Uromodulin (Tamm–Horsfall protein): guardian of urinary and systemic homeostasis

Biology has taught us that a protein as abundantly made and conserved among species as Tamm–Horsfall protein (THP or uromodulin) cannot just be a waste product serving no particular purpose. However, for many researchers, THP is merely a nuisance during urine proteome profiling or exosome purification and for clinicians an enigmatic entity without clear disease implications. Thanks to recent human genetic and correlative studies and animal modeling, we now have a renewed appreciation of this highly prevalent protein in not only guarding urinary homeostasis, but also serving as a critical mediator in systemic inter-organ signaling. Beyond a mere barrier that lines the tubules, or a surrogate for nephron mass, mounting evidence suggests that THP is a multifunctional protein critical for modulating renal ion channel activity, salt/water balance, renal and systemic inflammatory response, intertubular communication, mineral crystallization and bacterial adhesion. Indeed, mutations in THP cause a group of inherited kidney diseases, and altered THP expression is associated with increased risks of urinary tract infection, kidney stone, hypertension, hyperuricemia and acute and chronic kidney diseases. Despite the recent surge of information surrounding THP’s physiological functions and disease involvement, our knowledge remains incomplete regarding how THP is normally regulated by external and intrinsic factors, how precisely THP deficiency leads to urinary and systemic pathophysiology and in what clinical settings THP can be used as a theranostic biomarker and a target for modulation to improve patient outcomes

Photoproduction of π0\pi^0-pairs off protons and off neutrons

Total cross sections, angular distributions, and invariant-mass distributions have been measured for the photoproduction of $\pi^0\pi^0$ pairs off free protons and off nucleons bound in the deuteron. The experiments were performed at the MAMI accelerator facility in Mainz using the Glasgow photon tagging spectrometer and the Crystal Ball/TAPS detector. The accelerator delivered electron beams of 1508 and 1557~MeV, which produced bremsstrahlung in thin radiator foils. The tagged photon beam covered energies up to 1400~MeV. The data from the free proton target are in good agreement with previous measurements and were only used to test the analysis procedures. The results for differential cross sections (angular distributions and invariant-mass distributions) for free and quasi-free protons are almost identical in shape, but differ in absolute magnitude up to 15\%. Thus, moderate final-state interaction effects are present. The data for quasi-free neutrons are similar to the proton data in the second resonance region (final state invariant masses up to $\approx$1550~MeV), where both reactions are dominated by the $N(1520)3/2^-\rightarrow \Delta(1232)3/2^+\pi$ decay. At higher energies, angular and invariant-mass distributions are different. A simple analysis of the shapes of the invariant-mass distributions in the third resonance region is consistent with strong contributions of an $N^{\star}\rightarrow N\sigma$ decay for the proton, while the reaction is dominated by a sequential decay via a $\Delta\pi$ intermediate state for the neutron. The data are compared to predictions from the Two-Pion-MAID model and the Bonn-Gatchina coupled channel analysis.Comment: accepted for publication in Eur. Phys. J.

The isospin structure of photoproduction of pi-eta pairs from the nucleon in the threshold region

Photoproduction of $\pi\eta$-pairs from nucleons has been investigated from threshold up to incident photon energies of $\approx$~1.4~GeV. The quasi-free reactions $\gamma p\rightarrow p\pi^0\eta$, $\gamma n\rightarrow n\pi^0\eta$, $\gamma p\rightarrow n\pi^+\eta$, and $\gamma n\rightarrow p\pi^-\eta$ were for the first time measured from nucleons bound in the deuteron. The corresponding reactions from a free-proton target were also studied to investigate final-state interaction effects (for neutral pions the free-proton results could be compared to previous measurements; the $\gamma p\rightarrow n\pi^+\eta$ reaction was measured for the first time). For the $\pi^0\eta$ final state coherent production via the $\gamma d\rightarrow d\pi^0\eta$ reaction was also investigated. The experiments were performed at the tagged photon beam of the Mainz MAMI accelerator using an almost $4\pi$ coverage electromagnetic calorimeter composed of the Crystal Ball and TAPS detectors. The total cross sections for the four different final states obey the relation $\sigma(p\pi^0\eta)$ $\approx$ $\sigma(n\pi^0\eta)$ $\approx$ $2\sigma(p\pi^-\eta)$ $\approx$ $2\sigma(n\pi^+\eta)$ as expected for a dominant contribution from a $\Delta^{\star}\rightarrow\eta\Delta(1232)\rightarrow\pi\eta N$ reaction chain, which is also supported by the shapes of the invariant-mass distributions of nucleon-meson and $\pi$-$\eta$ pairs. The experimental results are compared to the predictions from an isobar reaction model.Comment: accepted for publication in Phys. Lett.

