403 research outputs found
Economic modelling using constraint logic programming
No full textThis paper investigates the use of constraint logic programming (CLP) in economic modelling
through the design and implementation of two economic models. The first model, the Desai-
Henry model contains only linear equations while the second model, constructed by the author,
contains non-linear elements. In order to implement the second model, a non-linear constraint
solver was constructed. This was necessary because, although CLP is a very powerful
programming paradigm, currently available implementations lack any on-linear constraint
solving mechanisms
Kinase-mediated quasi-dimers of EGFR
No full textLigand-induced dimerization of the epidermal growth factor receptor (ErbB-1/EGFR) involves conformational changes that expose an extracellular dimerization interface. Subsequent alterations within the cytoplasmic kinase domain, which culminate in tyrosine phosphorylation, are less understood. Our study addressed this question by using two strategies: a chimeric receptor approach employed ErbB-3, whose defective kinase domain was replaced by the respective part of EGFR. The implanted full-length kinase, unlike its subdomains, conferred dimerization and catalysis. The data infer that the kinase function of EGFR is restrained by the carboxyl tail; once grafted distally to the ectopic tail of ErbB-3, the kinase domain acquires quasi-dimerization and activation. In an attempt to alternatively refold the cytoplasmic tail, our other approach employed kinase inhibitors. Biophysical measurements and covalent cross-linking analyses showed that inhibitors targeting the active conformation of EGFR, in contrast to a compound recognizing the inactive conformation, induce quasi-dimers in a manner similar to the chimeric ErbB-3 molecule. Collectively, these observations unveil kinase domain-mediated quasi-dimers, which are regulated by an autoinhibitory carboxyl tail. On the basis of these observations, we propose that quasi-dimers precede formation of ligand-induced, fully active dimers, which are stabilized by both extracellular and intracellular receptor-receptor interactions.-Bublil, E. M., Pines, G., Patel, G., Fruhwirth, G., Ng, T., Yosef Yarden. Kinase-mediated quasi-dimers of EGFR. FASEB J. 24, 4744-4755 (2010). www.fasebj.or
Radiolabelling of Polyclonally Expanded Human Regulatory T Cells (Treg) with 89Zr-oxine for Medium-Term In Vivo Cell Tracking.
No full textRegulatory T cells (Tregs) are a promising candidate cell therapy to treat autoimmune diseases and aid the longevity of transplanted solid organs. Despite increasing numbers of clinical trials using human Treg therapy, important questions pertaining to their in vivo fate, distribution, and function remain unanswered. Treg accumulation in relevant tissues was found to be crucial for Treg therapy efficacy, but existing blood-borne biomarkers are unlikely to accurately reflect the tissue state. Non-invasive Treg tracking by whole-body imaging is a promising alternative and can be achieved by direct radiolabelling of Tregs and following the radiolabelled cells with positron emission tomography (PET). Our goal was to evaluate the radiolabelling of polyclonal Tregs with 89Zr to permit their in vivo tracking by PET/CT for longer than one week with current preclinical PET instrumentation. Weused [89Zr]Zr(oxinate)4 as the cell-labelling agent and achieved successful radiolabelling efficiency of human Tregs spanning 0.1–11.1 Bq 89Zr/Treg cell, which would be compatible with PET tracking beyond one week. We characterized the 89Zr-Tregs, assessing their phenotypes, and found that they were not tolerating these intracellular 89Zr amounts, as they failed to survive or expand in a89Zr-dose-dependent manner. Even at 0.1 Bq 89Zr per Treg cell, while 89Zr-Tregs remained functional as determined by a five-day-long effector T cell suppression assay, they failed to expand beyond day 3 in vitro. Moreover, PET imaging revealed signs of 89Zr-Treg death after adoptive transfer in vivo. In summary, 89Zr labelling of Tregs at intracellular radioisotope amounts compatible with cell trackingover several weeks did not achieve the desired outcomes, as 89Zr-Tregs failed to expand and survive. Consequently, we conclude that indirect Treg labelling is likely to be the most effective alternative method to satisfy the requirements of this cell tracking scenario
Supplementary Figure 1 Gating strategy for Treg phenotype analysis.
