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    Going Beyond Counting First Authors in Author Co-citation Analysis

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    The present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed

    Der Verlust von Junctional Adhesion Molecule A im Darmepithel ist mit einer moderaten Progression der NASH assoziiert

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    Excessive consumption of carbohydrates and fatty acids leads to hepatocellular steatosis, fibrosis and a chronic inflammation of the liver. All these histological abnormalities result in an advanced damage of hepatic structure and function, so called steatohepatitis. In the following doctoral thesis, the relation between the steatohepatitis as a chronic disease and the impact of a dysfunctional intestinal barrier due to the loss of JAM-A (junctional adhesion molecule A) has been analyzed. The mutual influence between intestine and liver is called gut-liver-axis. JAM-A is part of the endothelial tight junctions and therefore plays a key role concerning the integrity of the intestinal barrier. The uptake of essential, but depending on the amount also harmful nutritional components (e.g. fatty acids) and the defense against bacterial toxins or pathogen-associated molecular patterns (e.g. LPS) are only two of several functions attributed to tight junctions and JAM-A. In order to research the specific function of intestinal JAM-A in the gut-liver-axis, steatohepatitis is induced in genetically modified mice with an intestinal JAM-A knockout (JAM-AΔIE) by feeding them a high-fat and high-carbohydrate diet for thirty weeks. Consequently, the liver tissue is analyzed for the pathological changes, including fibrosis, inflammation and steatosis. It is shown that the high-fat diet lead to a more severe fibrosis and angiogenesis in liver parenchyma of JAM-AΔIE-mice. Especially the expression of αSMA and KDR is up-regulated in comparison to wild type-mice. By counting CD45+ and F4/80+ immune cells in liver sections and analyzing the gene expression of IL-1β an increased inflammatory phenotype in JAM-AΔIE-mice is determined. Certainly, detailed investigations on hepatic fat metabolism do not show any differences in the different genotypes. In conclusion, it is demonstrated that the intestinal knockout of JAM-A provokes a moderately severe steatohepatitis. Both, the theory of the gut-liver-axis and the gut leakage caused by loss of JAM-A are confirmed. The moderately pathological changes could be traced back to the fact of diminished chronic damage in a thirty weeks model and compensatory mechanisms of tight junctions and hepatic cells

    Die Synthese von Resveratrol-Photoprodukten und Modelluntersuchungen zur Komplexchemie und Bioaktivität von Cuprizon

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    The first part of this work deals with the photoinduced cyclization of Trimethoxystilbene to Trimethoxyphenanthrene and the cyclization of resveratrol to Trihydroxyphenanthrene. It has been possible to carry out extensive reaction optimization, which is why it is now possible to produce Trimethoxyphenanthrene almost quantitatively. The production of Trihydroxyphenanthrene was also successful, but purification proved difficult. Performed bioactivity tests of the prepared compounds show that Trimethoxyphenanthrene is not biologically active. In contrast, Trihydroxyphenanthrene shows 90% inhibition. In addition to the photochemical work of resveratrol, a UV/VIS technical investigation of cuprizone and BiMPi in combination with copper salts is also undertaken. In summary, it can be said that the two tested cuprizone-copper complexes, differ significantly in their effect. For example, copper(II)chloride in combination with cuprizone and Oxalyldihydrazide shows a linear increase in absorption with no sign of saturation. For copper(II)acetate, on the other hand, it is observed that the intensity of the absorption with both cuprizone and Oxalyldihydrazide runs into a plateau from the addition of 2 equivalents of copper salt. Furthermore, BiMPi with copper(II)chloride shows the formation of a complex, which, however, decays after a short time. The only exception is the BiMPi:copper(II)chloride ratio of 2:1, and it has been possible to obtain a crystal of this complex. The investigation of an observed Tyndall effect by TEM confirmed the assumption that nanoparticles are present in the solution. However, the images also suggest that damage to the particles occurs due to the drying process. Efforts to find a suitable surfactant that would provide sufficient stabilization of the particles yielded most promising results. With this surfactant PVP 40000 g/mol it is possible to stabilize the particles over a limited period of time at a very good particle size of about 15 nm and a PDI of 0.3. Furthermore, experiments are also being undertaken to make cuprizone analogs accessible for bioactivity testing. A cuprizone derivative, BiMPi, has been successfully synthesized and characterized with excellent water solubility of over 300 mg/mL. The tests performed with it, indicate that it has a congruent response of cells as cuprizone. This makes BiMPi suitable as a potential in vitro replacement for cuprizone. In addition to BiMPi, several other derivatives are being tested for biological activity. A rapid assay reveals that compounds 24b,d, 25b and 27a show inhibition of SOD activity, with no effect on XO, which is also present. These promising compounds should be tested for further biological activity, using the gene expression experiments already performed for BiMPi. In the final part of the work, cyclic cuprizone analogs were successfully prepared. It cannot be excluded that this new structural element is responsible for the biological activity of cuprizone in the numerous medical studies. Which is why the compounds produced are interesting. With a water solubility of 190 mg/mL, the compound 46 prepared has a sufficient water solubility to be used for in-vitro assays. Bioactivity tests such as SOD, LDH, CTB can provide valuable information on whether the cyclic structural element is indeed responsible for the bioactivity of cuprizone

    Molecular and histopathological validation of the combined Cup-EAE (cuprizone/experimental autoimmune encephalomyelitis) mouse model of multiple sclerosis

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    Multiple sclerosis (MS) is the most common chronic inflammatory disease of the central nervous system. However, compared to similarly common diseases, the underlying pathological processes and pathogenesis are poorly understood. While a variety of drugs are already available, they show only a small reduction in the frequency of MS relapses. For a better understanding of the pathology as well as for the development of new therapies, a realistic experimental animal model is essential. However, the models mainly used so far show significant weaknesses. Experimental autoimmune encephalomyelitis (EAE), an immunization approach against myelin components, shows its effects mainly in the spinal cord and hardly in the brain. Cuprizone treatment is based on the direct depletion of oligodendrocytes, but it cannot adequately represent the autoimmune reaction of MS. Recently, a new experimental approach has been introduced that combines the two models to compensate for their weaknesses. In this study, the combined model was compared with the individual models in terms of similarity to human MS. To this end, the extent and nature of the inflammatory response in the cortex, corpus callosum, and spinal cord of mice were studied histologically and on a biochemical basis. Considered aspects were the extent of demyelination, the occurrence of oxidative stress, and the cellular responses to it. This study showed that the combination of cuprizone and EAE reliably leads to recruitment of immune cells to the brain. At the same time, there was a greater induction of pro inflammatory cytokines such as Tnf and Cxcl9. In addition, the combined model evoked clear signs of oxidative stress and, as a cellular response to it, increased expression of the antioxidant enzyme Ho-1. The relevance of antioxidant therapeutic strategies was also evaluated considering current research. The following conclusions are derived from this work: The combined Cup-EAE is an effective evolution of the earlier models, which has clear similarities to multiple sclerosis and thus also better reflects the disease. Oxidative stress is an important part of the pathological basis of multiple sclerosis and offers a target for future therapies
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