscopy and fluorescent ligands2012Inngår i: Receptor Binding Techniques / [ed] Anthony P. Davenport, New York: Humana Press, 2012, Vol. 897, s. 95-107Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    The use of fluorescent ligands to analyze receptor distribution is increasing in popularity. This is due to the ever growing number of fluorescent ligands and the increased sensitivity of microscope-based technologies. Image-analysis methods have advanced to a stage where quantification of fluorescent signals is relatively simple (if used appropriately). In this chapter we describe a method of analyzing the 2D and 3D distribution of fluorescent ligands in segments of blood vessels. In addition, we introduce the issues surrounding the accurate analysis of colocalization of two different fluorescent ligands.

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