Dietary cholesterol promotes repair of demyelinated lesions in the adult brain

Multiple Sclerosis (MS) is an inflammatory demyelinating disorder in which remyelination failure contributes to persistent disability. Cholesterol is rate-limiting for myelin biogenesis in the developing CNS; however, whether cholesterol insufficiency contributes to remyelination failure in MS, is unclear. Here, we show the relationship between cholesterol, myelination and neurological parameters in mouse models of demyelination and remyelination. In the cuprizone model, acute disease reduces serum cholesterol levels that can be restored by dietary cholesterol. Concomitant with blood-brain barrier impairment, supplemented cholesterol directly supports oligodendrocyte precursor proliferation and differentiation, and restores the balance of growth factors, creating a permissive environment for repair. This leads to attenuated axon damage, enhanced remyelination and improved motor learning. Remarkably, in experimental autoimmune encephalomyelitis, cholesterol supplementation does not exacerbate disease expression. These findings emphasize the safety of dietary cholesterol in inflammatory diseases and point to a previously unrecognized role of cholesterol in promoting repair after demyelinating episodes

Physiological and pathophysiological homeostasis of astroglial channel proteins by Nedd4-2

Nedd4-2 is an E3 ubiquitin ligase, missense mutation of which is related to familial epilepsy, indicating its critical role in regulating neuronal network activity. However, Nedd4-2 substrates involved in neuronal network function have yet to be identified. Using mouse lines lacking Nedd4-1 and Nedd4-2, we identified astrocytic channel proteins inwardly rectifying K+ channel 4.1 (Kir4.1) and Connexin43 as Nedd4-2 substrates. We found that the expression of Kir4.1 and Connexin43 is increased upon conditional deletion of Nedd4-2 in astrocytes, leading to an elevation of astrocytic membrane ion permeability and gap junction activity, with a consequent reduction of γ-oscillatory neuronal network activity. Interestingly, our biochemical data demonstrate that missense mutations found in familial epileptic patients produce gain-of-function of Nedd4-2 gene product. Our data reveal a process of coordinated astrocytic ion channel proteostasis that controls astrocyte function and astrocyte-dependent neuronal network activity, and elucidate a potential mechanism by which aberrant Nedd4-2 function leads to epilepsy

Anesthesia triggers drug delivery to experimental glioma in mice by hijacking caveolar transport

Abstract Background: Pharmaceutical intervention in the CNS is hampered by the shielding function of the blood-brain barrier (BBB). To induce clinical anesthesia, general anesthetics such as isoflurane readily penetrate the BBB. Here, we investigated whether isoflurane can be utilized for therapeutic drug delivery. Methods: Barrier function in primary endothelial cells was evaluated by transepithelial/transendothelial electrical resistance, and nanoscale STED and SRRF microscopy. In mice, BBB permeability was quantified by extravasation of several fluorescent tracers. Mouse models including the GL261 glioma model were evaluated by MRI, immunohistochemistry, electron microscopy, western blot, and expression analysis. Results: Isoflurane enhances BBB permeability in a time- and concentration-dependent manner. We demonstrate that, mechanistically, isoflurane disturbs the organization of membrane lipid nanodomains and triggers caveolar transport in brain endothelial cells. BBB tightness re-establishes directly after termination of anesthesia, providing a defined window for drug delivery. In a therapeutic glioblastoma trial in mice, simultaneous exposure to isoflurane and cytotoxic agent improves efficacy of chemotherapy. Conclusions: Combination therapy, involving isoflurane-mediated BBB permeation with drug administration has far-reaching therapeutic implications for CNS malignancies

Aerodynamic testing in a free-flight spark range /

"Final report for the period June 1990-March 1997.""62602F-2502-67-03.""April 1997."Includes bibliographical references.Mode of access: Internet

Effects of wall cooling and leading-edge blunting on ramp-induced, laminar flow separations at Mach numbers from 3 through 6 /

The effects of wall cooling and nose bluntness on laminar and transitional reattaching flows induced by a 9.5-degree ramp were investigated at Mach numbers from 3 through 6 measuring the longitudinal surface pressure and heat-transfer rate distributions, as well as the flow-field pressures, at several longitudinal stations. Reynolds number based on flat-plate length was varied from 0.25 to 1.0 million. The trend in the change in interaction length with Reynolds number increase indicated laminar reattachment at all test Reynolds numbers at M = 6 and transitional at the two higher Reynolds numbers at M = 3.Report was prepared by ARO, Inc., a subsidiary of Sverdrup & Parcel and Associates, Inc."Final ReportNovember 30, 1970, to April 16, 1971.""March 1972."Includes bibliographic references (page 83).The effects of wall cooling and nose bluntness on laminar and transitional reattaching flows induced by a 9.5-degree ramp were investigated at Mach numbers from 3 through 6 measuring the longitudinal surface pressure and heat-transfer rate distributions, as well as the flow-field pressures, at several longitudinal stations. Reynolds number based on flat-plate length was varied from 0.25 to 1.0 million. The trend in the change in interaction length with Reynolds number increase indicated laminar reattachment at all test Reynolds numbers at M = 6 and transitional at the two higher Reynolds numbers at M = 3.Mode of access: Internet

Computation and evaluation of dynamic derivatives using CFD

This paper focuses on the computation of dynamic derivatives for full aircraft configurations. The flow is modelled using the Euler and RANS equations and an unsteady time-domain solver is used for the computation of aerodynamic loads for forced periodic motions. The study investigates the variation of damping values through the transonic regime and for several permutations of motion parameters for the Standard Dynamics Model geometry. A benchmark against experimental data is presented for the Transonic CRuiser wind tunnel geometry. For the SDM, strake vortices and their breakdown are observed when increasing the mean angle of attack during the applied pitch sinusoidal motion. A good agreement is obtained with available experimental data. For the TCR, a validation of longitudinal aerodynamic characteristics is first considered. Numerical experiments for the estimation of damping derivatives and for large amplitude forced oscillations in pitch axis are compared to wind tunnel data. Simulations are in agreement with experimental data up to high angles of attack