251 research outputs found
During postnatal development endogenous neurosteroids influence GABA-ergic neurotransmission of mouse cortical neurons
AbstractAs neuronal development progresses, GABAergic synaptic transmission undergoes a defined program of reconfiguration. For example, GABAA receptor (GABAAR)-mediated synaptic currents, (miniature inhibitory postsynaptic currents; mIPSCs), which initially exhibit a relatively slow decay phase, become progressively reduced in duration, thereby supporting the temporal resolution required for mature network activity. Here we report that during postnatal development of cortical layer 2/3 pyramidal neurons, GABAAR-mediated phasic inhibition is influenced by a resident neurosteroid tone, which wanes in the second postnatal week, resulting in the brief phasic events characteristic of mature neuronal signalling. Treatment of cortical slices with the immediate precursor of 5α-pregnan-3α-ol-20-one (5α3α), the GABAAR-inactive 5α-dihydroprogesterone, (5α-DHP), greatly prolonged the mIPSCs of P20 pyramidal neurons, demonstrating these more mature neurons retain the capacity to synthesize GABAAR-active neurosteroids, but now lack the endogenous steroid substrate. Previously, such developmental plasticity of phasic inhibition was ascribed to the expression of synaptic GABAARs incorporating the α1 subunit. However, the duration of mIPSCs recorded from L2/3 cortical neurons derived from α1 subunit deleted mice, were similarly under the developmental influence of a neurosteroid tone. In addition to principal cells, synaptic GABAARs of L2/3 interneurons were modulated by native neurosteroids in a development-dependent manner. In summary, local neurosteroids influence synaptic transmission during a crucial period of cortical neurodevelopment, findings which may be of importance for establishing normal network connectivity
A multiorganism pipeline for antiseizure drug discovery:Identification of chlorothymol as a novel Îł-aminobutyric acidergic anticonvulsant
OBJECTIVE:Current medicines are ineffective in approximately one-third of people with epilepsy. Therefore, new antiseizure drugs are urgently needed to address this problem of pharmacoresistance. However, traditional rodent seizure and epilepsy models are poorly suited to high-throughput compound screening. Furthermore, testing in a single species increases the chance that therapeutic compounds act on molecular targets that may not be conserved in humans. To address these issues, we developed a pipeline approach using four different organisms. METHODS:We sequentially employed compound library screening in the zebrafish, Danio rerio, chemical genetics in the worm, Caenorhabditis elegans, electrophysiological analysis in mouse and human brain slices, and preclinical validation in mouse seizure models to identify novel antiseizure drugs and their molecular mechanism of action. RESULTS:Initially, a library of 1690 compounds was screened in an acute pentylenetetrazol seizure model using D rerio. From this screen, the compound chlorothymol was identified as an effective anticonvulsant not only in fish, but also in worms. A subsequent genetic screen in C elegans revealed the molecular target of chlorothymol to be LGC-37, a worm Îł-aminobutyric acid type A (GABAA ) receptor subunit. This GABAergic effect was confirmed using in vitro brain slice preparations from both mice and humans, as chlorothymol was shown to enhance tonic and phasic inhibition and this action was reversed by the GABAA receptor antagonist, bicuculline. Finally, chlorothymol exhibited in vivo anticonvulsant efficacy in several mouse seizure assays, including the 6-Hz 44-mA model of pharmacoresistant seizures. SIGNIFICANCE:These findings establish a multiorganism approach that can identify compounds with evolutionarily conserved molecular targets and translational potential, and so may be useful in drug discovery for epilepsy and possibly other conditions
A study of CP violation in the decays B±â[K+K-Ï+Ï-]Dh± (h= K, Ï) and B±â[Ï+Ï-Ï+Ï-]Dh±
The first study of CP violation in the decay mode B±â[K+K-Ï+Ï-]Dh± , with h= K, Ï , is presented, exploiting a data sample of protonâproton collisions collected by the LHCb experiment that corresponds to an integrated luminosity of 9 \,fb - 1 . The analysis is performed in bins of phase space, which are optimised for sensitivity to local CP asymmetries. CP -violating observables that are sensitive to the angle Îł of the Unitarity Triangle are determined. The analysis requires external information on charm-decay parameters, which are currently taken from an amplitude analysis of LHCb data, but can be updated in the future when direct measurements become available. Measurements are also performed of phase-space integrated observables for B±â[K+K-Ï+Ï-]Dh± and B±â[Ï+Ï-Ï+Ï-]Dh± decays
Test of lepton universality in decays
The first simultaneous test of muon-electron universality using
and decays is performed, in two ranges of the dilepton
invariant-mass squared, . The analysis uses beauty mesons produced in
proton-proton collisions collected with the LHCb detector between 2011 and
2018, corresponding to an integrated luminosity of 9 . Each
of the four lepton universality measurements reported is either the first in
the given interval or supersedes previous LHCb measurements. The
results are compatible with the predictions of the Standard Model.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-046.html (LHCb
public pages
Measurement of lepton universality parameters in and decays
A simultaneous analysis of the and decays is performed to test muon-electron universality in
two ranges of the square of the dilepton invariant mass, . The measurement
uses a sample of beauty meson decays produced in proton-proton collisions
collected with the LHCb detector between 2011 and 2018, corresponding to an
integrated luminosity of . A sequence of multivariate
selections and strict particle identification requirements produce a higher
signal purity and a better statistical sensitivity per unit luminosity than
previous LHCb lepton universality tests using the same decay modes. Residual
backgrounds due to misidentified hadronic decays are studied using data and
included in the fit model. Each of the four lepton universality measurements
reported is either the first in the given interval or supersedes previous
LHCb measurements. The results are compatible with the predictions of the
Standard Model.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-045.html (LHCb
public pages
Observation of a resonant structure near the threshold in the decay
An amplitude analysis of the decay is carried out to
study for the first time its intermediate resonant contributions, using
proton-proton collision data collected with the LHCb detector at centre-of-mass
energies of 7, 8 and 13 TeV. A near-threshold peaking structure, referred to as
, is observed in the invariant-mass spectrum with
significance greater than 12 standard deviations. The mass, width and the
quantum numbers of the structure are measured to be MeV,
MeV and , respectively, where the first
uncertainties are statistical and the second systematic. The properties of the
new structure are consistent with recent theoretical predictions for a state
composed of quarks. Evidence for an additional structure is
found around 4140 MeV in the invariant mass, which might be
caused either by a new resonance with the assignment or by a coupled-channel effect.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-018.html (LHCb
public pages
Search for violation in the phase space of decays with the energy test
A search for violation in decays is reported,
using collision data collected by the LHCb experiment from 2015 to 2018
corresponding to an integrated luminosity of 6. An unbinned
model-independent approach provides sensitivity to local violation within
the two-dimensional phase space of the decay. The method is validated using the
Cabibbo-favoured channel \D^0 \to \K^-\pi^+\pi^0 and background regions of
the signal mode. The results are consistent with symmetry in this decay.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2023-005.html (LHCb
public pages
First observation and branching fraction measurement of the decay
The first observation of the decay is presented
using proton-proton collision data collected by the LHCb experiment at a
centre-of-mass energy of , corresponding to a
total integrated luminosity of . Using the
decay as the normalisation mode, the branching
fraction of the decay is measured to be
, where the first uncertainty is statistical, the second systematic
and the third due to uncertainties in the branching fractions of the
, and decays.Comment: All figures and tables, along with any supplementary material and
additional information, are available at
https://cern.ch/lhcbproject/Publications/p/LHCb-PAPER-2022-038.html (LHCb
public pages
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