Functional Analysis of the Neurofibromatosis Type 2 Protein by Means of Disease-Causing Point Mutations

Despite intense study of the neurofibromatosis type 2 (NF2) tumor-suppressor protein merlin, the biological properties and tumor-suppressor functions of merlin are still largely unknown. In this study, we examined the molecular activities of NF2-causing mutant merlin proteins in transfected mammalian cells, to elucidate the merlin properties that are critical for tumor-suppressor function. Most important, we found that 80% of the merlin mutants studied significantly altered cell adhesion, causing cells to detach from the substratum. This finding implies a function for merlin in regulating cell-matrix attachment, and changes in cell adhesion caused by mutant protein expression may be an initial step in the pathogenesis of NF2. In addition, five different mutations in merlin caused a significant increase in detergent solubility of merlin compared to wild type, indicating a decreased ability to interact with the cytoskeleton. Although not correlated to the cell-adhesion phenotype, four missense mutations decreased the binding of merlin to the ERM-interacting protein EBP-50, implicating this interaction in merlin inhibition of cell growth. Last, we found that some NF2 point mutations in merlin most closely resembled gain-of-function alleles in their cellular phenotype, which suggests that mutant NF2 alleles may not always act in a loss-of-function manner, as had been assumed, but may include a spectrum of allelic types with different phenotypic effects on the function of the protein. In aggregate, these cellular phenotypes provide a useful assay for identifying the functional domains and molecular partners necessary for merlin tumor-suppressor activity

Molecular Carbon Chains and Rings in TMC-1

We present mapping results in several rotational transitions of HC3N, C6H, both cyclic and linear C3H2 and C3H, towards the cyanopolyyne peak of the filamentary dense cloud TMC-1 using the IRAM 30m and MPIfR 100m telescopes. The spatial distribution of the cumulene carbon chain propadienylidene H2C3 (hereafter l-C3H2) is found to deviate significantly from the distributions of the cyclic isomer c-C3H2, HC3N, and C6H which in turn look very similar. The cyclic over linear abundance ratio of C3H2 increases by a factor of 3 across the filament, with a value of 28 at the cyanopolyyne peak. This abundance ratio is an order of magnitude larger than the range (3 to 5) we observed in the diffuse interstellar medium. The cyclic over linear abundance ratio of C3H also varies by ~2.5 in TMC-1, reaching a maximum value (13) close to the cyanopolyyne peak. These behaviors might be related to competitive processes between ion-neutral and neutral-neutral reactions for cyclic and linear species.Comment: Accepted for publication in The Astrophysical Journal, part I. 24 pages, including 4 tables, 7 figures, and figure caption

Quantum Stabilization of General-Relativistic Variable-Density Degenerate Stars

Research by one of the authors suggested that the critical mass of constant-density neutron stars will be greater than eight solar masses when the majority of their neutrons group into bosons that form a Bose-Einstein condensate, provided the bosons interact with each other and have scattering lengths on the order of a picometer. That analysis was able to use Newtonian theory for the condensate with scattering lengths on this order, but general relativity provides a more fundamental analysis. In this paper, we determine the equilibrium states of a static, spherically-symmetric variable-density mixture of a degenerate gas of noninteracting neutrons and a Bose-Einstein condensate using general relativity. We use a Klein-Gordan Lagrangian density with a Gross-Pitaevskii term for the condensate and an effective field for the neutrons. We show that a new class of compact stars can exist with masses above the Oppenheimer-Volkoff limit, provided the scattering length of the bosons is large enough. These stars have no internal singularities, obey causality, and demonstrate a quantum mechanism consistent with general relativity that could prevent collapsed stars from becoming black holes

A Model For the Formation of High Density Clumps in Proto-Planetary Nebulae

The detection of NaCl at large radii in the Egg Nebula, CRL 2688, requires densities of 10^7 - 10^8 cm^-3 in a thick shell of r ~ a few X 10^17 cm. To explain these results, a mechanism is needed for producing high densities at a considerable distance from the central star. In two dimensional simulations of the interaction of the fast wind with an ambient medium, the material becomes thermally unstable. The resulting clumps can achieve the requisite conditions for NaCl excitation. We present 2D models with simple physics as proof-of-principle calculations to show that the clumping behavior is robust. Clumping is a natural outcome of cooling in the colliding wind model and comparable to that inferred from observations.Comment: 12 pages, 3 figures. Accepted for publication in the Astrophysical Journal Letter

