Dopamine-depleting lesions of the striatum that mimic Parkinson's disease induce a profound pruning of spines and glutamatergic synapses in striatopallidal medium spiny neurons, leaving striatonigral medium spiny neurons intact. The mechanisms that underlie this cell type-specific loss of connectivity are poorly understood. The Kir2 K(+) channel is an important determinant of dendritic excitability in these cells. Here we show that opening of these channels is potently reduced by signaling through M1 muscarinic receptors in striatopallidal neurons, but not in striatonigral neurons. This asymmetry could be attributed to differences in the subunit composition of Kir2 channels. Dopamine depletion alters the subunit composition further, rendering Kir2 channels in striatopallidal neurons even more susceptible to modulation. Reduced opening of Kir2 channels enhances dendritic excitability and synaptic integration. This cell type-specific enhancement of dendritic excitability is an essential trigger for synaptic pruning after dopamine depletion, as pruning was prevented by genetic deletion of M1 muscarinic receptors.
Propane dehydrogenation (PDH) to propene is an important alternative to oil-based cracking processes, to produce this industrially important platform chemical1,2. The commercial PDH technologies utilizing Cr-containing (refs. 3,4) or Pt-containing (refs. 5–8) catalysts suffer from the toxicity of Cr(vi) compounds or the need to use ecologically harmful chlorine for catalyst regeneration9. Here, we introduce a method for preparation of environmentally compatible supported catalysts based on commercial ZnO. This metal oxide and a support (zeolite or common metal oxide) are used as a physical mixture or in the form of two layers with ZnO as the upstream layer. Supported ZnOx species are in situ formed through a reaction of support OH groups with Zn atoms generated from ZnO upon reductive treatment above 550 °C. Using different complementary characterization methods, we identify the decisive role of defective OH groups for the formation of active ZnOx species. For benchmarking purposes, the developed ZnO–silicalite-1 and an analogue of commercial K–CrOx/Al2O3 were tested in the same setup under industrially relevant conditions at close propane conversion over about 400 h on propane stream. The developed catalyst reveals about three times higher propene productivity at similar propene selectivity.
CO adsorption structures and energetics on the iron (100), (110), (111), (210), (211), and (310) surfaces from the lowest coverage up to saturation have been computed using spin-polarized density functional theory and ab initio thermodynamics. It is found that different adsorption configurations on each of these surfaces at high coverage can coexist. The stepwise adsorption energies and dissociation barriers at different coverage reveal equilibriums between desorption and dissociation of adsorbed CO molecules. Only molecular CO adsorption is possible at very high coverage and only dissociative CO adsorption at very low coverage, whereas mixed molecular and dissociative CO adsorption becomes possible at medium coverage. The computed stable adsorption configurations and the respective C–O and Fe–C stretching frequencies as well as desorption temperatures on the (100), (110), and (111) surfaces agree very well with the available experimental data. Such agreements between theory and experiment validate our computational methods and allow us to reasonably predict the experimentally unknown CO activation mechanisms on the (210), (211), and (310) surfaces. Our results might provide some references for the study of CO related reaction mechanisms.
Striatal dopamine depletion profoundly reduces the density of spines and corticostriatal glutamatergic synapses formed on D2 dopamine receptor expressing striatopallidal medium spiny neurons, leaving D1 receptor expressing striatonigral medium spiny neurons relatively intact. Because D2 dopamine receptors diminish the excitability of striatopallidal MSNs, the pruning of synapses could be a form of homeostatic plasticity aimed at restoring activity into a preferred range. To characterize the homeostatic mechanisms controlling synapse density in striatal medium spiny neurons, striatum from transgenic mice expressing a D2 receptor reporter construct was co-cultured with wild-type cerebral cortex. Sustained depolarization of these co-cultures induced a profound pruning of glutamatergic synapses and spines in striatopallidal medium spiny neurons. This pruning was dependent upon Ca2+ entry through Cav1.2 L-type Ca2+ channels, activation of the Ca2+-dependent protein phosphatase calcineurin and up-regulation of myocyte enhancer factor 2 (MEF2) transcriptional activity. Depolarization and MEF2 up-regulation increased the expression of two genes linked to synaptic remodeling – Nur77 and Arc. Taken together, these studies establish a translational framework within with striatal adaptations linked to the symptoms of Parkinson's disease can be explored.
