3,672 research outputs found
NMDA Currents Modulate the Synaptic InputâOutput Functions of Neurons in the Dorsal Nucleus of the Lateral Lemniscus in Mongolian Gerbils
Neurons in the dorsal nucleus of the lateral lemniscus (DNLL) receive excitatory and inhibitory inputs from the superior olivary complex (SOC) and convey GABAergic inhibition to the contralateral DNLL and the inferior colliculi. Unlike the fast glycinergic inhibition in the SOC, this GABAergic inhibition outlasts auditory stimulation by tens of milliseconds. Two mechanisms have been postulated to explain this persistent inhibition. One, an âintegration-basedâ mechanism, suggests that postsynaptic excitatory integration in DNLL neurons generates prolonged activity, and the other favors the synaptic time course of the DNLL output itself. The feasibility of the integration-based mechanism was tested in vitro in DNLL neurons of Mongolian gerbils by quantifying the cellular excitability and synaptic inputâoutput functions (IO-Fs). All neurons were sustained firing and generated a near monotonic IO-F on current injections. From synaptic stimulations, we estimate that activation of approximately five fibers, each on average liberating âź18 vesicles, is sufficient to trigger a single postsynaptic action potential. A strong single pulse of afferent fiber stimulation triggered multiple postsynaptic action potentials. The steepness of the synaptic IO-F was dependent on the synaptic NMDA component. The synaptic NMDA receptor current defines the slope of the synaptic IO-F by enhancing the temporal and spatial EPSP summation. Blocking this NMDA-dependent amplification during postsynaptic integration of train stimulations resulted into a âź20% reduction of the decay time course of the GABAergic inhibition. Thus, our data show that the NMDA-dependent amplification of the postsynaptic activity contributes to the GABAergic persistent inhibition generated by DNLL neurons
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Pro-Secretory Activity and Pharmacology in Rabbits of an Aminophenyl-1,3,5-Triazine CFTR Activator for Dry Eye Disorders.
PurposePharmacological activation of ocular surface cystic fibrosis transmembrane conductance regulator (CFTR) chloride channels is a potential pro-secretory approach to treat dry eye disorders. We previously reported the discovery of aminophenyl-1,3,5-triazines, one of which, N-methyl-N-phenyl-6-(2,2,3,3-tetrafluoropropoxy)-1,3,5-triazine-2,4-diamine (herein called CFTRact-K267), fully activated human wildtype CFTR with EC50 âź 30 nM and increased tear volume for 8 hours in mice. Here, functional and pharmacological studies of CFTRact-K267 were done in adult New Zealand white rabbits.MethodsCFTR chloride conductance was measured in vivo by ocular surface potential differences and in ex vivo conjunctiva by short-circuit current. Tear volume was measured by the Schirmer tear test II and CFTRact-K267 pharmacokinetics and tissue distribution by liquid chromatography/mass spectrometry. Toxicity profile was studied for 28 days with twice-daily topical administration.ResultsElectrophysiological measurements in vivo and in ex vivo conjunctiva demonstrated CFTR activation by CFTRact-K267. A single topical dose of 3 nmol CFTRact-K267 increased tear production by >5 mm for 9 hours by the Schirmer tear test, with predicted therapeutic concentrations maintained in tear fluid. No tachyphylaxis was seen following 28-day twice-daily administration, and changes were not observed in corneal surface integrity or thickness, intraocular pressure, or ocular histology. At day 28, CFTRact-K267 was concentrated in the cornea and conjunctiva and was not detectable in blood or peripheral organs.ConclusionsThese studies support the development of CFTRact-K267 as a pro-secretory therapy for dry eye disorders
InterAKTions with FKBPs - mutational and pharmacological exploration
The FK506-binding protein 51 (FKBP51) is an Hsp90-associated co-chaperone which regulates steroid receptors and kinases. In pancreatic cancer cell lines, FKBP51 was shown to recruit the phosphatase PHLPP to facilitate dephosphorylation of the kinase Akt, which was associated with reduced chemoresistance. Here we show that in addition to FKBP51 several other members of the FKBP family bind directly to Akt. FKBP51 can also form complexes with other AGC kinases and mapping studies revealed that FKBP51 interacts with Akt via multiple domains independent of their activation or phosphorylation status. The FKBP51-Akt1 interaction was not affected by FK506 analogs or Akt active site inhibitors, but was abolished by the allosteric Akt inhibitor VIII. None of the FKBP51 inhibitors affected AktS473 phosphorylation or downstream targets of Akt. In summary, we show that FKBP51 binds to Akt directly as well as via Hsp90. The FKBP51-Akt interaction is sensitive to the conformation of Akt1, but does not depend on the FK506-binding pocket of FKBP51. Therefore, FKBP inhibitors are unlikely to inhibit the Akt-FKBP-PHLPP network
