Impaired osteoblast differentiation in annexin A2- and -A5-deficient cells.

Annexins are a class of calcium-binding proteins with diverse functions in the regulation of lipid rafts, inflammation, fibrinolysis, transcriptional programming and ion transport. Within bone, they are well-characterized as components of mineralizing matrix vesicles, although little else is known as to their function during osteogenesis. We employed shRNA to generate annexin A2 (AnxA2)- or annexin A5 (AnxA5)-knockdown pre-osteoblasts, and determined whether proliferation or osteogenic differentiation was altered in knockdown cells, compared to pSiren (Si) controls. We report that DNA content, a marker of proliferation, was significantly reduced in both AnxA2 and AnxA5 knockdown cells. Alkaline phosphatase expression and activity were also suppressed in AnxA2- or AnxA5-knockdown after 14 days of culture. The pattern of osteogenic gene expression was altered in knockdown cells, with Col1a1 expressed more rapidly in knock-down cells, compared to pSiren. In contrast, Runx2, Ibsp, and Bglap all revealed decreased expression after 14 days of culture. In both AnxA2- and AnxA5-knockdown, interleukin-induced STAT6 signaling was markedly attenuated compared to pSiren controls. These data suggest that AnxA2 and AnxA5 can influence bone formation via regulation of osteoprogenitor proliferation, differentiation, and responsiveness to cytokines in addition to their well-studied function in matrix vesicles

Brain stimulation treatments in epilepsy: Basic mechanisms and clinical advances

Drug-resistant epilepsy, characterized by ongoing seizures despite appropriate trials of anti-seizure medications, affects approximately one-third of people with epilepsy. Brain stimulation has recently become available as an alternative treatment option to reduce symptomatic seizures in short and long-term follow-up studies. Several questions remain on how to optimally develop patient-specific treatments and manage therapy over the long term. This review aims to discuss the clinical use and mechanisms of action of Responsive Neural Stimulation and Deep Brain Stimulation in the treatment of epilepsy and highlight recent advances that may both improve outcomes and present new challenges. Finally, a rational approach to device selection is presented based on current mechanistic understanding, clinical evidence, and device features

Update on results of SPRE testing at NASA Lewis

The Space Power Research Engine (SPRE), a free-piston Stirling engine with a linear alternator, is being tested at NASA Lewis Research Center as part of the Civilian Space Technology Initiative (CSTI) as a candidate for high capacity space power. Results are presented from recent SPRE tests designed to investigated the effects of variation in the displacer seal clearance and piston centering port area on engine performance and dynamics. The impact of these variations on PV power and efficiency are presented. Comparisons of the displacer seal clearance tests results with HFAST code predictions show good agreement for PV power, but show poor agreement for PV efficiency. Correlations are presented relating the piston midstroke position to the dynamic Delta P across the piston and the centering port area. Test results indicate that a modest improvement in PV power and efficiency may be realized with a reduction in piston centering port area

Vaginal Microbicides: Detecting Toxicities in Vivo that Paradoxically Increase Pathogen Transmission

BACKGROUND: Microbicides must protect against STD pathogens without causing unacceptable toxic effects. Microbicides based on nonoxynol-9 (N9) and other detergents disrupt sperm, HSV and HIV membranes, and these agents are effective contraceptives. But paradoxically N9 fails to protect women against HIV and other STD pathogens, most likely because it causes toxic effects that increase susceptibility. The mouse HSV-2 vaginal transmission model reported here: (a) Directly tests for toxic effects that increase susceptibility to HSV-2, (b) Determines in vivo whether a microbicide can protect against HSV-2 transmission without causing toxicities that increase susceptibility, and (c) Identifies those toxic effects that best correlate with the increased HSV susceptibility. METHODS: Susceptibility was evaluated in progestin-treated mice by delivering a low-dose viral inoculum (0.1 ID50) at various times after delivering the candidate microbicide to detect whether the candidate increased the fraction of mice infected. Ten agents were tested – five detergents: nonionic (N9), cationic (benzalkonium chloride, BZK), anionic (sodium dodecylsulfate, SDS), the pair of detergents in C31G (C14AO and C16B); one surface active agent (chlorhexidine); two non-detergents (BufferGel®, and sulfonated polystyrene, SPS); and HEC placebo gel (hydroxyethylcellulose). Toxic effects were evaluated by histology, uptake of a 'dead cell' dye, colposcopy, enumeration of vaginal macrophages, and measurement of inflammatory cytokines. RESULTS: A single dose of N9 protected against HSV-2 for a few minutes but then rapidly increased susceptibility, which reached maximum at 12 hours. When applied at the minimal concentration needed for brief partial protection, all five detergents caused a subsequent increase in susceptibility at 12 hours of ~20–30-fold. Surprisingly, colposcopy failed to detect visible sign of the N9 toxic effect that increased susceptibility at 12 hours. Toxic effects that occurred contemporaneously with increased susceptibility were rapid exfoliation and re-growth of epithelial cell layers, entry of macrophages into the vaginal lumen, and release of one or more inflammatory cytokines (Il-1β, KC, MIP 1α, RANTES). The non-detergent microbicides and HEC placebo caused no significant increase in susceptibility or toxic effects. CONCLUSION: This mouse HSV-2 model provides a sensitive method to detect microbicide-induced toxicities that increase susceptibility to infection. In this model, there was no concentration at which detergents provided protection without significantly increasing susceptibility.JHU Woodrow Wilson Fellowship; National Institutes of Health (Program Project A1 45967

Motion and Heating During Atmosphere Reentry of Space Vehicles

The results of an analysis of the motion and heating during atmospheric reentry of manned space vehicles has shown the following: 1. Flight-corridor depths which allow reentry in a single pass decrease rapidly as the reentry speed increases if the maximum deceleration is limited to 10 g. 2. Use of aerodynamic lift can result in a three-to five fold increase in corridor depth over that available to a ballistic vehicle for the same deceleration limits. 3. Use of aerodynamic lift to widen these reentry corridors causes a heating penalty which becomes severe for values of the lift-drag ratio greater than unity for constant lift-drag entry. 4. In the region of most intense convective heating the inviscid flow is generally in chemical equilibrium but the boundary-layer flows are out of equilibrium. Heating rates for the nonequilibrium boundary layer are generally lower than for the corresponding equilibrium case. 5. Radiative heating from the hot gas trapped between the shock wave and the body stagnation region may be as severe as the convective heating and unfortunately occurs at approximately the same time in the flight

Additional experiments with flat-top wing-body combinations at high supersonic speeds

Flat top wing body configuration effects on aerodynamic characteristics of supersonic aircraf