Multimodale MRT-Analysen des cholinergen basalen Vorderhirns über das Alzheimerspektrum

Ziel der Arbeit war es, die Wertigkeit für die Frühdiagnose einer Alzheimer Erkrankung in der präklinischen Phase von drei verschiedenen MRT-Modalitäten zu testen. Analysiert wurden funktionelle Konnektivität (FC), mittlere Diffusivität (MD) und Volumen im cholinergen basalen Vorderhirn, wobei eine Bestimmung der Amyloidveränderungen aus dem Liquor einbezogen wurde. Zur FC-Analyse standen 477, zur DTI-Analyse standen 243 Personendatensätze zur Verfügung. Weder die FC noch die MD zeigte eine relevante Differenzierung der Gruppen im präklinischen Bereich.The aim of this study was to test the value of three different MRI modalities for the early diagnosis of Alzheimer's disease in the preclinical phase. Functional connectivity (FC), mean diffusivity (MD), and volume in the cholinergic basal forebrain were analyzed, including determination of amyloid changes from CSF. 477 data sets were available for FC analysis and 243 for DTI analysis. Neither the FC nor the MD showed a relevant differentiation of groups in the preclinical stage

CD69 is a TGF-β/1α,25-dihydroxyvitamin D3 target gene in monocytes

CD69 is a transmembrane lectin that can be expressed on most hematopoietic cells. In monocytes, it has been functionally linked to the 5-lipoxygenase pathway in which the leukotrienes, a class of highly potent inflammatory mediators, are produced. However, regarding CD69 gene expression and its regulatory mechanisms in monocytes, only scarce data are available. Here, we report that CD69 mRNA expression, analogous to that of 5-lipoxygenase, is induced by the physiologic stimuli transforming growth factor-β (TGF-β) and 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) in monocytic cells. Comparison with T- and B-cell lines showed that the effect was specific for monocytes. CD69 expression levels were increased in a concentration-dependent manner, and kinetic analysis revealed a rapid onset of mRNA expression, indicating that CD69 is a primary TGF-β/1α,25(OH)2D3 target gene. PCR analysis of different regions of the CD69 mRNA revealed that de novo transcription was initiated and proximal and distal parts were induced concomitantly. In common with 5-lipoxygenase, no activation of 0.7 kb or ~2.3 kb promoter fragments by TGF-β and 1α,25(OH)2D3 could be observed in transient reporter assays for CD69. Analysis of mRNA stability using a transcription inhibitor and a 3′UTR reporter construct showed that TGF-β and 1α,25(OH)2D3 do not influence CD69 mRNA stability. Functional knockdown of Smad3 clearly demonstrated that upregulation of CD69 mRNA, in contrast to 5-LO, depends on Smad3. Comparative studies with different inhibitors for mitogen activated protein kinases (MAPKs) revealed that MAPK signalling is involved in CD69 gene regulation, whereas 5-lipoxygenase gene expression was only partly affected. Mechanistically, we found evidence that CD69 gene upregulation depends on TAK1-mediated p38 activation. In summary, our data indicate that CD69 gene expression, conforming with 5-lipoxygenase, is regulated monocyte-specifically by the physiologic stimuli TGF-β and 1α,25(OH)2D3 on mRNA level, although different mechanisms account for the upregulation of each gene

Cyclical regulation of the insulin-like growth factor binding protein 3 gene in response to 1α,25-dihydroxyvitamin D3

The nuclear receptor vitamin D receptor (VDR) is known to associate with two vitamin D response element (VDRE) containing chromatin regions of the insulin-like growth factor binding protein 3 (IGFBP3) gene. In non-malignant MCF-10A human mammary cells, we show that the natural VDR ligand 1α,25-dihydroxyvitamin D3 (1α,25(OH)2D3) causes cyclical IGFBP3 mRNA accumulation with a periodicity of 60 min, while in the presence of the potent VDR agonist Gemini the mRNA is continuously accumulated. Accordingly, VDR also showed cyclical ligand-dependent association with the chromatin regions of both VDREs. Histone deacetylases (HDACs) play an important role both in VDR signalling and in transcriptional cycling. From the 11 HDAC gene family members, only HDAC4 and HDAC6 are up-regulated in a cyclical fashion in response to 1α,25(OH)2D3, while even these two genes do not respond to Gemini. Interestingly, HDAC4 and HDAC6 proteins show cyclical VDR ligand-induced association with both VDRE regions of the IGFBP3 gene, which coincides with histone H4 deacetylation on these regions. Moreover, combined silencing of HDAC4 and HDAC6 abolishes the cycling of the IGFBP3 gene. We assume that due to more efficient VDR interaction, Gemini induces longer lasting chromatin activation and therefore no transcriptional cycling but monotonically increasing IGFBP3 mRNA. In conclusion, 1α,25(OH)2D3 regulates IGFBP3 transcription through short-term cyclical association of VDR, HDAC4 and HDAC6 to both VDRE-containing chromatin regions

Transport de charges lourdes sur les voies navigables internes

International audience; Die Nette verband das römische Steinbruch- und Bergbaurevier um Mayen mit dem Rhein als wichtiger WasserstraÃe. Ausgehend von der Nette werden die Argumente vorgestellt, welche für die Nutzung auch anderer kleiner Wasserläufe für Schwerlasttransporte in der Antike sprechen. In diesem Zusammenhang wird besonders auf die Verteilung von römischen Werkstätten, Lagern und Grabdenkmälern entlang kleiner Flüsse hingewiesen.; The river Nette connected the Roman quarry and mining district around Mayen with the important waterway of the Rhine. Starting from the Nette the arguments are presented which speak for the use also of other small water courses for heavy load transport in Antiquity. In this context special reference is given to the distribution of Roman workshops, storehouses and funerary monuments along small rivers.; La Nette reliait le district des carrières et des mines romaines autour de Mayen à l'importante voie navigable du Rhin. En se basant sur la Nette, des arguments sont présentés qui plaident aussi en faveur de l'utilisation d'autres petits cours d'eau pour le transport de charges lourdes dans l'Antiquité. Dans ce contexte, une référence particulière est faite à la répartition des ateliers, des entrepôts et des monuments funéraires romains le long des petits cours d'eau. Document type: Part of book or chapter of boo