This study describes the novel role of Rap1 as a molecular switch for down-regulation of the Rho-dependent pathway of agonist-induced endothelial hyperpermeability. The Rho-Rap-Rac autoregulation loop may represent a fundamental mechanism of homeostasis and be critical for reestablishment of cell monolayer integrity in pathological conditions.
Circulating barrier disruptive agonists bind specific cell membrane receptors and trigger signal transduction pathways leading to activation of cell contractility and endothelial cell (EC) permeability. Although all cells in tissues including vascular EC are surrounded by compliant extracellular matrix, the impact of matrix stiffness on agonist-induced signaling, cytoskeletal remodeling and EC barrier regulation is not well understood. This study examined agonist-induced cytoskeletal and signaling changes associated with EC barrier disruption and recovery using pulmonary EC grown on compliant substrates of physiologically relevant (8.6 kPa) stiffness, very low (0.55 kPa) and very high (42 kPa) stiffness. Human pulmonary microvascular and macrovascular EC grown on 0.55 kPa substrate contained a few actin stress fibers, while stress fiber amount increased with increasing matrix stiffness. Thrombin-induced stress fiber formation was maximal in EC grown on 42 kPa substrate, diminished on 8.6 kPa substrate, and was minimal on 0.55 kPa substrate. These effects were linked to a stiffness-dependent increase in thrombin-induced phosphorylation of the Rho kinase target, myosin light chain phosphatase (MYPT1), and regulatory myosin light chains (MLC). Surprisingly, EC barrier recovery and activation of Rac GTPase-dependent barrier protective signaling reached maximal levels in EC grown on 8.6 kPa, but not on 0.55 kPa substrate. In conclusion, these data show a critical role of extracellular matrix stiffness in the regulation of the Rac/Rho signaling balance during onset and resolution of agonist-induced EC permeability. The optimal conditions for the Rho/Rac signaling switch, which provides an effective and reversible EC cytoskeletal and permeability response to agonist, are reached in cells grown on the matrix of physiologically relevant stiffness.
Bis(trimethylsilyl)benzohexathia[7]helicene 1, naphthalene cored double helicene 2 (the fused dimer of 1), and a novel ten-membered cyclic diketone with four moieties of dithieno[2,3-b:3',2'-d]thiophene (3) were efficiently synthesized. Their crystal structures were determined with single-crystal X-ray analysis. In their crystal packings, they all show multiple short contacts including intermolecular pi...pi, pi...S, and S...S interactions. UV/vis spectra indicate that significant pi-electron delocalization existed in 1, 2, and 3.
Excessive concentrations of oxidized phospholipids (OxPL), the products of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphatidylcholine (PAPC) oxidation have been detected in atherosclerosis, septic inflammation, and ALI; and have been shown to induce vascular barrier dysfunction. In contrast, oxidized PAPC (OxPAPC) at low concentrations exhibit potent barrier protective effects. The nature of such biphasic effects remains unclear. We tested the hypothesis that barrier-disruptive effects of high OxPAPC doses on endothelial cell (EC) monolayer are defined by fragmented products of PAPC oxidation (lyso-PC, POVPC, PGPC), while barrier enhancing effects are mediated by full length oxidated PAPC products and may be reproduced by single compounds contained in the OxPAPC such as PEIPC. All three fragmented OxPAPC products increased EC permeability in a dose-dependent manner, while PEIPC decreased it and reversed barrier disruptive effects of lyso-PC, POVPC and PGPC monitored by measurements of transendothelial electrical resistance. Immunofluorescence staining and western blot analysis showed that PGPC mimicked the cytoskeletal remodeling and tyrosine phosphorylation of adherens junction (AJ) protein VE-cadherin leading to EC barrier dysfunction induced by high OxPAPC concentrations. Barrier-disruptive effects of PGPC were abrogated by ROS inhibitor, N-acetyl cysteine, or Src kinase inhibitor, PP-2. The results of this study show that barrier disruptive effects of fragmented OxPAPC constituents (lyso-PC, POVPC, PGPC) are balanced by barrier enhancing effects of full length oxygenated products (PEIPC). These data strongly suggest that barrier disruptive effects of OxPAPC at higher concentrations are dictated by predominant effects of fragmented phospholipids such as PGPC, which promote ROS-dependent activation of Src kinase and VE-cadherin phosphorylation at Tyr658 and Tyr731 leading to disruption of endothelial cell AJs.
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