| 1. |
- Lilja, L, et al.
(författare)
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Cyclin-dependent kinase 5 promotes insulin exocytosis
- 2001
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Ingår i: Journal of Biological Chemistry. - 0021-9258 .- 1083-351X. ; 276:36, s. 34199-34205
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Tidskriftsartikel (refereegranskat)abstract
- Cyclin-dependent kinase 5 (Cdk5) is widely expressed although kinase activity has been described preferentially in neuronal systems. Cdk5 has an impact on actin polymerization during neuronal migration and neurite outgrowth and deregulation of the kinase has been implicated in the promotion of neurodegeneration. Recently it was shown that Cdk5 modulates dopamine signaling in neurons by regulating DARPP-32 function. In addition, Cdk5 phosphorylates munc-18 and synapsin I, two essential components of the exocytotic machinery. We have shown by reverse transcriptase-polymerase chain reaction, immunocytochemistry, and Western blotting that Cdk5 is present in the insulin-secreting pancreatic beta-cell. Subcellular fractionation of isolated beta-cells revealed a glucose-induced translocation of membrane-bound Cdk5 protein to lower density fractions. Inhibition of Cdk5 with roscovitine reduced insulin secretion with approximately 35% compared with control after glucose stimulation and with approximately 65% after depolarization with glucose and KCl. Capacitance measurements performed on single beta-cells that expressed a dominant-negative Cdk5 mutant showed impaired exocytosis. The effect on exocytosis by Cdk5 appeared to be independent of changes in free cytoplasmic Ca(2+) concentration. Taken together these results show that Cdk5 is present in beta-cells and acts as a positive regulator of insulin exocytosis.
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| 8. |
- Arkhammar, P., et al.
(författare)
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Protein kinase C modulates the insulin secretory process by maintaining a proper function of the beta-cell voltage-activated Ca2+ channels
- 1994
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Ingår i: Journal of Biological Chemistry. - : Baishideng Publishers. - 0021-9258 .- 1083-351X. ; 269:4, s. 2743-2749
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Tidskriftsartikel (refereegranskat)abstract
- In the present study an attempt was made to further elucidate the molecular mechanisms whereby protein kinase C (PKC) modulates the beta-cell stimulus-secretion coupling. Regulation of Ca2+ channel activity, [Ca2+]i, and insulin release were investigated in both normal pancreatic mouse beta-cells and in similar beta-cells deprived of PKC activity. [Ca2+]i was measured with the intracellular fluorescent Ca2+ indicator fura-2 and the Ca2+ channel activity was estimated by the whole cell configuration of the patch-clamp technique. To reveal the various isoenzymes of PKC present in the mouse beta-cell, proteins were separated by one-dimensional gel electrophoresis and Western blotting was performed. The production of inositol phosphates was measured by ion-exchange chromatography and insulin release was measured radioimmunologically. Acute stimulation with the phorbol ester 12-O-tetradecanoylphorbol-13-acetate resulted in suppression of both the carbamylcholine-induced increase in [Ca2+]i and production of inositol 1,4,5-trisphosphate. Under these conditions the increase in [Ca2+]i in response to glucose was similar to that found in control cells. When beta-cells were deprived of PKC, by exposure to 200 nM 12-O-tetradecanoylphorbol-13-acetate for 24-48 h, there was an enhanced response to carbamylcholine. This response constituted increases in both the [Ca2+]i signal and production of inositol 1,4,5-trisphosphate. Interestingly, cells with down-regulated PKC activity responded more slowly to glucose stimulation, when comparing the initial increase in [Ca2+]i, than control cells. On the other hand, the maximal increase in [Ca2+]i was similar whether or not PKC was present. Moreover, PKC down-regulated cells exhibited a significant reduction of maximal whole cell Ca2+ currents, a finding that may explain the altered kinetics with regard to the [Ca2+]i increase in response to the sugar. Both the alpha and beta 1 forms of the PKC isoenzymes were present in the mouse beta-cell and were also subjected to PKC down-regulation. Hence, either of these isoenzymes or both may be involved in the modulation of phospholipase C and Ca2+ channel activity. Since insulin release under physiological conditions is critically dependent on Ca(2+)-influx through the voltage-gated L-type Ca2+ channels, the kinetics of hormone release was expected to demonstrate a similar delay as that of the [Ca2+]i increase. Although not as pronounced, such a delay was indeed also observed in the onset of insulin release. There was, however, no effect on the total amounts of hormone released. There was,h owever, no effect on thet otal amounts of hormone released. The present study con- firms that PKC has multiple roles and thereby interacta at different sites in the complex series of events consti- tuting the #?-cell signal-transduction pathway. It is sug- gested that PKC may be tonically active and effective in the maintenance of the phosphorylation state of the voltage-gated L-type Ca2+ channel, enabling an appro- priate function of this channel in the insulin secretory process.
