Urinary secretion and extracellular aggregation of mutant uromodulin isoforms

Uromodulin is exclusively expressed in the thick ascending limb and is the most abundant protein secreted in urine where it is found in high-molecular-weight polymers. Its biological functions are still elusive, but it is thought to play a protective role against urinary tract infection, calcium oxalate crystal formation, and regulation of water and salt balance in the thick ascending limb. Mutations in uromodulin are responsible for autosomal-dominant kidney diseases characterized by defective urine concentrating ability, hyperuricemia, gout, tubulointerstitial fibrosis, renal cysts, and chronic kidney disease. Previous in vitro studies found retention in the endoplasmic reticulum as a common feature of all uromodulin mutant isoforms. Both in vitro and in vivo we found that mutant isoforms partially escaped retention in the endoplasmic reticulum and reached the plasma membrane where they formed large extracellular aggregates that have a dominant-negative effect on coexpressed wild-type protein. Notably, mutant uromodulin excretion was detected in patients carrying uromodulin mutations. Thus, our results suggest that mutant uromodulin exerts a gain-of-function effect that can be exerted by both intra- and extracellular forms of the protein

Urinary secretion and extracellular aggregation of mutant uromodulin isoforms.

Uromodulin is exclusively expressed in the thick ascending limb and is the most abundant protein secreted in urine where it is found in high-molecular-weight polymers. Its biological functions are still elusive, but it is thought to play a protective role against urinary tract infection, calcium oxalate crystal formation, and regulation of water and salt balance in the thick ascending limb. Mutations in uromodulin are responsible for autosomal-dominant kidney diseases characterized by defective urine concentrating ability, hyperuricemia, gout, tubulointerstitial fibrosis, renal cysts, and chronic kidney disease. Previous in vitro studies found retention in the endoplasmic reticulum as a common feature of all uromodulin mutant isoforms. Both in vitro and in vivo we found that mutant isoforms partially escaped retention in the endoplasmic reticulum and reached the plasma membrane where they formed large extracellular aggregates that have a dominant-negative effect on coexpressed wild-type protein. Notably, mutant uromodulin excretion was detected in patients carrying uromodulin mutations. Thus, our results suggest that mutant uromodulin exerts a gain-of-function effect that can be exerted by both intra- and extracellular forms of the protein

The UA9 experimental layout

The UA9 experimental equipment was installed in the CERN-SPS in March '09 with the aim of investigating crystal assisted collimation in coasting mode. Its basic layout comprises silicon bent crystals acting as primary collimators mounted inside two vacuum vessels. A movable 60 cm long block of tungsten located downstream at about 90 degrees phase advance intercepts the deflected beam. Scintillators, Gas Electron Multiplier chambers and other beam loss monitors measure nuclear loss rates induced by the interaction of the beam halo in the crystal. Roman pots are installed in the path of the deflected particles and are equipped with a Medipix detector to reconstruct the transverse distribution of the impinging beam. Finally UA9 takes advantage of an LHC-collimator prototype installed close to the Roman pot to help in setting the beam conditions and to analyze the efficiency to deflect the beam. This paper describes in details the hardware installed to study the crystal collimation during 2010.Comment: 15pages, 11 figure, submitted to JINS

Charged kaon lifetime at KLOE

Preliminary result on the charged kaon lifetime, obtained by the KLOE experiment operating at DA$\Phi$NE, the Frascati $\phi$-factory, is presentedComment: 3 pages, 3 figures, to appear in the proceedings of 42nd Rencontres de Moriond on Electroweak Interactions and Unified Theories, La Thuile, Aosta Valley, Italy, 10-17 Mar 200

Measurement of the leptonic decay widths of the phi-meson with the KLOE detector

The phi-meson leptonic widths, Gee and Gmm, are obtained, respectively, from the e+e- forward-backward asymmetry and the muon cross section around the phi-mass energy. We find Gee=1.32⊕0.05⊕0.03 kev and sqrt(GeeGmm)= 1.320⊕0.018⊕0.017 kev. These results, compatible with Gee=Gmm, provide a precise test of lepton universality. Combining the two results gives G_lept=1.320⊕0.023 kev.Comment: 10 pages and 8 figures to be submitted to Phys.Lett.

Upper Limit on the eta to gamma gamma gamma Branching Ratio with the KLOE Detector

We have searched for the C-violating decay eta to gamma gamma gamma in a sample of ~ 18 million eta mesons produced in phi to eta gamma decays, collected with the KLOE detector at the Frascati phi-factory DAFNE. No signal is observed and we obtain the upper limit BR(eta to gamma gamma gamma) less equal than 1.6x10^(-5) at 90 % C.L.Comment: 8 pages, 5 figures Systematic study refined, some figures reordere

A direct search for the CP-violating decay Ks->3p^0 with the KLOE detector at DAFNE

We have searched for the decay Ks->3p^0 with the KLOE experiment at DAFNE using data from e^+ e^- collisions at a center of mass energy W= m(phi) for an integrated luminosity L=450 pb^-1. The search has been performed with a pure Ks beam obtained by tagging with Kl interactions in the calorimeter and detecting six photons. We find an upper limit for the branching ratio of 1.2x10^-7 at 90% C.L.Comment: 15 pages, 6 figures. To be submitted to Physics Letter