Mutations in the
gene, which encodes the A subunit of the cyclic guanosine monophosphate (cGMP)-gated cation channel in cone photoreceptor outer segments, cause total colour blindness, also referred ...to as achromatopsia. Cones lacking this channel protein are non-functional, accumulate high levels of the second messenger cGMP and degenerate over time after induction of ER stress. The cell death mechanisms that lead to loss of affected cones are only partially understood. Here, we explored the disease mechanisms in the
knockout (KO) mouse model of achromatopsia. We found that another important effector of cGMP, the cGMP-dependent protein kinase 2 (Prkg2) is crucially involved in cGMP cytotoxicity of cones in
KO mice. Virus-mediated knockdown or genetic ablation of
in
KO mice counteracted degeneration and preserved the number of cones. Analysis of markers of endoplasmic reticulum stress and unfolded protein response confirmed that induction of these processes in
KO cones also depends on Prkg2. In conclusion, we identified Prkg2 as a novel key mediator of cone photoreceptor degeneration in achromatopsia. Our data suggest that this cGMP mediator could be a novel pharmacological target for future neuroprotective therapies.
The KArlsruhe TRItium Neutrino (KATRIN) experiment will measure the absolute mass scale of neutrinos with a sensitivity of mν = 200 meV c2 by high-precision spectroscopy close to the tritium β-decay ...endpoint at 18.6 keV. Its Windowless Gaseous Tritium Source (WGTS) is a β-decay source of high intensity (1011 s−1) and stability, where high-purity molecular tritium at 30 K is circulated in a closed loop with a yearly throughput of 10 kg. To limit systematic effects the column density of the source has to be stabilized at the 10−3 level. This requires extensive sensor instrumentation and dedicated control and monitoring systems for parameters such as the beam tube temperature, injection pressure, gas composition and so on. In this paper, we give an overview of these systems including a dedicated laser-Raman system as well as several β-decay activity monitors. We also report on the results of the WGTS demonstrator and other large-scale test experiments giving proof-of-principle that all parameters relevant to the systematics can be controlled and monitored on the 10−3 level or better. As a result of these works, the WGTS systematics can be controlled within stringent margins, enabling the KATRIN experiment to explore the neutrino mass scale with the design sensitivity.
Abstract
Tet3 is the main α-ketoglutarate (αKG)-dependent dioxygenase in neurons that converts 5-methyl-dC into 5-hydroxymethyl-dC and further on to 5-formyl- and 5-carboxy-dC. Neurons possess high ...levels of 5-hydroxymethyl-dC that further increase during neural activity to establish transcriptional plasticity required for learning and memory functions. How αKG, which is mainly generated in mitochondria as an intermediate of the tricarboxylic acid cycle, is made available in the nucleus has remained an unresolved question in the connection between metabolism and epigenetics. We show that in neurons the mitochondrial enzyme glutamate dehydrogenase, which converts glutamate into αKG in an NAD
+
-dependent manner, is redirected to the nucleus by the αKG-consumer protein Tet3, suggesting on-site production of αKG. Further, glutamate dehydrogenase has a stimulatory effect on Tet3 demethylation activity in neurons, and neuronal activation increases the levels of αKG. Overall, the glutamate dehydrogenase-Tet3 interaction might have a role in epigenetic changes during neural plasticity.
The aim of the KArlsruhe TRItium Neutrino experiment KATRIN is the determination of the absolute neutrino mass scale down to 0.2 eV, with essentially smaller model dependence than from cosmology and ...neutrinoless double beta decay. For this purpose, the integral electron energy spectrum is measured close to the endpoint of molecular tritium beta decay. The endpoint, together with the neutrino mass, should be fitted from the KATRIN data as a free parameter. The right-handed couplings change the electron energy spectrum close to the endpoint, therefore they have some effect also to the precise neutrino mass determination. The statistical calculations show that, using the endpoint as a free parameter, the unaccounted right-handed couplings constrained by many beta decay experiments can change the fitted neutrino mass value, relative to the true neutrino mass, by not larger than about 5–10%. Using, incorrectly, the endpoint as a fixed input parameter, the above change of the neutrino mass can be much larger, order of 100%, and for some cases it can happen that for large true neutrino mass value the fitted neutrino mass squared is negative. Publications using fixed endpoint and presenting large right-handed coupling effects to the neutrino mass determination are not relevant for the KATRIN experiment.
The Karlsruhe Tritium Neutrino (KATRIN) experiment will determine the mass of the electron neutrino with a sensitivity of 0.2 eV (90% CL) via a measurement of the β-spectrum of gaseous tritium near ...its endpoint of E0 = 18.57 keV. An ultra-low background of about b = 10 mHz is among the requirements on reaching this sensitivity. In the KATRIN main beam line, two spectrometers of MAC-E filter type are used in tandem configuration. This setup, however, produces a Penning trap, which could lead to increased background. We have performed test measurements showing that the filter energy of the pre-spectrometer can be reduced by several keV in order to diminish this trap. These measurements were analyzed with the help of a complex computer simulation, modeling multiple electron reflections from both the detector and the photoelectric electron source used in our test setup.
.
The first high-statistics and high-resolution data set for the integrated recoil-ion energy spectrum following the
decay of
35
Ar has been collected with the WITCH retardation spectrometer located ...at CERN-ISOLDE. Over 25 million recoil-ion events were recorded on a large-area multichannel plate (MCP) detector with a time-stamp precision of 2ns and position resolution of 0.1mm due to the newly upgraded data acquisition based on the LPC Caen FASTER protocol. The number of recoil ions was measured for more than 15 different settings of the retardation potential, complemented by dedicated background and half-life measurements. Previously unidentified systematic effects, including an energy-dependent efficiency of the main MCP and a radiation-induced time-dependent background, have been identified and incorporated into the analysis. However, further understanding and treatment of the radiation-induced background requires additional dedicated measurements and remains the current limiting factor in extracting a beta-neutrino angular correlation coefficient for
35
Ar decay using the WITCH spectrometer.
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