221 research outputs found
Phosphorylation of the HCN channel auxiliary subunit TRIP8b is altered in an animal model of temporal lobe epilepsy and modulates channel function
Temporal lobe epilepsy (TLE) is a prevalent neurological disorder with many patients experiencing poor seizure control with existing anti-epileptic drugs. Thus, novel insights into the mechanisms of epileptogenesis and identification of new drug targets can be transformative. Changes in ion channel function have been shown to play a role in generating the aberrant neuronal activity observed in TLE. Previous work demonstrates that hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability and are mislocalized within CA1 pyramidal cells in a rodent model of TLE. The subcellular distribution of HCN channels is regulated by an auxiliary subunit, tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b), and disruption of this interaction correlates with channel mislocalization. However, the molecular mechanisms responsible for HCN channel dysregulation in TLE are unclear. Here we investigated whether changes in TRIP8b phosphorylation are sufficient to alter HCN channel function. We identified a phosphorylation site at residue Ser237 of TRIP8b that enhances binding to HCN channels and influences channel gating by altering the affinity of TRIP8b for the HCN cytoplasmic domain. Using a phosphospecific antibody, we demonstrate that TRIP8b phosphorylated at Ser237 is enriched in CA1 distal dendrites and that phosphorylation is reduced in the kainic acid model of TLE. Overall, our findings indicate that the TRIP8b-HCN interaction can be modulated by changes in phosphorylation and suggest that loss of TRIP8b phosphorylation may affect HCN channel properties during epileptogenesis. These results highlight the potential of drugs targeting posttranslational modifications to restore TRIP8b phosphorylation to reduce excitability in TLE
A search for low-mass WIMPs with EDELWEISS-II heat-and-ionization detectors
We report on a search for low-energy (E < 20 keV) WIMP-induced nuclear
recoils using data collected in 2009 - 2010 by EDELWEISS from four germanium
detectors equipped with thermal sensors and an electrode design (ID) which
allows to efficiently reject several sources of background. The data indicate
no evidence for an exponential distribution of low-energy nuclear recoils that
could be attributed to WIMP elastic scattering after an exposure of 113 kg.d.
For WIMPs of mass 10 GeV, the observation of one event in the WIMP search
region results in a 90% CL limit of 1.0x10^-5 pb on the spin-independent
WIMP-nucleon scattering cross-section, which constrains the parameter space
associated with the findings reported by the CoGeNT, DAMA and CRESST
experiments.Comment: PRD rapid communication accepte
Axion searches with the EDELWEISS-II experiment
We present new constraints on the couplings of axions and more generic
axion-like particles using data from the EDELWEISS-II experiment. The EDELWEISS
experiment, located at the Underground Laboratory of Modane, primarily aims at
the direct detection of WIMPs using germanium bolometers. It is also sensitive
to the low-energy electron recoils that would be induced by solar or dark
matter axions. Using a total exposure of up to 448 kg.d, we searched for
axion-induced electron recoils down to 2.5 keV within four scenarios involving
different hypotheses on the origin and couplings of axions. We set a 95% CL
limit on the coupling to photons GeV in
a mass range not fully covered by axion helioscopes. We also constrain the
coupling to electrons, , similar to the more
indirect solar neutrino bound. Finally we place a limit on , where is the
effective axion-nucleon coupling for Fe. Combining these results we
fully exclude the mass range keV for DFSZ axions and
keV for KSVZ axions
Background studies for the EDELWEISS dark matter experiment
The EDELWEISS-II collaboration has completed a direct search for WIMP dark
matter using cryogenic Ge detectors (400 g each) and 384 kgdays of
effective exposure. A cross-section of pb is excluded at
90% C.L. for a WIMP mass of 85 GeV. The next phase, EDELWEISS-III, aims to
probe spin-independent WIMP-nucleon cross-sections down to a few
pb. We present here the study of gamma and neutron background
coming from radioactive decays in the set-up and shielding materials. We have
carried out Monte Carlo simulations for the completed EDELWEISS-II setup with
GEANT4 and normalised the expected background rates to the measured
radioactivity levels (or their upper limits) of all materials and components.
The expected gamma-ray event rate in EDELWEISS-II at 20-200 keV agrees with the
observed rate of 82 events/kg/day within the uncertainties in the measured
concentrations. The calculated neutron rate from radioactivity of 1.0-3.1
events (90% C.L.) at 20-200 keV in the EDELWEISS-II data together with the
expected upper limit on the misidentified gamma-ray events (), surface
betas (), and muon-induced neutrons (), do not contradict 5
observed events in nuclear recoil band. We have then extended the simulation
framework to the EDELWEISS-III configuration with 800 g crystals, better
material purity and additional neutron shielding inside the cryostat. The
gamma-ray and neutron backgrounds in 24 kg fiducial mass of EDELWEISS-III have
been calculated as 14-44 events/kg/day and 0.7-1.4 events per year,
respectively. The results of the background studies performed in the present
work have helped to select better purity components and improve shielding in
EDELWEISS-III to further reduce the expected rate of background events in the
next phase of the experiment.Comment: 15 pages, 9 figures, to be published in Astroparticle Physic
Muon-induced background in the EDELWEISS dark matter search
A dedicated analysis of the muon-induced background in the EDELWEISS dark
matter search has been performed on a data set acquired in 2009 and 2010. The
total muon flux underground in the Laboratoire Souterrain de Modane (LSM) was
measured to be \,muons/m/d. The
modular design of the muon-veto system allows the reconstruction of the muon
trajectory and hence the determination of the angular dependent muon flux in
LSM. The results are in good agreement with both MC simulations and earlier
measurements. Synchronization of the muon-veto system with the phonon and
ionization signals of the Ge detector array allowed identification of
muon-induced events. Rates for all muon-induced events and of WIMP-like events were extracted. After
vetoing, the remaining rate of accepted muon-induced neutrons in the
EDELWEISS-II dark matter search was determined to be at 90%\,C.L. Based on
these results, the muon-induced background expectation for an anticipated
exposure of 3000\,\kgd\ for EDELWEISS-3 is
events.Comment: 21 pages, 16 figures, Accepted for publication in Astropart. Phy
Unveiling Novel RecO Distant Orthologues Involved in Homologous Recombination
The generation of a RecA filament on single-stranded DNA is a critical step in homologous recombination. Two main pathways leading to the formation of the nucleofilament have been identified in bacteria, based on the protein complexes mediating RecA loading: RecBCD (AddAB) and RecFOR. Many bacterial species seem to lack some of the components involved in these complexes. The current annotation of the Helicobacter pylori genome suggests that this highly diverse bacterial pathogen has a reduced set of recombination mediator proteins. While it is now clear that homologous recombination plays a critical role in generating H. pylori diversity by allowing genomic DNA rearrangements and integration through transformation of exogenous DNA into the chromosome, no complete mediator complex is deduced from the sequence of its genome. Here we show by bioinformatics analysis the presence of a RecO remote orthologue that allowed the identification of a new set of RecO proteins present in all bacterial species where a RecR but not RecO was previously identified. HpRecO shares less than 15% identity with previously characterized homologues. Genetic dissection of recombination pathways shows that this novel RecO and the remote RecB homologue present in H. pylori are functional in repair and in RecA-dependent intrachromosomal recombination, defining two initiation pathways with little overlap. We found, however, that neither RecOR nor RecB contributes to transformation, suggesting the presence of a third, specialized, RecA-dependent pathway responsible for the integration of transforming DNA into the chromosome of this naturally competent bacteria. These results provide insight into the mechanisms that this successful pathogen uses to generate genetic diversity and adapt to changing environments and new hosts
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