Comparison of Dynamics Stability Testing Techniques with Magnetic Suspension Wind Tunnel Capabilities

Dynamic stability testing techniques currently utilized at NASA Langley Research Center (LaRC) are conducted in multiple facilities and consists of free flight, forced oscillation, and free-to-oscillate tests. The NASA/ODU Magnetic Suspension and Balance System (MSBS) has been recommissioned to explore its utility as an additional facility to expand the dynamic stability test capabilities currently available at NASA LaRC. Simulations were created to replicate each current test facility and method as closely as possible. Data collected from the simulated environments was corrupted with replicated noise sources of the different testing environments and then compared to real data collected during tests when such data was available. The corrupted data was then passed through data reduction and System Identification (SID) to estimate the accuracy of the results with the known aerodynamic model that was utilized within the simulation to generate the original data. Magnitudes of noise were varied utilizing Monte Carlo analysis to perform sensitivity analysis of each noise source on the extracted dynamic stability coefficients. Some preliminary results will be presented

Hydroxyl radical is produced via the Fenton reaction in submitochondrial particles under oxidative stress: implications for diseases associated with iron accumulation

Mitochondrial dysfunction and reactive oxygen species (ROS) are often implicated in diseases involving oxidative stress and elevated iron. As mitochondria produce ATP by oxidative phosphorylation, ROS by-products are generated from the electron transport chain. Although superoxide and hydrogen peroxide have been thoroughly investigated, little evidence documents hydroxyl radical (HO•) production in mitochondria. In order to determine whether HO• is generated under oxidative stress conditions by a Fenton-type mechanism, bovine heart submitochondrial particles were examined for HO• in the presence and absence of iron ligands, antioxidant enzymes and HO• scavengers. HO• was measured as 2,3- and 2,5-dihydroxybenzoic acid (DHBA), using HPLC with electrochemical detection. The iron ligand desferrioxamine significantly decreased DHBAs, indicating that HO• generation required iron redox-cycling. In addition, results from exogenous SOD and catalase, exogenous hydrogen peroxide, and HO•-scavenger studies support a Fenton-type reaction mechanism. The results indicate that increased HO• levels occur in mitochondria under oxidative stress and that the HO• levels can be modulated with antioxidant enzymes and iron ligands. Our findings together with reports on iron accumulation in degenerative diseases highlight the importance of developing mitochondrial-targeted antioxidants for the therapeutic intervention of diseases associated with mitochondrial dysfunction and oxidative stress

Kinematics of Molecular Hydrogen Emission from Pre-planetary Nebulae: RAFGL 2688 and RAFGL 618

We present high spectral resolution maps of near-infrared molecular hydrogen emission from the bipolar pre-planetary nebulae RAFGL 2688 and RAFGL 618, obtained with the NOAO Phoenix spectrometer. The measured velocity gradients along the polar axes of both nebulae indicate that the highest velocity gas lies closest to the central stars. These results support the suggestion that the polar H_2 emission regions of both nebulae contain shocked gas formed as fast (~50-150 km/s), collimated, post-asymptotic giant branch (AGB) winds collide with slower-moving (~10-20 km/s) material previously ejected while the central stars were still on the AGB. The kinematics of H_2 emission perpendicular to the polar axis of RAFGL 2688 are consistent with a model combining expansion along the equator at 5-10 km/s with rotation about the polar axis at 5-10 km/s. The rapid onset of the common envelope phase of a close binary system may explain both the bipolar structure of RAFGL 2688 and the presence and complex kinematics of its shocked H_2 emission.Comment: 21 pages, 8 figures; to be published in the Astrophysical Journal (Jan. 1, 2001 issue

Long term (5 Year) safety of bronchial thermoplasty: Asthma Intervention Research (AIR) trial

