Toxic proteinaceous deposits and alterations in excitability and activity levels characterize vulnerable neuronal populations in neurodegenerative diseases. Using in vivo two-photon imaging in ...behaving spinocerebellar ataxia type 1 (Sca1) mice, wherein Purkinje neurons (PNs) degenerate, we identify an inhibitory circuit element (molecular layer interneurons MLINs) that becomes prematurely hyperexcitable, compromising sensorimotor signals in the cerebellum at early stages. Mutant MLINs express abnormally elevated parvalbumin, harbor high excitatory-to-inhibitory synaptic density, and display more numerous synaptic connections on PNs, indicating an excitation/inhibition imbalance. Chemogenetic inhibition of hyperexcitable MLINs normalizes parvalbumin expression and restores calcium signaling in Sca1 PNs. Chronic inhibition of mutant MLINs delayed PN degeneration, reduced pathology, and ameliorated motor deficits in Sca1 mice. Conserved proteomic signature of Sca1 MLINs, shared with human SCA1 interneurons, involved the higher expression of FRRS1L, implicated in AMPA receptor trafficking. We thus propose that circuit-level deficits upstream of PNs are one of the main disease triggers in SCA1.
•Increased molecular layer interneuron (MLIN) activity drives SCA1 pathophysiology•Inhibition of MLIN ameliorates network and behavioral SCA1 phenotypes•Mimicking MLIN hyperexcitability in healthy mice generates SCA1-like pathophysiology•MLIN hyperexcitability is conserved in human SCA1 patient-derived GABAergic neurons
Pilotto et al. identify early hyperexcitability of molecular layer interneurons (MLINs) in SCA1 driving circuit dysfunction and motor deficits. Inhibition of MLINs in SCA1 mice induced lasting improvements of circuit pathology and behavior. MLIN proteomics revealed a signature accounting for hyperexcitability, conserved in patient-derived GABAergic neurons.
Lean thinking has become pervasive in manufacturing, but its use in sales remains exploratory. In this paper, we demonstrate the sales application of an essential tool for lean management called ...value stream mapping. We conceptualize sales as a process in which a buyer and seller jointly participate in creating value, and using a case study, we demonstrate how this process can be mapped and analyzed. Finally, we discuss opportunities and challenges for future research, particularly the importance of customer-centric value metrics.
Challenges for governments to modify financial regulation and supervision following the global financial crisis while maintaining stability of financial markets and not limiting dynamic market ...development - a framework of cooperation and coordination is central to success - regulatory competition - harmonisation and decentralisation.
We characterized the pulsed Rydberg-positronium production inside the Antimatter Experiment: Gravity, Interferometry, Spectroscopy (AE¯gIS) apparatus in view of antihydrogen formation by means of a ...charge exchange reaction between cold antiprotons and slow Rydberg-positronium atoms. Velocity measurements on the positronium along two axes in a cryogenic environment (≈10K) and in 1T magnetic field were performed. The velocimetry was done by microchannel-plate (MCP) imaging of a photoionized positronium previously excited to the n=3 state. One direction of velocity was measured via Doppler scan of this n=3 line, another direction perpendicular to the former by delaying the exciting laser pulses in a time-of-flight measurement. Self-ionization in the magnetic field due to the motional Stark effect was also quantified by using the same MCP-imaging technique for Rydberg positronium with an effective principal quantum number neff ranging between 14 and 22. We conclude with a discussion about the optimization of our experimental parameters for creating Rydberg positronium in preparation for an efficient pulsed production of antihydrogen.
Ionically conductive polypyrrole films have been deposited at 295 K from anhydrous acetonitrile, acetonitrile/H
2O and NaBF
4 aqueous solutions onto platinum, mild steel and stainless steel discs, ...using cyclic voltammetry, potentiostatic and galvanostatic techniques. Cyclic voltammetry of the polymer films has been studied as a function of water content of the acetonitrile solvent, polypyrrole concentration and potential sweep rate. Potentiostatic growth of thicker (<
30 micron) films on stainless steel allowed free-standing polypyrrole membranes to be produced. Well adherent and conductive films were deposited at constant potential in stirred solutions from acetonitrile electrolytes containing 1% (v/v) of water. The membrane resistivity of the reduced films in 0.5 mol dm
−
3
KCl
(aq) at 295 K was ≈
1
×
10
6 Ω cm, while the resistivity of the oxidised membrane was 2700 Ω cm.
A series of potent indol-3-yl-tetramethylcyclopropyl ketones have been prepared as CB2 cannabinoid receptor ligands. Two unsubstituted indoles (5, 32) were the starting points for an investigation of ...the effect of indole ring substitutions on CB2 and CB1 binding affinities and activity in a CB2 in vitro functional assay. Indole ring substitutions had varying effects on CB2 and CB1 binding, but were generally detrimental to agonist activity. Substitution on the indole ring did lead to improved CB2/CB1 binding selectivity in some cases (i.e., 7−9, 15−20). All indoles with the morpholino-ethyl side chain (32−43) exhibited weaker binding affinity and less agonist activity relative to that of their tetrahydropyranyl-methyl analogs (5−31). Several agonists were active in the complete Freund’s adjuvant model of chronic inflammatory thermal hyperalgesia (32, 15).
We describe a system designed to re-bunch positron pulses delivered by an accumulator supplied by a positron source and a Surko-trap. Positron pulses from the accumulator are magnetically guided in a ...0.085T field and are injected into a region free of magnetic fields through a μ-metal field terminator. Here positrons are temporally compressed, electrostatically guided and accelerated towards a porous silicon target for the production and emission of positronium into vacuum. Positrons are focused in a spot of less than 4mm FWTM in bunches of ∼8ns FWHM. Emission of positronium into the vacuum is shown by single shot positron annihilation lifetime spectroscopy.
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