Photoproduction of π0-pairs off protons and off neutrons

Total cross sections, angular distributions, and invariant-mass distributions have been measured for the photoproduction of π0π0 pairs off free protons and off nucleons bound in the deuteron. The experiments were performed at the MAMI accelerator facility in Mainz using the Glasgow photon tagging spectrometer and the Crystal Ball/TAPS detector. The accelerator delivered electron beams of 1508 and 1557MeV, which produced bremsstrahlung in thin radiator foils. The tagged photon beam covered energies up to 1400MeV. The data from the free proton target are in good agreement with previous measurements and were only used to test the analysis procedures. The results for differential cross sections (angular distributions and invariant-mass distributions) for free and quasi-free protons are almost identical in shape, but differ in absolute magnitude up to 15%. Thus, moderate final-state interaction effects are present. The data for quasi-free neutrons are similar to the proton data in the second resonance region (final-state invariant masses up to ≈1550 MeV), where both reactions are dominated by the N(1520)3/2−→Δ(1232)3/2+π decay. At higher energies, angular and invariant-mass distributions are different. A simple analysis of the shapes of the invariant-mass distributions in the third resonance region is consistent with strong contributions of an N⋆→Nσ decay for the proton, while the reaction is dominated by a sequential decay via a Δπ intermediate state for the neutron. The data are compared to predictions from the Two-Pion-MAID model and the Bonn-Gatchina coupled-channel analysis

Circulating Uromodulin inhibits systemic oxidative stress by inactivating the TRPM2 channel

High serum concentrations of kidney-derived protein uromodulin (Tamm-Horsfall protein or THP) have recently been shown to be independently associated with low mortality in both older adults and cardiac patients, but the underlying mechanism remains unclear. Here, we show that THP inhibits the generation of reactive oxygen species (ROS) both in the kidney and systemically. Consistent with this experimental data, the concentration of circulating THP in patients with surgery-induced acute kidney injury (AKI) correlated with systemic oxidative damage. THP in the serum dropped after AKI, and was associated with an increase in systemic ROS. The increase in oxidant injury correlated with post-surgical mortality and need for dialysis. Mechanistically, THP inhibited the activation of the transient receptor potential cation channel, subfamily M, member 2 (TRPM2) channel. Furthermore, inhibition of TRPM2 in vivo in a mouse model, mitigated the systemic increase in ROS during AKI and THP deficiency. Our results suggest that THP is a key regulator of systemic oxidative stress by suppressing TRPM2 activity and our findings might help to explain how circulating THP deficiency is linked with poor outcomes and increased mortality

Measurement of the beam-helicity asymmetry I⊙I^{\odot} in the photoproduction of π0π±\pi^0\pi^{\pm}-pairs off protons and off neutrons

Beam-helicity asymmetries have been measured at the MAMI accelerator in Mainz for the photoproduction of mixed-charge pion pairs in the reactions $\boldsymbol{\gamma}p\rightarrow n\pi^0\pi^+$ off free protons and $\boldsymbol{\gamma}d\rightarrow (p)p\pi^0\pi^-$ and $\boldsymbol{\gamma}d\rightarrow (n)n\pi^0\pi^+$ off quasi-free nucleons bound in the deuteron for incident photon energies up to 1.4 GeV. Circularly polarized photons were produced from bremsstrahlung of longitudinally polarized electrons and tagged with the Glasgow-Mainz magnetic spectrometer. The charged pions, recoil protons, recoil neutrons, and decay photons from $\pi^0$ mesons were detected in the 4$\pi$ electromagnetic calorimeter composed of the Crystal Ball and TAPS detectors. Using a complete kinematic reconstruction of the final state, excellent agreement was found between the results for free and quasi-free protons, suggesting that the quasi-free neutron results are also a close approximation of the free-neutron asymmetries. A comparison of the results to the predictions of the Two-Pion-MAID reaction model shows that the reaction mechanisms are still not well understood, in particular at low incident photon energies in the second nucleon-resonance region.Comment: accepted for publication in Eur. phys. J.

