1,861 research outputs found
Striatal cholinergic dysfunction as a unifying theme in the pathophysiology of dystonia
No full textDystonia is a movement disorder of both genetic and non-genetic causes, which typically results in twisted posturing due to abnormal muscle contraction. Evidence from dystonia patients and animal models of dystonia indicate a crucial role for the striatal cholinergic system in the pathophysiology of dystonia. In this review, we focus on striatal circuitry and the centrality of the acetylcholine system in the function of the basal ganglia in the control of voluntary movement and ultimately clinical manifestation of movement disorders. We consider the impact of cholinergic interneurons (ChIs) on dopamine-acetylcholine interactions and examine new evidence for impairment of ChIs in dysfunction of the motor systems producing dystonic movements, particularly in animal models. We have observed paradoxical excitation of ChIs in the presence of dopamine D2 receptor agonists and impairment of striatal synaptic plasticity in a mouse model of DYT1 dystonia, which are improved by administration of recently developed M1 receptor antagonists. These findings have been confirmed across multiple animal models of DYT1 dystonia and may represent a common endophenotype by which to investigate dystonia induced by other types of genetic and non-genetic causes and to investigate the potential effectiveness of pharmacotherapeutics and other strategies to improve dystonia
Association of AMPA receptors with a subset of glutamate receptor-interacting protein in vivo
No full textThe NMDA and AMPA classes of ionotropic glutamate receptors are concentrated at postsynaptic sites in excitatory synapses. NMDA receptors interact via their NR2 subunits with PSD-95/SAP90 family proteins, whereas AMPA receptors bind via their GluR2/3 subunits to glutamate receptor-interacting protein (GRIP), AMPA receptor-binding protein (ABP), and protein interacting with C kinase 1 (PICK1). We report here a novel cDNA (termed ABP-L/GRIP2) that is virtually identical to ABP except for additional GRIP-like sequences at the N-terminal and G-terminal ends. Like GRIP (which we now term GR(PI), AEP-L/GRIP2 contains a seventh PDZ domain at its C terminus. Using antibodies that recognize both these proteins, we examined the subcellular localization of GRIP1 and ABP-L/GRIP2 (collectively termed GRIP) and their biochemical association with AMPA receptors. Immunogold electron microscopy revealed the presence of GRIP at excitatory synapses and also at nonsynaptic membranes and within intracellular compartments. The association of native GRIP and AMPA receptors was confirmed biochemically by coimmunoprecipitation from rat brain extracts. A majority of detergent-extractable GluR2/3 was complexed with GRIP in the brain. However, only approximately half of GRIP was associated with AMPA receptors. Unexpectedly, immunocytochemistry of cultured hippocampal neurons and rat brain at the light microscopic level showed enrichment of GRIP in GABAergic neurons and in GABAergic nerve terminals. Thus GRIP is associated with inhibitory as well as excitatory synapses. Collectively, these findings support a role for GRIP in the synaptic anchoring of AMPA receptors but also suggest that GRIP has additional functions unrelated to the binding of AMPA receptors
Altered responses to dopaminergic D2 receptor activation and N-type calcium currents in striatal cholinergic interneurons in a mouse model of DYT1 dystonia
No full textEarly-onset torsion dystonia (DYT1) is an autosomal dominant disease caused by a deletion in the gene encoding the protein torsinA. Recently, a transgenic mouse model of DYT1 has been described, expressing either the human wild-type torsinA (hWT) or mutant torsinA (hMT). We recorded the activity of striatal cholinergic interneurons of hWT, hMT, and control mice. In slice preparations, no significant differences were observed in resting membrane potential (RMP), firing activity, action potential duration or Ih current. Quinpirole, a D2-like dopamine receptor agonist, did not produce detectable effects on RMP of cholinergic interneurons in control mice and hWT mice, but in the hMT mice caused membrane depolarization and an increase in the firing rate. D2 receptor activation inhibits N-type high-voltage-activated calcium currents. We found that, in isolated interneurons from hMT mice, the quinpirole-mediated inhibition of N-type currents was significantly larger than in hWT and controls. Moreover, the N-type component was significantly over-represented in hMT mice. The altered sensitivity of N-type channels in hMT mice could account for the paradoxical excitatory effect of D2 stimulation. Our data support the existence of an imbalance between striatal dopaminergic and cholinergic signaling in DYT1 dystonia. © 2006 Elsevier Inc. All rights reserved
Discontinuous Galerkin Methods for Numerical Weather Prediction: DG in a large-eddy simulation
