Information-analytical systems as a basis of improving the efficiency of risk management

Building an effective system-risk management in an enterprise on the basis of integrated integration of risk management procedures into virtually all enterprise processes is associated with a wide range of tasks. Such integration processes can be simplified by using modern information technologies

Podocyte injury underlies the progression of focal segmental glomerulosclerosis in the fa/fa Zucker rat

Podocyte injury underlies the progression of focal segmental glomerulosclerosis in the fa/faZucker rat.BackgroundThe progression of diabetic nephropathy to chronic renal failure is based on the progressive loss of viable nephrons. The manner in which nephrons degenerate in diabetic nephropathy and whether the injury could be transferred from nephron to nephron are insufficiently understood. We studied nephron degeneration in the fa/fa Zucker rat, which is considered to be a model for non-insulin-dependent diabetes mellitus.MethodsKidneys of fa/fa rats with an established decline of renal function and of fa/+ controls were structurally analyzed by advanced morphological techniques, including serial sectioning, high-resolution light microscopy, transmission electron microscopy, cytochemistry, and immunohistochemistry. In addition, tracer studies with ferritin were performed.ResultsThe degenerative process started in the glomerulus with damage to podocytes, including foot process effacement, pseudocyst formation, and cytoplasmic accumulation of lysosomal granules and lipid droplets. The degeneration of the nephron followed the tuft adhesion-mediated pathway with misdirected filtration from capillaries included in the adhesion toward the interstitium. This was followed by the formation of paraglomerular spaces that extended around the entire glomerulus, as well as via the glomerulotubular junction, to the corresponding tubulointerstitium. This mechanism appeared to play a major role in the progression of the segmental glomerular injury to global sclerosis as well as to the degeneration of the corresponding tubule.ConclusionsThe way a nephron undergoes degeneration in this process assures that the destructive effects remain confined to the initially affected nephron. No evidence for a transfer of the disease from nephron to nephron at the level of the tubulointerstitium was found. Thus, each nephron entering this pathway to degeneration appears to start separately with the same initial injuries at the glomerulus

The LIM-homeodomain transcription factor Lmx1b plays a crucial role in podocytes

Patients with nail-patella syndrome often suffer from a nephropathy, which ultimately results in chronic renal failure. The finding that this disease is caused by mutations in the transcription factor LMX1B, which in the kidney is expressed exclusively in podocytes, offers the opportunity for a better understanding of the renal pathogenesis. In our analysis of the nephropathy in nail-patella syndrome, we have made use of the Lmx1b knockout mouse. Transmission electron micrographs showed that glomerular development in general and the differentiation of podocytes in particular were severely impaired. The glomerular capillary network was poorly elaborated, fenestrae in the endothelial cells were largely missing, and the glomerular basement membrane was split. In addition podocytes retained a cuboidal shape and did not form foot processes and slit diaphragms. Expression of the α4 chain of collagen IV and of podocin was also severely reduced. Using gel shift assays, we demonstrated that LMX1B bound to two AT-rich sequences in the promoter region of NPHS2, the gene encoding podocin. Our results demonstrate that Lmx1b regulates important steps in glomerular development and establish a link between three hereditary kidney diseases: nail-patella syndrome (Lmx1b), steroid-resistant nephrotic syndrome (podocin), and Alport syndrome (collagen IV α4)

Dose Enhancement Effects of Gold Nanoparticles Specifically Targeting RNA in Breast Cancer Cells [Dataset]

Localization microscopy has shown to be capable of systematic investigations on the arrangement and counting of cellular uptake of gold nanoparticles (GNP) with nanometer resolution. In this article, we show that the application of specially modified RNA targeting gold nanoparticles (“SmartFlares”) can result in ring like shaped GNP arrangements around the cell nucleus. Transmission electron microscopy revealed GNP accumulation in vicinity to the intracellular membrane structures including them of the endoplasmatic reticulum. A quantification of the radio therapeutic dose enhancement as a proof of principle was conducted with γH2AX foci analysis: The application of both – SmartFlares and unmodified GNPs – lead to a significant dose enhancement with a factor of up to 1.2 times the dose deposition compared to non-treated breast cancer cells. This enhancement effect was even more pronounced for SmartFlares. Furthermore, it was shown that a magnetic field of 1 Tesla simultaneously applied during irradiation has no detectable influence on neither the structure nor the dose enhancement dealt by gold nanoparticles

Dose enhancement effects of gold nanoparticles specifically targeting RNA in breast cancer cells.

Localization microscopy has shown to be capable of systematic investigations on the arrangement and counting of cellular uptake of gold nanoparticles (GNP) with nanometer resolution. In this article, we show that the application of specially modified RNA targeting gold nanoparticles ("SmartFlares") can result in ring like shaped GNP arrangements around the cell nucleus. Transmission electron microscopy revealed GNP accumulation in vicinity to the intracellular membrane structures including them of the endoplasmatic reticulum. A quantification of the radio therapeutic dose enhancement as a proof of principle was conducted with γH2AX foci analysis: The application of both-SmartFlares and unmodified GNPs-lead to a significant dose enhancement with a factor of up to 1.2 times the dose deposition compared to non-treated breast cancer cells. This enhancement effect was even more pronounced for SmartFlares. Furthermore, it was shown that a magnetic field of 1 Tesla simultaneously applied during irradiation has no detectable influence on neither the structure nor the dose enhancement dealt by gold nanoparticles

Epifluorescence image of SkBr3 cells transfected with SmartFlares illuminated with a 671 nm laser.

<p>While Cy5 signals can be clearly seen in the cytoplasm of the cells, cells treated with no or unmodified GNP are almost not visible due to the very low auto-fluorescence at 671 nm (not shown). The scale bar equals 20 μm.</p

Comparison of the averaged detected foci count for control (orange), unmodified GNP (green) and SmartFlare probes (brown) at 0 Gy, 2 Gy and 4 Gy.

<p>The standard deviation is highlighted as black arrow line. A significance level of 0.05 was used for all statistical tests. In <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0190183#pone.0190183.t002" target="_blank">Table 2</a> (below) the significance levels are presented which would be required that the significance disappears. These values have to be seen in relation to 0.05 if one compares the histograms in this figure.</p