A Retrospective Analysis of the Fake News Challenge Stance Detection Task
The 2017 Fake News Challenge Stage 1 (FNC-1) shared task addressed a stance
classification task as a crucial first step towards detecting fake news. To
date, there is no in-depth analysis paper to critically discuss FNC-1's
experimental setup, reproduce the results, and draw conclusions for
next-generation stance classification methods. In this paper, we provide such
an in-depth analysis for the three top-performing systems. We first find that
FNC-1's proposed evaluation metric favors the majority class, which can be
easily classified, and thus overestimates the true discriminative power of the
methods. Therefore, we propose a new F1-based metric yielding a changed system
ranking. Next, we compare the features and architectures used, which leads to a
novel feature-rich stacked LSTM model that performs on par with the best
systems, but is superior in predicting minority classes. To understand the
methods' ability to generalize, we derive a new dataset and perform both
in-domain and cross-domain experiments. Our qualitative and quantitative study
helps interpreting the original FNC-1 scores and understand which features help
improving performance and why. Our new dataset and all source code used during
the reproduction study are publicly available for future research
Quantum Oscillations Can Prevent the Big Bang Singularity in an Einstein-Dirac Cosmology
We consider a spatially homogeneous and isotropic system of Dirac particles
coupled to classical gravity. The dust and radiation dominated closed
Friedmann-Robertson-Walker space-times are recovered as limiting cases. We find
a mechanism where quantum oscillations of the Dirac wave functions can prevent
the formation of the big bang or big crunch singularity. Thus before the big
crunch, the collapse of the universe is stopped by quantum effects and reversed
to an expansion, so that the universe opens up entering a new era of classical
behavior.
Numerical examples of such space-times are given, and the dependence on
various parameters is discussed. Generically, one has a collapse after a finite
number of cycles. By fine-tuning the parameters we construct an example of a
space-time which is time-periodic, thus running through an infinite number of
contraction and expansion cycles.Comment: 8 pages, LaTeX, 4 figures, statement on energy conditions correcte
Modal analysis of high-fidelity simulations in turbomachinery
We revisit recently published high-fidelity implicit large eddy simulation
datasets obtained with a high-order discontinuous Galerkin spectral element
method and analyse them using Proper Orthogonal Decomposition (POD) as well as
Spectral Proper Orthogonal Decomposition (SPOD). The first configuration is the
MTU T161 low-pressure turbine cascade with resolved end wall boundary layers in
a clean version and one with incoming turbulent wakes. We focus on the
behaviour of the laminar separation bubble and the secondary flow system and
how these phenomena are affected by incoming wakes. The second configuration is
a transonic compressor cascade in which we analyse the unsteady behaviour of
the shock wave boundary layer interaction. Throughout the paper, we try to
discuss not only the flow physics but also insights into how the modal
decomposition techniques can help facilitate understanding and where their
limitations are.Comment: Submitted to Cambridge Unsteady Flow Symposium 202
Transitional Delayed Detached-Eddy Simulation for a Compressor Cascade:A Critical Assessment
The accurate prediction of transitional flows is crucial for the industrial turbomachinery design process. While a Reynolds-averaged NavierâStokes approach inherently brings conceptual weaknesses, large-eddy simulation will still be too expensive in the near future to affordably analyze complex turbomachinery configurations. We introduce a transitional delayed detached-eddy simulation (DDES) model, namely, DDES-Îł, and analyze the numerical results of the compressor cascade V103. A comparison with the fullyturbulent DDES approach emphasizes the benefit of coupling DDES with a transition model. Issues with undesired decay of modeled turbulent kinetic energy in the freestream are improved when running DDES-Îłin combination with the synthetic turbulence generator method. The best results for DDES-Îł are obtained when changing the inviscid flux solver blending from dynamic to constant mode. We show that DDES-Îł is capable ofpredicting the transitional flow through a linear compressor cascade, but we also critically discuss the general concept and results
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