No full textThe coarse grid of numerical weather prediction and climate models requires parametrization models to resolve atmospheric processes that are smaller than the grid size. For parametrization development, these processes are simulated by a high resolution model. At the Royal Netherlands MeteorologicalInstitute, the Dutch Atmospheric Large-Eddy Simulation (DALES) is used. This three-dimensional high resolution model uses advection schemes that are too diffusive when steep gradients are present. In this thesis, an advection scheme based on the Discontinuous Galerkin (DG) method is implementedfor DALES.The DG method is known to be dispersive. To remove those non-physical oscillations, the moment limiter of Krivodonova is used. Krivodonova constructed the limiter for one- and two-dimensions. In this thesis the moment limiter and limiting order are derived for three-dimensions. DALES is a model based on the finite difference method and uses operational splitting. Therefore, the DG advection scheme needs a mapping from each cell average to all nodal values that are needed for one DG cell, and a mapping back, which we called mapping a and b respectively. Mappings a that are discussed are taking the cell average as value for all nodal points of the DG cell (cell average a), and taking the L -projection of the cell average to the continuous finite element space (L -projection). This thesis describes mappings b that calculate cell averages of nodal DG values (cell average b)and calculate the cell averages of the tendencies of DG values (cell average of tendency). Using cell average a combined with cell average of tendency, made the DG method as diffusive as the first order upwind scheme. Substituting the cell average a method with the L -projection, the DG method becamevery dispersive, meaning that there was not enough diffusion. At last, cell average b was tested with the L -projection. Its numerical results showed that the speed of the advection was slower than the theoretical velocity. Therefore, a method is suggested which does not need mappings. An option couldbe a supergrid that takes multiple DALES cells as a DG cell.Applied Mathematic
Increasing Distributed Generation Penetration using Soft Normally-Open Points
No full textThis paper considers the effects of various voltage control solutions on facilitating an increase in allowable levels of distributed generation installation before voltage violations occur. In particular, the voltage control solution that is focused on is the implementation of `soft' normally-open points (SNOPs), a term which refers to power electronic devices installed in place of a normally-open point in a medium-voltage distribution network which allows for control of real and reactive power flows between each end point of its installation sites. While other benefits of SNOP installation are discussed, the intent of this paper is to determine whether SNOPs are a viable alternative to other voltage control strategies for this particular application. As such, the SNOPs ability to affect the voltage profile along feeders within a distribution system is focused on with other voltage control options used for comparative purposes. Results from studies on multiple network models with varying topologies are presented and a case study which considers economic benefits of increasing feasible DG penetration is also given
Dg algebras with enough idempotents, their dg modules and their derived categories
No full textWe develop the theory dg algebras with enough idempotents and their dg modules and show their equivalence with that of small dg categories and their dg modules. We introduce the concept of dg adjunction and show that the classical covariant tensor-Hom and contravariant Hom-Hom adjunctions of modules over associative unital algebras are extended as dg adjunctions between categories of dg bimodules. The corresponding adjunctions of the associated triangulated functors are studied, and we investigate when they are one-sided parts of bifunctors which are triangulated on both variables. We finally show that, for a dg algebra with enough idempotents, the perfect left and right derived categories are dual to each other.The author is highly indebted to Alexander Zimmermann for the careful reading of these notes, for his comments and for his help in improving the presentation. This work is backed by reseach projects from the Ministerio de Economía y Competitividad of Spain(MTM201346837-P and MTM201677445-P) and the Fundación ’Séneca’ of Murcia(19880/GERM/15), both with a part of FEDER funds. We thank these institutions for their support
Life cycle comparison of petroleum- and bio-based paper binder from distillers grains (DG)