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| 9. |
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| 10. |
- Avall, K, et al.
(författare)
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The yin and yang of apolipoprotein CIII
- 2018
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Ingår i: Diabetes & metabolism. - : Elsevier BV. - 1878-1780 .- 1262-3636. ; 44:3, s. 303-304
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 15. |
- Chandra, J, et al.
(författare)
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Role of apoptosis in pancreatic beta-cell death in diabetes
- 2001
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 5050 Suppl 1, s. S44-S47
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Tidskriftsartikel (refereegranskat)abstract
- Apoptosis is a physiological form of cell death that occurs during normal development, and critical mediators of this process include caspases, reactive oxygen species, and Ca2+. Excessive apoptosis of the pancreatic beta-cell has been associated with diabetes. Consequently, apoptosis research has focused on how infiltrating macrophages or cytotoxic T-cells might kill pancreatic beta-cells using cytokines or death receptor triggering. Meanwhile, the intracellular events in the target beta-cell have been largely ignored. Elucidation of such targets might help develop improved treatment strategies for diabetes. This article will outline recent developments in apoptosis research, with emphasis on mechanisms that may be relevant to beta-cell death in type 1 and type 2 diabetes. Several of the models proposed in beta-cell killing converge on Ca2+ signaling, indicating that the pancreatic beta-cell may be an ideal system in which to carefully dissect the role of Ca2+ during apoptosis.
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| 16. |
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| 17. |
- Dekki, N, et al.
(författare)
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Type 1 diabetic serum interferes with pancreatic beta-cell Ca2+-handling
- 2007
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Ingår i: Bioscience reports. - : Portland Press Ltd.. - 0144-8463 .- 1573-4935. ; 27:6, s. 321-326
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to clarify the frequency of patients with type 1 diabetes that have serum that increases pancreatic β-cell cytoplasmic free Ca2+ concentration, [Ca2+]i, and if such an effect is also present in serum from first-degree relatives. We also studied a possible link between the serum effect and ethnic background as well as presence of autoantibodies. Sera obtained from three different countries were investigated as follows: 82 Swedish Caucasians with newly diagnosed type 1 diabetes, 56 Americans with different duration of type 1 diabetes, 117 American first-degree relatives of type 1 diabetic patients with a mixed ethnic background and 31 Caucasian Finnish children with newly diagnosed type 1 diabetes. Changes in [Ca2+]i, upon depolarization, were measured in β-cells incubated overnight with sera from type 1 diabetic patients, first-degree relatives or healthy controls. Our data show that there is a group constituting approximately 30% of type 1 diabetic patients of different gender, age, ethnic background and duration of the disease, as well as first-degree relatives of type 1 diabetic patients, that have sera that interfere with pancreatic β-cell Ca2+-handling. This effect on β-cell [Ca2+]i could not be correlated to the presence of autoantibodies. In a defined subgroup of patients with type 1 diabetes and first-degree relatives a defect Ca2+-handling may aggravate development of β-cell destruction.
