Differential Effects of the Mitochondria-Active Tetrapeptide SS-31 (D-Arg-dimethylTyr-Lys-Phe-NH₂) and Its Peptidase-Targeted Prodrugs in Experimental Acute Kidney Injury.

The mitochondria-active tetrapeptide SS-31 can control oxidative tissue damage in kidney diseases. To investigate other potential beneficial nephroprotective effects of SS-31, in vivo murine models of acute tubular injury and glomerular damage were developed. Reduction of acute kidney injury was demonstrated in mice treated with SS-31. The expression of mRNAs involved in acute inflammatory and oxidative stress responses in the diseased kidneys confirmed that SS-31 could regulate these pathways in our in vivo models. Furthermore, ex vivo histoenzymography of mouse kidneys showed that aminopeptidase A (APA), the enzyme involved in the processing of angiotensin (Ang) II to Ang III, was induced in the diseased kidneys, and its activity was inhibited by SS-31. As the renin-angiotensin system (RAS) is a main regulator of kidney functions, the modulation of Ang receptors (ATR) and APA by SS-31 was further investigated using mRNAs extracted from diseased kidneys. Following acute tubular and/or glomerular damage, the expression of the AT <sub>1</sub> R mRNA was upregulated, which could be selectively downregulated upon SS-31 administration to the animals. At the same time, SS-31 was able to increase the expression of the AT <sub>2</sub> R, which may contribute to limit renal damage. Consequently, SS-31-based prodrugs were developed as substrates and/or inhibitors for APA and were screened using cells expressing high levels of APA, showing its selective regulation by α-Glu-SS-31. Thus, a link between SS-31 and the RAS opens new therapeutic implications for SS-31 in kidney diseases

Targeted γ-secretase inhibition of Notch signaling activation in acute renal injury.

The Notch pathway has been reported to control tissue damage in acute kidney diseases. To investigate potential beneficial nephroprotective effects of targeting Notch, we developed chemically functionalized γ-secretase inhibitors (GSIs) targeting γ-glutamyltranspeptidase (γ-GT) and/or γ-glutamylcyclotransferase (γ-GCT), two enzymes overexpressed in the injured kidney, and evaluated them in in vivo murine models of acute tubular and glomerular damage. Exposure of the animals to disease-inducing drugs together with the functionalized GSIs improved proteinuria and, to some extent, kidney dysfunction. The expression of genes involved in the Notch pathway, acute inflammatory stress responses, and the renin-angiotensin system was enhanced in injured kidneys, which could be downregulated upon administration of functionalized GSIs. Immunohistochemistry staining and Western blots demonstrated enhanced activation of Notch1 as detected by its cleaved active intracellular domain during acute kidney injury, and this was downregulated by concomitant treatment with the functionalized GSIs. Thus targeted γ-secretase-based prodrugs developed as substrates for γ-GT/γ-GCT have the potential to selectively control Notch activation in kidney diseases with subsequent regulation of the inflammatory stress response and the renin-angiotensin pathways

CLIC: a Two-Beam Multi-TeV e±e\pm Linear Collider

The CLIC study of a high-energy (0.5 - 5 TeV), high-luminosity (1034 - 1035 cm-2 sec-1) e+e- linear collider is presented. Beam acceleration using high frequency (30 GHz) normal-conducting structures operating at high accelerating fields (150 MV/m) significantly reduces the length and, in consequence, the cost of the linac. Using parameters derived from general scaling laws for linear colliders, the beam stability is shown to be similar to lower frequency designs in spite of the strong wake-field dependency on frequency. A new cost-effective and efficient drive beam generation scheme for RF power production by the so-called "Two-Beam Acceleration" method is described. It uses a thermionic gun and a fully-loaded normal-conducting linac operating at low frequency (937 MHz) to generate and accelerate the drive beam bunches, and RF multiplication by funnelling in compressor rings to produce the desired bunch structure. Recent 30 GHz hardware developments and CLIC Test Facility (CTF) results are described

A new tool for advanced vehicle simulations

7th International Conference on Engines for Automobile ICE 2005, CAPRI, ITALIE, 11-/09/2005 - 16/09/2005To overcome future stringent regulations on pollutant emissions and to decrease CO emissions and fuel consumption, hybrid vehicles seem to be one of the near future most promising technologies. This type of car uses complex energy management and control strategy. Simulation can be very useful for the development of such a control system. This paper highlights a new library developed under the AMESim software that enables the simulation of complex interactive systems in vehicles. In addition, the possibility to combine with other AMESim modules, allows the users to add more complexity to any of the sub-components of the vehicle. As an illustration of this new tool capability, we propose in this paper a simulation example of the Prius, the most known hybrid vehicle which was the first commercial vehicle in 1997 and selected as the 2004 Car of the Year in Europe. Comparisons between measurements and simulations of the response of different components are presented on different driving cycles

Targeted γ-Secretase Inhibition To Control the Notch Pathway in Renal Diseases.

Notch is a membrane inserted protein activated by the membrane-inserted γ-secretase proteolytic complex. The Notch pathway is a potential therapeutic target for the treatment of renal diseases but also controls the function of other cells, requiring cell-targeting of Notch antagonists. Toward selective targeting, we have developed the γ-secretase inhibitor-based prodrugs 13a and 15a as substrates for γ-glutamyltranspeptidase (γ-GT) and/or γ-glutamylcyclotransferase (γ-GCT) as well as aminopeptidase A (APA), which are overexpressed in renal diseases, and have evaluated them in experimental in vitro and in vivo models. In nondiseased mice, the cleavage product from Ac-γ-Glu-γ-secretase inhibitor prodrug 13a (γ-GT-targeting and γ-GCT-targeting) but not from Ac-α-Glu-γ-secretase inhibitor prodrug 15a (APA-targeting) accumulated in kidneys when compared to blood and liver. Potential nephroprotective effects of the γ-secretase inhibitor targeted prodrugs were investigated in vivo in a mouse model of acute kidney injury, demonstrating that the expression of Notch1 and cleaved Notch1 could be selectively down-regulated upon treatment with the Ac-γ-Glu-γ-secretase-inhibitor 13a