No full textSupplementary Figure 1. Gating strategy for Treg phenotype analysis. | Isolated and purified cells (see Methods) were analysed by flow cytometry with (A) gating performed as indicated including the exclusion of dead cells (by Live/Dead staining kit) and analysing only CD4+CD25+ double-positive cells. (B) These cells were then stained with indicated marker antibodies. The histogram quantification areas indicated by the black bars were set against control staining performed with non-specific isotype antibodies corresponding to each marker antibody
Oxidized phospholipids: From molecular properties to disease
No full textAbstractOxidized lipids are generated from (poly)unsaturated diacyl- and alk(en)ylacyl glycerophospholipids under conditions of oxidative stress. The great variety of reaction products is defined by the degree of modification, hydrophobicity, chemical reactivity, physical properties and biological activity. The biological activities of these compounds may depend on both, the recognition of the particular molecular structures by specific receptors and on the unspecific physical and chemical effects on their target systems (membranes, proteins). In this review, we aim at highlighting the molecular features that are essential for the understanding of the biological actions of pure oxidized phospholipids. Firstly, their chemical structures are described as a basis for an understanding of their physical and (bio)chemical properties in membrane- and protein-bound form. Secondly, the biological activities of oxidized phospholipids are discussed in terms of their unspecific effects on the membrane level as well as their potential interactions with specific targets (receptors) affecting a large set of (signaling) molecules. Finally, the role of oxidized phospholipids as important mediators in pathophysiology is discussed with emphasis on atherosclerosis
Production technology and characteristics of Styrian pumpkin seed oil
No full textCucurbita pepo subsp. pepo var. Styriaca, the so-called Styrian oil pumpkin, is a phylogenetically young member of the Cucurbita spp. A single mutation occurred only in the 19(th) century and led to dark green seeds with stunted outer hulls. This mutation facilitated the production of Styrian pumpkin seed oil that became a regional specialty oil in the south-eastern part of Europe during the last few decades. We describe in this article the production and economic value of this edible specialty oil as well as the most important parameters relevant for its quality. Furthermore, we report on its molecular composition including fatty acids, vitamins, phytosterols, minerals, polyphenols, and those compounds that are responsible for its color, taste and flavor. Finally, information is provided on potential contaminants of Styrian pumpkin seed oil as well as its putative beneficial health effects.</p
Fluorescence assays for lipid oxidation and its inhibition by antioxidants
No full textLipid oxidation and its inhibition by antioxidants can be determined accurately and with high sensitivity using the fluorescent marker DPH-PC. We describe its application for the measurement of antioxidant capacities of edible oils, relative efficiencies of different antioxidants, and the influence of antioxidants on the ease of oxidation of human seru
Mediation of apoptosis by oxidized phospholipids
No full textFree radical-mediated oxidation of (poly)unsaturated glycerophospholipids in membranes and lipoproteins leads to the formation of a plethora of products. Some of these oxidized phospholipids, especially the truncated forms, induce apoptosis depending on their chemical structure, concentration and cell type. Depending on the phospholipid and the cell type, two pathways have so far been identified for the intracellular transmission of the apoptotic signals. One pathway involves activation of acid sphingomyelinase, which gives rise to the formation of ceramide and is followed by phosphorylation of pro-apoptotic mitogen-activated protein kinases. Alternatively, oxidized phospholipids act directly on mitochondria leading to efflux of pro-apoptotic effectors in endothelial cells. During the execution of the apoptotic program additional oxidized phospholipids are generated. The apoptotic cascade itself leads to oxidation and exposure of e.g. membrane phosphatidylserine. Oxidized phospholipids on the outer leaflet of the plasma membrane can form surface lipid patterns that specifically bind to phagocytic cells, e.g. macrophages.In this manuscript we review the recent literature reporting on apoptosis-inducing glycerophospholipids. In addition, we describe the cellular processes that lead to phospholipid oxidation as part of the apoptotic mode of cell death and are likely to enhance the recognition of apoptotic cells by phagocytic macrophages
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