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| 21. |
- Li, LS, et al.
(författare)
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Defects in β-cell Ca2+ dynamics in age-induced diabetes
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 63:12, s. 4100-4114
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Tidskriftsartikel (refereegranskat)abstract
- Little is known about the molecular mechanisms underlying age-dependent deterioration in β-cell function. We now demonstrate that age-dependent impairment in insulin release, and thereby glucose homeostasis, is associated with subtle changes in Ca2+ dynamics in mouse β-cells. We show that these changes are likely to be accounted for by impaired mitochondrial function and to involve phospholipase C/inositol 1,4,5-trisphosphate–mediated Ca2+ mobilization from intracellular stores as well as decreased β-cell Ca2+ influx over the plasma membrane. We use three mouse models, namely, a premature aging phenotype, a mature aging phenotype, and an aging-resistant phenotype. Premature aging is studied in a genetically modified mouse model with an age-dependent accumulation of mitochondrial DNA mutations. Mature aging is studied in the C57BL/6 mouse, whereas the 129 mouse represents a model that is more resistant to age-induced deterioration. Our data suggest that aging is associated with a progressive decline in β-cell mitochondrial function that negatively impacts on the fine tuning of Ca2+ dynamics. This is conceptually important since it emphasizes that even relatively modest changes in β-cell signal transduction over time lead to compromised insulin release and a diabetic phenotype.
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| 24. |
- Miettinen, PJ, et al.
(författare)
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Downregulation of EGF receptor signaling in pancreatic islets causes diabetes due to impaired postnatal beta-cell growth
- 2006
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 55:12, s. 3299-3308
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Tidskriftsartikel (refereegranskat)abstract
- Epidermal growth factor receptor (EGF-R) signaling is essential for proper fetal development and growth of pancreatic islets, and there is also evidence for its involvement in β-cell signal transduction in the adult. To study the functional roles of EGF-R in β-cell physiology in postnatal life, we have generated transgenic mice that carry a mutated EGF-R under the pancreatic duodenal homeobox-1 promoter (E1-DN mice). The transgene was expressed in islet β- and δ-cells but not in α-cells, as expected, and it resulted in an ∼40% reduction in pancreatic EGF-R, extracellular signal–related kinase, and Akt phosphorylation. Homozygous E1-DN mice were overtly diabetic after the age of 2 weeks. The hyperglycemia was more pronounced in male than in female mice. The relative β-cell surface area of E1-DN mice was highly reduced at the age of 2 months, while α-cell surface area was not changed. This defect was essentially postnatal, since the differences in β-cell area of newborn mice were much smaller. An apparent explanation for this is impaired postnatal β-cell proliferation; the normal surge of β-cell proliferation during 2 weeks after birth was totally abolished in the transgenic mice. Heterozygous E1-DN mice were glucose intolerant in intraperitoneal glucose tests. This was associated with a reduced insulin response. However, downregulation of EGF-R signaling had no influence on the insulinotropic effect of glucagon-like peptide-1 analog exendin-4. In summary, our results show that even a modest attenuation of EGF-R signaling leads to a severe defect in postnatal growth of the β-cells, which leads to the development of diabetes.
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| 29. |
- Recio-Lopez, P, et al.
(författare)
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Apolipoprotein CIII Reduction Protects White Adipose Tissues against Obesity-Induced Inflammation and Insulin Resistance in Mice
- 2022
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 23:1
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Tidskriftsartikel (refereegranskat)abstract
- Apolipoprotein CIII (apoCIII) is proinflammatory and increases in high-fat diet (HFD)-induced obesity and insulin resistance. We have previously shown that reducing apoCIII improves insulin sensitivity in vivo by complex mechanisms involving liver and brown adipose tissue. In this study the focus was on subcutaneous (SAT) and visceral (VAT) white adipose tissue (WAT). Mice were either given HFD for 14 weeks and directly from start also treated with antisense oligonucleotide (ASO) against apoCIII or given HFD for 10 weeks and HFD+ASO for an additional 14 weeks. Both groups had animals treated with inactive (Scr) ASO as controls and in parallel chow-fed mice were injected with saline. Preventing an increase or lowering apoCIII in the HFD-fed mice decreased adipocytes’ size, reduced expression of inflammatory cytokines and increased expression of genes related to thermogenesis and beiging. Isolated adipocytes from both VAT and SAT from the ASO-treated mice had normal insulin-induced inhibition of lipolysis compared to cells from Scr-treated mice. In conclusion, the HFD-induced metabolic derangements in WATs can be prevented and reversed by lowering apoCIII.
