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Joan Mir-Coll Tilo Moede Meike Paschen Aparna Neelakandhan Ismael Valladolid-Acebes Barbara Leibiger Adelinn Biernath Carina mml Ingo B. Leibiger Burcak Yesildag Per-Olof Berggren 《International journal of molecular sciences》2021,22(4)
Loss of pancreatic β-cell function is a critical event in the pathophysiology of type 2 diabetes. However, studies of its underlying mechanisms as well as the discovery of novel targets and therapies have been hindered due to limitations in available experimental models. In this study we exploited the stable viability and function of standardized human islet microtissues to develop a disease-relevant, scalable, and reproducible model of β-cell dysfunction by exposing them to long-term glucotoxicity and glucolipotoxicity. Moreover, by establishing a method for highly-efficient and homogeneous viral transduction, we were able to monitor the loss of functional β-cell mass in vivo by transplanting reporter human islet microtissues into the anterior chamber of the eye of immune-deficient mice exposed to a diabetogenic diet for 12 weeks. This newly developed in vitro model as well as the described in vivo methodology represent a new set of tools that will facilitate the study of β-cell failure in type 2 diabetes and would accelerate the discovery of novel therapeutic agents. 相似文献
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Leibiger S. Huber J. Qazi S. Frankwicz P. Goepfert I.D. 《Semiconductor Manufacturing, IEEE Transactions on》2004,17(4):612-618
This paper presents a system of BiCMOS process step simulation, development, and verification using automatically generated physical test structures. During process development, detailed unit process step deliverables are compiled in a document called the process technology table (PTT). These targets are initially set by equipment capabilities, product needs, and process simulations, but every PTT entry must be ultimately verified on silicon. Therefore, the process development engineers require a method of specifying, simulating, and analyzing a large variety of process test structures. A computer-aided design system to do this has been developed. The particulars of its use during the integration of a 0.35-/spl mu/m BiCMOS process flow are presented. Details about a novel cross-sectional structure labeling and identification scheme are also presented. 相似文献
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MS Islam I Leibiger B Leibiger D Rossi V Sorrentino TJ Ekstr?m H Westerblad FH Andrade PO Berggren 《Canadian Metallurgical Quarterly》1998,95(11):6145-6150
Molecular mechanisms that regulate in situ activation of ryanodine receptors (RY) in different cells are poorly understood. Here we demonstrate that caffeine (10 mM) released Ca2+ from the endoplasmic reticulum (ER) in the form of small spikes in only 14% of cultured fura-2 loaded beta cells from ob/ob mice. Surprisingly, when forskolin, an activator of adenylyl cyclase was present, caffeine induced larger Ca2+ spikes in as many as 60% of the cells. Forskolin or the phosphodiesterase-resistant PKA activator Sp-cAMPS alone did not release Ca2+ from ER. 4-Chloro-3-ethylphenol (4-CEP), an agent that activates RYs in other cell systems, released Ca2+ from ER, giving rise to a slow and small increase in [Ca2+]i in beta cells. Prior exposure of cells to forskolin or caffeine (5 mM) qualitatively altered Ca2+ release by 4-CEP, giving rise to Ca2+ spikes. In glucose-stimulated beta cells forskolin induced Ca2+ spikes that were enhanced by 3,9-dimethylxanthine, an activator of RYs. Analysis of RNA from islets and insulin-secreting betaTC-3-cells by RNase protection assay, using type-specific RY probes, revealed low-level expression of mRNA for the type 2 isoform of the receptor (RY2). We conclude that in situ activation of RY2 in beta cells requires cAMP-dependent phosphorylation, a process that recruits the receptor in a functionally operative form. 相似文献
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