Pathophysiology of the endothelin system - lessons from genetically manipulated animal models

Shortly after discovery of ET-1 in 1988, the entire endothelin system was characterized. The endothelin system consists of the three peptides ET-1, ET-2 and ET-3, their G-protein-coupled receptors endothelin receptor A and B (ETRA and ETRB) and the two endothelin-converting enzymes (ECE-1 and ECE-2). Genetically modified animal models are an important tool in biomedical research. Here we describe the key findings obtained from genetically modified animal models either over-expressing compounds of the ET system or lacking these compounds (knockout mice). Results from the different transgenic and knockout models disclose that the ET system plays a major role in embryonic development. Two ET system-dependent neural crest-driven developmental pathways become obvious: one of them being an ET-1/ETAR axis, responsible for cardio-renal function and development as well as cranial development; the other seems to be an ET-3/ETBR mediated signalling pathway. Mutations within this axis are associated with disruptions in epidermal melanocytes and enteric neurons. These findings led to the discovery of similar findings in humans with Hirschsprung disease. In adult life the ET system is most important in the cardiovascular system and plays a role in fibrotic remodelling of the heart, lung and kidney as well as in the regulation of water and salt excretion

Evidence for the Appearance of Atmospheric Tau Neutrinos in Super-Kamiokande

Super-Kamiokande atmospheric neutrino data were fit with an unbinned maximum likelihood method to search for the appearance of tau leptons resulting from the interactions of oscillation-generated tau neutrinos in the detector. Relative to the expectation of unity, the tau normalization is found to be 1.42 \pm 0.35 \ (stat) {\}^{+0.14}_{-0.12}\ (syst) excluding the no-tau-appearance hypothesis, for which the normalization would be zero, at the 3.8$\sigma$ level. We estimate that 180.1 \pm 44.3\ (stat) {\}^{+17.8}_{-15.2}\ (syst) tau leptons were produced in the 22.5 kton fiducial volume of the detector by tau neutrinos during the 2806 day running period. In future analyses, this large sample of selected tau events will allow the study of charged current tau neutrino interaction physics with oscillation produced tau neutrinos.Comment: 7 pages, 4 figures. This is the version as published in Physical Review Letters including the supplemental figure. A typographical error in the description of figure 3 is also correcte

Search for dinucleon decay into pions at Super-Kamiokande

A search for dinucleon decay into pions with the Super-Kamiokande detector has been performed with an exposure of 282.1 kiloton-years. Dinucleon decay is a process that violates baryon number by two units. We present the first search for dinucleon decay to pions in a large water Cherenkov detector. The modes $^{16}$O$(pp) \rightarrow$ $^{14}$C$\pi^{+}\pi^{+}$, $^{16}$O$(pn) \rightarrow$ $^{14}$N$\pi^{+}\pi^{0}$, and $^{16}$O$(nn) \rightarrow$ $^{14}$O$\pi^{0}\pi^{0}$ are investigated. No significant excess in the Super-Kamiokande data has been found, so a lower limit on the lifetime of the process per oxygen nucleus is determined. These limits are: $\tau_{pp\rightarrow\pi^{+}\pi^{+}} > 7.22 \times 10^{31}$ years, $\tau_{pn\rightarrow\pi^{+}\pi^{0}} > 1.70 \times 10^{32}$ years, and $\tau_{nn\rightarrow\pi^{0}\pi^{0}} > 4.04 \times 10^{32}$ years. The lower limits on each mode are about two orders of magnitude better than previous limits from searches for dinucleon decay in iron.Comment: 20 pages, 17 figures. Accepted for publication in Physical Review D on March 30, 201