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| 36. |
- Tun, SBB, et al.
(författare)
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Islet Transplantation to the Anterior Chamber of the Eye-A Future Treatment Option for Insulin-Deficient Type-2 Diabetics? A Case Report from a Nonhuman Type-2 Diabetic Primate
- 2020
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Ingår i: Cell transplantation. - : SAGE Publications. - 1555-3892 .- 0963-6897. ; 29, s. 963689720913256-
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Tidskriftsartikel (refereegranskat)abstract
- Replacement of the insulin-secreting beta cells through transplantation of pancreatic islets to the liver is a promising treatment for type-1 diabetes. However, low oxygen tension, shear stress, and the induction of inflammation lead to significant islet dysfunction and loss. The anterior chamber of the eye (ACE) has gained considerable interest and represents an alternative therapeutic islet transplantation site because of its accessibility, high oxygen tension, and immune-privileged milieu. We have previously demonstrated the feasibility of intraocular islet transplant in mouse and nonhuman primate models of type-1 diabetes and are now assessing its efficacy on glucose homeostasis in a nonhuman primate model of type-2 diabetes. We transplanted allogeneic donor islets (1,500 islet equivalents/kg) into the anterior chamber of one eye in a cynomolgus monkey with high-fat-diet-induced type-2 diabetes. Repeated examinations of the anterior and posterior segments of both eyes were done to monitor the engrafted islets and assess the overall ocular health. Fasting blood glucose level, blood biochemistry, and other metabolic parameters were routinely evaluated to determine the function of the islet graft and diabetes status. The transplanted islets were rapidly engrafted onto the iris and became vascularized 1 month after transplantation. We did not detect changes in intraocular pressure, cataract formation, ophthalmitis, or retinal vessel deformation. A significant lower fasting blood glucose level was observed while the graft was in place, and the transplantation reverts the progression of diabetes. The metabolic markers, hemoglobin A1C and fructosamine, demonstrated improvement following islet transplantation. As a conclusion, intraocular islet transplantation in one eye of a cynomolgus monkey with type-2 diabetes improved its overall plasma glucose homeostasis, as evidenced by short-term measures and long-term metabolic markers. These results further support the future application of the ACE as an alternative site for clinical islet transplants in the context of type-2 diabetes.
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| 37. |
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| 38. |
- Valladolid-Acebes, I, et al.
(författare)
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Apolipoprotein CIII Is an Important Piece in the Type-1 Diabetes Jigsaw Puzzle
- 2021
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Ingår i: International journal of molecular sciences. - : MDPI AG. - 1422-0067. ; 22:2
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Tidskriftsartikel (refereegranskat)abstract
- It is well known that type-2 diabetes mellitus (T2D) is increasing worldwide, but also the autoimmune form, type-1 diabetes (T1D), is affecting more people. The latest estimation from the International Diabetes Federation (IDF) is that 1.1 million children and adolescents below 20 years of age have T1D. At present, we have no primary, secondary or tertiary prevention or treatment available, although many efforts testing different strategies have been made. This review is based on the findings that apolipoprotein CIII (apoCIII) is increased in T1D and that in vitro studies revealed that healthy β-cells exposed to apoCIII became apoptotic, together with the observation that humans with higher levels of the apolipoprotein, due to mutations in the gene, are more susceptible to developing T1D. We have summarized what is known about apoCIII in relation to inflammation and autoimmunity in in vitro and in vivo studies of T1D. The aim is to highlight the need for exploring this field as we still are only seeing the top of the iceberg.
