Remnants from Gamma-Ray Bursts

We model the intermediate time evolution of a "jetted" gamma-ray burst by two blobs of matter colliding with the interstellar medium. We follow the hydrodynamical evolution of this system numerically and calculate the bremsstrahlung and synchrotron images of the remnant. We find that for a burst energy of $10^{51}$ erg the remnant becomes spherical after $\sim 5000$ years when it collects $\sim 50M_\odot$ of interstellar mass. This result is independent of the exact details of the GRB, such as the opening angle. After this time a gamma-ray burst remnant has an expanding sphere morphology. The similarity to a supernova remnant makes it difficult distinguish between the two at this stage. The expected number of non-spherical gamma-ray burst remnants is $\sim0.05$ per galaxy for a beaming factor of 0.01 and a burst energy of $10^{51}$ erg. Our results suggest that that the double-shell object DEM L 316 is not a GRB remnant.Comment: 16 pages, 9 figures, Substantial revisions, Accepted by Ap

New patient-oriented summary measure of net total gain in certainty for dichotomous diagnostic tests

OBJECTIVES: To introduce a new, patient-oriented predictive index as a measure of gain in certainty. STUDY DESIGN: Algebraic equations. RESULTS: A new measure is suggested based on error rates in a patient population. The new Predictive Summary Index (PSI) reflects the true total gain in certainty obtained by performing a diagnostic test based on knowledge of disease prevalence, i.e., the overall additional certainty. We show that the overall gain in certainty can be expressed in the form of the following expression: PSI = PPV+NPV-1. PSI is a more comprehensive measure than the post-test probability or the Youden Index (J). The reciprocal of J is interpreted as the number of persons with a given disease who need to be examined in order to detect correctly one person with the disease. The reciprocal of PSI is suggested as the number of persons who need to be examined in order to correctly predict a diagnosis of the disease. CONCLUSION: PSI provides more information than J and the predictive values, making it more appropriate in a clinical setting

Mechanism of Ivermectin Facilitation of Human P2X4 Receptor Channels

Ivermectin (IVM), a widely used antiparasitic agent in human and veterinary medicine, was recently shown to augment macroscopic currents through rat P2X4 receptor channels (Khakh, B.S., W.R. Proctor, T.V. Dunwiddie, C. Labarca, and H.A. Lester. 1999. J. Neurosci. 19:7289–7299.). In the present study, the effects of IVM on the human P2X4 (hP2X4) receptor channel stably transfected in HEK293 cells were investigated by recording membrane currents using the patch clamp technique. In whole-cell recordings, IVM (≤10 μM) applied from outside the cell (but not from inside) increased the maximum current activated by ATP, and slowed the rate of current deactivation. These two phenomena likely result from the binding of IVM to separate sites. A higher affinity site (EC50 0.25 μM) increased the maximal current activated by saturating concentrations of ATP without significantly changing the rate of current deactivation or the EC50 and Hill slope of the ATP concentration-response relationship. A lower affinity site (EC50 2 μM) slowed the rate of current deactivation, and increased the apparent affinity for ATP. In cell-attached patch recordings, P2X4 receptor channels exhibited complex kinetics, with multiple components in both the open and shut distributions. IVM (0.3 μM) increased the number of openings per burst, without significantly changing the mean open or mean shut time within a burst. At higher concentrations (1.5 μM) of IVM, two additional open time components of long duration were observed that gave rise to long-lasting bursts of channel activity. Together, the results suggest that the binding of IVM to the higher affinity site increases current amplitude by reducing channel desensitization, whereas the binding of IVM to the lower affinity site slows the deactivation of the current predominantly by stabilizing the open conformation of the channel

Distinct Axonemal Processes Underlie Spontaneous and Stimulated Airway Ciliary Activity

Cilia are small organelles protruding from the cell surface that beat synchronously, producing biological transport. Despite intense research for over a century, the mechanisms underlying ciliary beating are still not well understood. Even the nature of the cytosolic molecules required for spontaneous and stimulated beating is debatable. In an effort to resolve fundamental questions related to cilia beating, we developed a method that integrates the whole-cell mode of the patch-clamp technique with ciliary beat frequency measurements on a single cell. This method enables to control the composition of the intracellular solution while the cilia remain intact, thus providing a unique tool to simultaneously investigate the biochemical and physiological mechanism of ciliary beating. Thus far, we investigated whether the spontaneous and stimulated states of cilia beating are controlled by the same intracellular molecular mechanisms. It was found that: (a) MgATP was sufficient to support spontaneous beating. (b) Ca2+ alone or Ca2+-calmodulin at concentrations as high as 1 μM could not alter ciliary beating. (c) In the absence of Ca2+, cyclic nucleotides produced a moderate rise in ciliary beating while in the presence of Ca2+ robust enhancement was observed. These results suggest that the axonemal machinery can function in at least two different modes

Reversible surface aggregation in pore formation by pardaxin

The mechanism of leakage induced by surface active peptides is not yet fully understood. To gain insight into the molecular events underlying this process, the leakage induced by the peptide pardaxin from phosphatidylcholine/ phosphatidylserine/cholesterol large unilamellar vesicles was studied by monitoring the rate and extent of dye release and by theoretical modeling. The leakage occurred by an all-or-none mechanism: vesicles either leaked or retained all of their contents. We further developed a mathematical model that includes the assumption that certain peptides become incorporated into the vesicle bilayer and aggregate to form a pore. The current experimental results can be explained by the model only if the surface aggregation of the peptide is reversible. Considering this reversibility, the model can explain the final extents of calcein leakage for lipid/peptide ratios of > 2000:1 to 25:1 by assuming that only a fraction of the bound peptide forms pores consisting of M = 6 +/- 3 peptides. Interestingly, less leakage occurred at 43 degrees C, than at 30 degrees C, although peptide partitioning into the bilayer was enhanced upon elevation of the temperature. We deduced that the increased leakage at 30 degrees C was due to an increase in the extent of reversible surface aggregation at the lower temperature. Experiments employing fluorescein-labeled pardaxin demonstrated reversible aggregation of the peptide in suspension and within the membrane, and exchange of the peptide between liposomes. In summary, our experimental and theoretical results support reversible surface aggregation as the mechanism of pore formation by pardaxin