Inhibition of PI-3-K and AKT amplifies Kv1.3 Inhibitor-induced death of human T leukemia cells

Background/Aims: We have previously shown that inhibition of the mitochondrial Kv1.3 channel results in an initial mitochondrial hyperpolarization and a release of oxygen radicals that mediate mitochondrial depolarization, cytochrome c release and death. Here, we investigated whether inhibition of Kv1.3 channels can also induce cellular resistance mechanisms that counteract the induction of cell death under certain conditions. Methods: We treated leukemic T cells with the mitochondria-targeted Kv1.3 inhibitor PCARBTP and determined the activity of different kinases associated with cell survival including ZAP70, PI-3-K, AKT, JNK and ERK by measuring the activation-associated phosphorylation of these proteins. Furthermore, we inhibited AKT and JNK and determined the effect of PCARBTP-induced tumor cell death. Results: We demonstrate that treatment of Jurkat T leukemia cells with low doses of the mitochondria-targeted inhibitor of Kv1.3 PCARBTP (0.25 \u3bcM or 1 \u3bcM) for 10 minutes induced a constitutive phosphorylation/activation of the pro-survival signaling molecules ZAP70, PI- 3-K, AKT and JNK, while the phosphorylation/activation of ERK was not affected. Stimulation of Jurkat cells via the TCR/CD3 complex induced an additional activation of a similar pattern of signaling events. Higher doses of the Kv1.3 inhibitor, i.e. 10 \u3bcM PCARBTP, reduced the basal phosphorylation/activation of these signaling molecules and also impaired their activation upon stimulation via the TCR/CD3 complex. A low dose of PCARBTP, i.e. 0.25 \u3bcM PCARBTP, was almost without any effect on cell death. In contrast, concomitant inhibition of PI-3-K or AKT greatly sensitized Jurkat leukemia cells to the Kv1.3 inhibitor PCARBTP and allowed induction of cell death already at 0.25 \u3bcM PCARBTP. Conclusion: These studies indicate that Jurkat leukemia cells respond to low doses of the mitochondria-targeted Kv1.3 inhibitor PCARBTP with an activation of survival signals counteracting cell death. Inhibition of these T cell survival signals sensitizes leukemia cells to death induced by mitochondria-targeted Kv1.3 inhibitors. High doses of the Kv1.3 inhibitor inactivate these signals directly permitting death

First search for axion dark matter with a Madmax prototype

International audienceThis paper presents the first search for dark matter axions with mass in the ranges 76.56 to 76.82 $\mu$eV and 79.31 to 79.53 $\mu$eV using a prototype setup for the MAgnetized Disk and Mirror Axion eXperiment (MADMAX). The experimental setup employs a dielectric haloscope consisting of three sapphire disks and a mirror to resonantly enhance the axion-induced microwave signal within the magnetic dipole field provided by the 1.6 T Morpurgo magnet at CERN. Over 14.5 days of data collection, no axion signal was detected. A 95% CL upper limit on the axion-photon coupling strength down to $|g_{a\gamma}| \sim 2 \times 10^{-11} \mathrm{GeV}^{-1}$ is set in the targeted mass ranges, surpassing previous constraints, assuming a local axion dark matter density $\rho_{a}$ of $0.3~\mathrm{GeV}/\mathrm{cm}^3$. This study marks the first axion dark matter search using a dielectric haloscope

First search for axion dark matter with a Madmax prototype

International audienceThis paper presents the first search for dark matter axions with mass in the ranges 76.56 to 76.82 $\mu$eV and 79.31 to 79.53 $\mu$eV using a prototype setup for the MAgnetized Disk and Mirror Axion eXperiment (MADMAX). The experimental setup employs a dielectric haloscope consisting of three sapphire disks and a mirror to resonantly enhance the axion-induced microwave signal within the magnetic dipole field provided by the 1.6 T Morpurgo magnet at CERN. Over 14.5 days of data collection, no axion signal was detected. A 95% CL upper limit on the axion-photon coupling strength down to $|g_{a\gamma}| \sim 2 \times 10^{-11} \mathrm{GeV}^{-1}$ is set in the targeted mass ranges, surpassing previous constraints, assuming a local axion dark matter density $\rho_{a}$ of $0.3~\mathrm{GeV}/\mathrm{cm}^3$. This study marks the first axion dark matter search using a dielectric haloscope

First mechanical realization of a tunable dielectric haloscope for the MADMAX axion search experiment

International audienceMADMAX, a future experiment to search for axion dark matter, is based on a novel detection concept called the dielectric haloscope. It consists of a booster composed of several dielectric disks positioned with $\mu$m precision. A prototype composed of one movable disk was built to demonstrate the mechanical feasibility of such a booster in the challenging environment of the experiment: high magnetic field to convert the axions into photons and cryogenic temperature to reduce the thermal noise. It was tested both inside a strong magnetic field up to 1.6 T and at cryogenic temperatures down to 35K. The measurements of the velocity and positioning accuracy of the disk are shown and are found to match the MADMAX requirements

First mechanical realization of a tunable dielectric haloscope for the MADMAX axion search experiment

International audienceMADMAX, a future experiment to search for axion dark matter, is based on a novel detection concept called the dielectric haloscope. It consists of a booster composed of several dielectric disks positioned with $\mu$m precision. A prototype composed of one movable disk was built to demonstrate the mechanical feasibility of such a booster in the challenging environment of the experiment: high magnetic field to convert the axions into photons and cryogenic temperature to reduce the thermal noise. It was tested both inside a strong magnetic field up to 1.6 T and at cryogenic temperatures down to 35K. The measurements of the velocity and positioning accuracy of the disk are shown and are found to match the MADMAX requirements

First search for dark photon dark matter with a MADMAX prototype

International audienceWe report the first result from a dark photon dark matter search in the mass range from ${78.62}$ to $83.95~\mathrm{\mu eV}/c^2$ with a dielectric haloscope prototype for MADMAX (Magnetized Disc and Mirror Axion eXperiment). Putative dark photons would convert to observable photons within a stack consisting of three sapphire disks and a mirror. The emitted power of this system is received by an antenna and successively digitized using a low-noise receiver. No dark photon signal has been observed. Assuming unpolarized dark photon dark matter with a local density of $\rho_{\chi}=0.3~\mathrm{GeV/cm^3}$ we exclude a dark photon to photon mixing parameter $\chi > 3.0 \times 10^{-12}$ over the full mass range and $\chi > 1.2 \times 10^{-13}$ at a mass of $80.57~\mathrm{\mu eV}/c^2$ with a 95% confidence level. This is the first physics result from a MADMAX prototype and exceeds previous constraints on $\chi$ in this mass range by up to almost three orders of magnitude