Co-regulation of Gremlin and Notch signalling in diabetic nephropathy

Diabetic nephropathy is currently the leading cause of end-stage renal disease worldwide, and occurs in approximately one third of all diabetic patients. The molecular pathogenesis of diabetic nephropathy has not been fully characterized and novel mediators and drivers of the disease are still being described. Previous data from our laboratory has identified the developmentally regulated gene Gremlin as a novel target implicated in diabetic nephropathy in vitro and in vivo. We used bioinformatic analysis to examine whether Gremlin gene sequence and structure could be used to identify other genes implicated in diabetic nephropathy. The Notch ligand Jagged1 and its downstream effector, hairy enhancer of split-1 (Hes1), were identified as genes with significant similarity to Gremlin in terms of promoter structure and predicted microRNA binding elements. This led us to discover that transforming growth factor-beta (TGFß1), a primary driver of cellular changes in the kidney during nephropathy, increased Gremlin, Jagged1 and Hes1 expression in human kidney epithelial cells. Elevated levels of Gremlin, Jagged1 and Hes1 were also detected in extracts from renal biopsies from diabetic nephropathy patients, but not in control living donors. In situ hybridization identified specific upregulation and co-expression of Gremlin, Jagged1 and Hes1 in the same tubuli of kidneys from diabetic nephropathy patients, but not controls. Finally, Notch pathway gene clustering showed that samples from diabetic nephropathy patients grouped together, distinct from both control living donors and patients with minimal change disease. Together, these data suggest that Notch pathway gene expression is elevated in diabetic nephropathy, co-incident with Gremlin, and may contribute to the pathogenesis of this disease.

Bachowskie przebudzenie Mozarta - studium kontekstu.

In Mozart Studies, it is widely acknowledged that Bach's influence is an important factor for Mozart's artistic development. Yet when discussing how Bach's music affected the development of his compositional styles and techniques, one realizes how tenuous it has been to advance one's arguments without actually seeing in detail how Mozart engaged with Bach’s music. This paper examines what Mozart may have thought when he edited Bach’s fugues for string quartet by attempting to clarify not only what he did and did not do, but also why he did or did not do something, so as to gain some fresh insight into his Bach experience in 1782. It then outlines a more general background of Bach’s fugues in Vienna before they reached the hand of Mozart in order to distinguish what he saw and did to Bach’s fugues.

A 'Teague' and a 'True Briton': Charles Johnstone, Ireland, and Empire

Charles Johnstone's literary output - which included Chrysal: or, the Adventures of a Guinea (1760) and a series of novels between 1762 and 1781 prior to his departure for Calcutta in 1782 - features a marked geographical and historical preoccupation with empire. The trajectory of Johnstone's life from Carrigogunnell and Dublin in Ireland, to London, and finally to Calcutta, indicates the remarkable possibilities for self-transformation which empire from Ireland to India offered during the eighteenth century. This paper examines the significance of empire in Johnstone's oeuvre, and identifies for the first time a series of articles written by him in The Calcutta Gazette in 1785.

Microscopy of heat treated titanium alloy BT16

Metallographic characterisation is combined with statistical analysis to study the microstructure of a BT16 titanium alloy after different heat treatment processes. It was found that the length, width and aspect ratio of α plates in this alloy follow the three-parameter Weibull distribution. Increasing annealing temperature or time causes the probability distribution of the length and the width of α plates to tend toward a normal distribution. The phase transformation temperature of the BT16 titanium alloy was found to be 875±5°C.

Hyperoxia Depletes (6R)-5,6,7,8-Tetrahydrobiopterin Levels in the Neonatal Retina: Implications for Nitric Oxide Synthase Function in Retinopathy

Retinopathy of prematurity is a sight-threatening complication of premature birth caused by nitrooxidativeinsult to the developing retinal vasculature during therapeutic hyperoxia exposure and laterischemia-induced neovascularization on supplemental oxygen withdrawal. In the vasodegenerativephase, during hyperoxia, defective endothelial nitric oxide synthase (NOS) produces reactive oxygenand nitrogen free radicals rather than vasoprotective nitric oxide for unclear reasons. More important,NOS critically depends on the availability of the cofactor (6R)-5,6,7,8-tetrahydrobiopterin (BH4).Because BH4 synthesis is controlled enzymatically by GTP cyclohydrolase (GTPCH), we used GTPCHdepletedmice [hyperphenylalanaemia strain Q4 (hph1)] to investigate the impact of hyperoxia on BH4bioavailability and retinal vascular pathology in the neonate. Hyperoxia decreased BH4 in retinas,lungs, and aortas in all experimental groups, resulting in a dose-dependent decrease in NOS activityand, in the wild-type group, elevated NOS-derived superoxide. Retinal dopamine levels were similarlydiminished, consistent with the dependence of tyrosine hydroxylase on BH4. Despite greater depletionof BH4, the hphþ/ and hph1/ groups did not show exacerbated hyperoxia-induced vessel closure,but exhibited greater vascular protection and reduced progression to neovascular disease. This vasoprotectiveeffect was independent of enhanced circulating vascular endothelial growth factor (VEGF),which was reduced by hyperoxia, but Q5 to local ganglion cell layerederived VEGF. A constitutively higherlevel of VEGF expression associated with retinal development protects GTPCH-deficient neonates fromoxygen-induced vascular damage.

Effect of turbine inlet temperature on blade tip leakage flow and heat transfer

One of the most critical gas turbine engine components, rotor blade tip and casing, are exposed to high thermal load. It becomes a significant design challenge to protect the turbine materials from this severe situation. As a result of geometric complexity and experimental limitations, Computational Fluid Dynamics (CFD) tools have been used to predict blade tip leakage flow aerodynamics and heat transfer at typical engine operating conditions. In this paper, the effect of turbine inlet temperature on the tip leakage flow structure and heat transfer has been studied numerically. Uniform low (LTIT: 444 K) and high (HTIT: 800 K) turbine inlet temperature have been considered. The results showed the higher turbine inlet temperature yields the higher velocity and temperature variations in the leakage flow aerodynamics and heat transfer. For a given turbine geometry and on-design operating conditions, the turbine power output can be increased by 1.48 times, when the turbine inlet temperature increases 1.80 times. Whereas the averaged heat fluxes on the casing and the blade tip become 2.71 and 2.82 times larger, respectively. Therefore, about 2.8 times larger cooling capacity is required to keep the same turbine material temperature. Furthermore, the maximum heat flux on the blade tip of high turbine inlet temperature case reaches up to 3.348 times larger than that of LTIT case. The effect of the interaction of stator and rotor on heat transfer features is also explored using unsteady simulations.