No full textAbstractThis study presents a comparative cradle-to-gate life cycle assessment (LCA) of distillers grain (DG) gum, a bio-based paper coating binder, and polyvinyl alcohol (PVA). Non-renewable energy use, greenhouse gas (GHG) emissions, and eutrophication potential were assessed for each binder. Economic, mass, and energy allocation were used to allocate the impacts of DG gum production with co-products (ethanol and livestock feed). DG production non-renewable energy use (269 to 183MJ) surpassed that associated with PVA production (168MJ). GHG emissions from DG gum production under mass and energy allocations were 28% and 37% lower than PVA production emissions, respectively. Corn cultivation is responsible for 55% to 78% of the eutrophication impacts of DG gum production under energy and economic allocation, respectively. Changes to natural gas consumption and fertilizer runoff had the largest influence on total energy use, GHG emissions, and eutrophication potential of DG gum production
The DG-category of secondary cohomology operations
No full textWe study track categories (i.e., groupoid-enriched categories) endowed with additive structure similar to that of a 1-truncated DG-category, except that composition is not assumed right linear. We show that if such a track category is right linear up to suitably coherent correction tracks, then it is weakly equivalent to a 1-truncated DG-category. This generalizes work of the first author on the strictification of secondary cohomology operations. As an application, we show that the secondary integral Steenrod algebra is strictifiable
Coderived and contraderived categories of locally presentable abelian DG-categories
No full textThe concept of an abelian DG-category, introduced by the first-named author in arXiv:2110.08237, unites the notions of abelian categories and (curved) DG-modules in a common framework. In this paper we consider coderived and contraderived categories in the sense of Becker. Generalizing some constructions and results from the preceding papers by Becker arXiv:1205.4473 and by the present authors arXiv:2101.10797, we define the contraderived category of a locally presentable abelian DG-category with enough projective objects and the coderived category of a Grothendieck abelian DG-category . We construct the related abelian model category structures and show that the resulting exotic derived categories are well-generated. Then we specialize to the case of a locally coherent Grothendieck abelian DG-category , and prove that its coderived category is compactly generated by the absolute derived category of finitely presentable objects of , thus generalizing a result from the second-named author\u27s preprint arXiv:1412.1615. In particular, the homotopy category of graded-injective left DG-modules over a DG-ring with a left coherent underlying graded ring is compactly generated by the absolute derived category of DG-modules with finitely presentable underlying graded modules. We also describe compact generators of the coderived categories of quasi-coherent matrix factorizations over coherent schemes.LaTeX 2e with xy-pic and one mathb symbol; 76 pages, 1 figure; v.2: a discussion of quasi-coherent matrix factorizations over coherent schemes added in a new Section 9; new Corollary 0.4, Sections 1.10 and 2.7, Examples 3.15, 6.12, 7.8, 8.8, and 8.10 inserted; a paragraph added at the end of Section 2.1, 4th paragraph of the introduction expanded; v.3: several misprints correcte
Evaluation of AZD1446 as a Therapeutic in DYT1 Dystonia
No full textDYT1 dystonia is an early-onset, hyperkinetic movement disorder caused by a deletion in the gene TOR1A, which encodes the protein torsinA. Several lines of evidence show that in animal models of DTY1 dystonia, there is impaired basal dopamine (DA) release and enhanced acetylcholine tone. Clinically, anticholinergic drugs are the most effective pharmacological treatment for DYT1 dystonia, but the currently used agents are non-selective muscarinic antagonists and associated with side effects. We used a DYT1 ∆GAG knock-in mouse model (DYT1 KI) to investigate whether nicotine and/or a non-desensitizing nicotinic agonist, AZD1446, would increase DA output in DYT1 dystonia. Using in vivo microdialysis, we found that DYT1 KI mice showed significantly increased DA output and greater sensitivity to nicotine compared to wild type (WT) littermate controls. In contrast, neither systemic injection (0.25–0.75 mg/kg) or intrastriatal infusion (30 μM–1 mM) of AZD1446 had a significant effect on DA efflux in WT or DYT1 KI mice. In vitro, we found that AZD1446 had no effect on the membrane properties of striatal spiny projection neurons (SPNs) and did not alter the spontaneous firing of ChI interneurons in either WT or DYT1 KI mice. We did observe that the firing frequency of dopaminergic neurons was significantly increased by AZD1446 (10 μM), an effect blocked by dihydro-beta-erythroidine (DHβE 3 μM), but the effect was similar in WT and DYT1 KI mice. Our results support the view that DYT1 models are associated with abnormal striatal cholinergic transmission, and that the DYT1 KI animals have enhanced sensitivity to nicotine. We found little effect of AZD1446 in this model, suggesting that other approaches to nicotinic modulation should be explored
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