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| 40. |
- Wroblewski, R, et al.
(författare)
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X-ray microanalysis of in situ and isolated pancreatic islets
- 1998
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Ingår i: Pancreas. - 0885-3177 .- 1536-4828. ; 16:2, s. 134-140
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Tidskriftsartikel (refereegranskat)abstract
- The effect of stimulation of insulin secretion in pancreatic beta cells on the elemental composition ofthese cells was investigated by x-ray microanalysis. In vitro experiments on isolated islets ofLangerhans from ob/ob mice were compared to in situ experiments. The only significant difference inthe elemental composition of beta cells from ob/ob mice versus their lean counterparts is a lower Ca concentration in the ob/ob animals. The nucleus of the beta cells has a higher concentration of P, K, and Na than the cytoplasm, which has a higher concentration of S and Cl. No polarized ion distributionin the cytoplasm of the beta cells was observed. Isolated beta cells show a higher concentration of Na and Cl and a lower concentration of K than their in situ counterparts. Stimulation of insulin secretion with glucose both in situ and in vitro showed only very small effects on the elemental composition of the beta cells: a tendency to a decreased P content was noted. In vitro experiments using stimulation with high extracellular K+ showed, in addition, a small increase in the intracellular K concentration. Inconclusion, while the elemental content of beta cells in vitro differs from that in situ, the response to glucose stimulation appears to be similar in both systems.
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| 45. |
- Catrina, SB, et al.
(författare)
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Breathless after separation... from tumour
- 2008
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 32:5, s. 1420-1421
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
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| 50. |
- Nyrén, Rakel, et al.
(författare)
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Localization of lipoprotein lipase and GPIHBP1 in mouse pancreas : effects of diet and leptin deficiency
- 2012
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Ingår i: BMC Physiology. - : BioMed Central (BMC). - 1472-6793. ; 12, s. 14-
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Lipoprotein lipase (LPL) hydrolyzes triglycerides in plasma lipoproteins and enables uptake of lipolysis products for energy production or storage in tissues. Our aim was to study the localization of LPL and its endothelial anchoring protein glycosylphosphatidylinositol-anchored high density lipoprotein-binding protein 1 (GPIHBP1) in mouse pancreas, and effects of diet and leptin deficiency on their expression patterns. For this, immunofluorescence microscopy was used on pancreatic tissue from C57BL/6 mouse embryos (E18), adult mice on normal or high-fat diet, and adult ob/ob-mice treated or not with leptin. The distribution of LPL and GPIHBP1 was compared to insulin, glucagon and CD31. Heparin injections were used to discriminate between intracellular and extracellular LPL.RESULTS: In the exocrine pancreas LPL was found in capillaries, and was mostly co-localized with GPIHBP1. LPL was releasable by heparin, indicating localization on cell surfaces. Within the islets, most of the LPL was associated with beta cells and could not be released by heparin, indicating that the enzyme remained mostly within cells. Staining for LPL was found also in the glucagon-producing alpha cells, both in embryos (E18) and in adult mice. Only small amounts of LPL were found together with GPIHBP1 within the capillaries of islets. Neither a high fat diet nor fasting/re-feeding markedly altered the distribution pattern of LPL or GPIHBP1 in mouse pancreas. Islets from ob/ob mice appeared completely deficient of LPL in the beta cells, while LPL-staining was normal in alpha cells and in the exocrine pancreas. Leptin treatment of ob/ob mice for 12 days reversed this pattern, so that most of the islets expressed LPL in beta cells.CONCLUSIONS: We conclude that both LPL and GPIHBP1 are present in mouse pancreas, and that LPL expression in beta cells is dependent on leptin.
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