<b>Background:</b> Bronchial thermoplasty (BT) is a bronchoscopic procedure that improves asthma control by reducing excess airway smooth muscle. Treated patients have been followed out to 5 years to evaluate long-term safety of this procedure. <br></br> <br></br> <b>Methods:</b> Patients enrolled in the Asthma Intervention Research Trial were on inhaled corticosteroids ≥200 μg beclomethasone or equivalent + long-acting-beta2-agonists and demonstrated worsening of asthma on long-acting-β2-agonist withdrawal. Following initial evaluation at 1 year, subjects were invited to participate in a 4 year safety study. Adverse events (AEs) and spirometry data were used to assess long-term safety out to 5 years post-BT. <br></br> <br></br> <b>Results:</b> 45 of 52 treated and 24 of 49 control group subjects participated in long-term follow-up of 5 years and 3 years respectively. The rate of respiratory adverse events (AEs/subject) was stable in years 2 to 5 following BT (1.2, 1.3, 1.2, and 1.1, respectively,). There was no increase in hospitalizations or emergency room visits for respiratory symptoms in Years 2, 3, 4, and 5 compared to Year 1. The FVC and FEV1 values showed no deterioration over the 5 year period in the BT group. Similar results were obtained for the Control group. <br></br><br></br> <b>Conclusions:</b> The absence of clinical complications (based on AE reporting) and the maintenance of stable lung function (no deterioration of FVC and FEV1) over a 5-year period post-BT in this group of patients with moderate to severe asthma support the long-term safety of the procedure out to 5 years

Managed delay for coronary artery bypass graft surgery: The experience at one Canadian center

AbstractObjectives. This study sought to assess the impact of delaying coronary artery bypass surgery at one Canadian academic tertiary referral center.Background. Universal access to medical services in Canada comes at the expense of waiting lists whose impact has been incompletely assessed.Methods. A prospective, observational study of all residents of Nova Scotia and Prince Edward Island accepted for bypass surgery between 1 April 1992 and 31 October 1992 was undertaken to determine 1) whether triage guidelines were being followed; and 2) the incidence of cardiac death, nonfatal myocardial infarction and worsening symptoms associated with delayed operation. The analysis had 90% power to detect a mortality rate of ≥3% (alpha 0.05).Results. Of 423 patients referred, 35% were triaged as urgent, 9.7% as semiurgent A, 39% as semiurgent B and 16.3% as elective, with no age or gender bias identified. Operation occurred at ≤1 week in 25%, ≤1 month in 47%, and >6 months in 1.4%. There were no nonfatal myocardial infarctions, but five cardiac deaths occurred (1.2%). Of 275 patients not initially classified as urgent, 12.4% required reclassification to higher priorities because of worsening symptoms: none had perioperative myocardial infarction or died. One in four patients queued longer than target waiting times. Only 4% of patients considered prioritization on the basis of medical need unfair, but 64% experienced at least moderate anxiety.Conclusions. This triage system equitably stratified patients to a queue. Deaths were rare and could not be attributed to the triage process. Patients with worsening clinical status were safely accommodated with earlier waiting times, but concerns remain regarding excessive waiting times and patient anxiety

Analysis of Control Strategies for Aircraft Flight Upset Recovery

This paper proposes a framework for studying the ability of a control strategy, consisting of a control law and a command law, to recover an aircraft from ight conditions that may extend beyond the normal ight envelope. This study was carried out (i) by evaluating time responses of particular ight upsets, (ii) by evaluating local stability over an equilibrium manifold that included stall, and (iii) by bounding the set in the state space from where the vehicle can be safely own to wings-level ight. These states comprise what will be called the safely recoverable ight envelope (SRFE), which is a set containing the aircraft states from where a control strategy can safely stabilize the aircraft. By safe recovery it is implied that the tran- sient response stays between prescribed limits before converging to a steady horizontal ight. The calculation of the SRFE bounds yields the worst-case initial state corresponding to each control strategy. This information is used to compare alternative recovery strategies, determine their strengths and limitations, and identify the most e ective strategy. In regard to the control law, the authors developed feedback feedforward laws based on the gain scheduling of multivariable controllers. In regard to the command law, which is the mechanism governing the exogenous signals driving the feed- forward component of the controller, we developed laws with a feedback structure that combines local stability and transient response considera- tions. The upset recovery of the Generic Transport Model, a sub-scale twin-engine jet vehicle developed by NASA Langley Research Center, is used as a case study