Photoproduction of pi0-mesons off neutrons in the nucleon resonance region

Precise angular distributions have been measured for the first time for the photoproduction of $\pi^{0}$-mesons off neutrons bound in the deuteron. The effects from nuclear Fermi motion have been eliminated by a complete kinematic reconstruction of the final state. The influence of final-state-interaction effects has been estimated by a comparison of the reaction cross section for quasi-free protons bound in the deuteron to the results for free protons and then applied as a correction to the quasi-free neutron data. The experiment was performed at the tagged photon facility of the Mainz Microtron MAMI with the Crystal Ball and TAPS detector setup for incident photon energies between $0.45$~GeV and $1.4$~GeV. The results are compared to the predictions from reaction models and partial-wave analyses based on data from other isospin channels. The model predictions show large discrepancies among each other and the present data will provide much tighter constraints. This is demonstrated by the results of a new analysis in the framework of the Bonn-Gatchina coupled-channel analysis which included the present data.Comment: accepted for publication in Phys; Rev. Let

First events from the CNGS neutrino beam detected in the OPERA experiment

The OPERA neutrino detector at the underground Gran Sasso Laboratory (LNGS) was designed to perform the first detection of neutrino oscillations in appearance mode, through the study of nu_mu to nu_tau oscillations. The apparatus consists of a lead/emulsion-film target complemented by electronic detectors. It is placed in the high-energy, long-baseline CERN to LNGS beam (CNGS) 730 km away from the neutrino source. In August 2006 a first run with CNGS neutrinos was successfully conducted. A first sample of neutrino events was collected, statistically consistent with the integrated beam intensity. After a brief description of the beam and of the various sub-detectors, we report on the achievement of this milestone, presenting the first data and some analysis results.Comment: Submitted to the New Journal of Physic

Highlights from the Pierre Auger Observatory

The Pierre Auger Observatory is the world's largest cosmic ray observatory. Our current exposure reaches nearly 40,000 km$^2$ str and provides us with an unprecedented quality data set. The performance and stability of the detectors and their enhancements are described. Data analyses have led to a number of major breakthroughs. Among these we discuss the energy spectrum and the searches for large-scale anisotropies. We present analyses of our X$_{max}$ data and show how it can be interpreted in terms of mass composition. We also describe some new analyses that extract mass sensitive parameters from the 100% duty cycle SD data. A coherent interpretation of all these recent results opens new directions. The consequences regarding the cosmic ray composition and the properties of UHECR sources are briefly discussed.Comment: 9 pages, 12 figures, talk given at the 33rd International Cosmic Ray Conference, Rio de Janeiro 201

Determination of the eta-transition form factor in the gamma p -< p eta -< p gamma e(+)e(-) reaction

The Dalitz decay eta -&gt; gamma e(+)e(-) has been measured using the combined Crystal Ball and TAPS photon detector setup at the electron accelerator MAMI-C. Compared to the most recent transition form-factor measurement in the e(+)e(-) channel, statistics have been improved by one order of magnitude. The e(+)e(-)invariant mass distribution shows a deviation from the QED prediction for a point-like particle, which can be described by a form-factor. Using the usual monopole transition form-factor parameterization, F(m(2)) = (1 - m(2)/Lambda(2))(-1), a value of Lambda(-2) = (1.92 +/- 0.35(stat) +/- 0.13(syst)) GeV(-2) has been determined. This value is in good agreement with a recent measurement of the eta Dalitz decay in the mu(+)mu(-) channel and with recent form-factor calculations. An improved value of the branching ratio BR(eta -&gt; gamma e(+)e(-)) = (6.6 +/- 0.4(stat) +/- 0.4(syst)) . 10(-3) has been determined. (C) 2011 Elsevier B.V. All rights reserved