Bcl-xL-mediated remodeling of rod and cone synaptic mitochondria after postnatal lead exposure: electron microscopy, tomography and oxygen consumption.

PurposePostnatal lead exposure produces rod-selective and Bax-mediated apoptosis, decreased scotopic electroretinograms (ERGs), and scotopic and mesopic vision deficits in humans and/or experimental animals. Rod, but not cone, inner segment mitochondria were considered the primary site of action. However, photoreceptor synaptic mitochondria were not examined. Thus, our experiments investigated the structural and functional effects of environmentally relevant postnatal lead exposure on rod spherule and cone pedicle mitochondria and whether Bcl-xL overexpression provided neuroprotection.MethodsC57BL/6N mice pups were exposed to lead only during lactation via dams drinking water containing lead acetate. The blood [Pb] at weaning was 20.6±4.7 µg/dl, which decreased to the control value by 2 months. To assess synaptic mitochondrial structural differences and vulnerability to lead exposure, wild-type and transgenic mice overexpressing Bcl-xL in photoreceptors were used. Electron microscopy, three-dimensional electron tomography, and retinal and photoreceptor synaptic terminal oxygen consumption (QO(2)) studies were conducted in adult control, Bcl-xL, lead, and Bcl-xL/lead mice.ResultsThe spherule and pedicle mitochondria in lead-treated mice were swollen, and the cristae structure was markedly changed. In the lead-treated mice, the mitochondrial cristae surface area and volume (abundance: measure correlated with ATP (ATP) synthesis) were decreased in the spherules and increased in the pedicles. Pedicles also had an increased number of crista segments per volume. In the lead-treated mice, the number of segments/crista and fraction of cristae with multiple segments (branching) similarly increased in spherule and pedicle mitochondria. Lead-induced remodeling of spherule mitochondria produced smaller cristae with more branching, whereas pedicle mitochondria had larger cristae with more branching and increased crista junction (CJ) diameter. Lead decreased dark- and light-adapted photoreceptor and dark-adapted photoreceptor synaptic terminal QO(2). Bcl-xL partially blocked many of the lead-induced alterations relative to controls. However, spherules still had partially decreased abundance, whereas pedicles still had increased branching, increased crista segments per volume, and increased crista junction diameter. Moreover, photoreceptor and synaptic QO(2) were only partially recovered.ConclusionsThese findings reveal cellular and compartmental specific differences in the structure and vulnerability of rod and cone inner segment and synaptic mitochondria to postnatal lead exposure. Spherule and pedicle mitochondria in lead-exposed mice displayed complex and distinguishing patterns of cristae and matrix damage and remodeling consistent with studies showing that synaptic mitochondria are more sensitive to Ca(2+) overload, oxidative stress, and ATP loss than non-synaptic mitochondria. The lead-induced decreases in QO(2) likely resulted from the decreased spherule cristae abundance and smaller cristae, perhaps due to Bax-mediated effects as they occurred in apoptotic rod inner segments. The increase in pedicle cristae abundance and CJ diameter could have resulted from increased Drp1-mediated fission, as small mitochondrial fragments were observed. The mechanisms of Bcl-xL-mediated remodeling might occur via interaction with formation of CJ protein 1 (Fcj1), whereas the partial protection of synaptic QO(2) might result from the enhanced efficiency of energy metabolism via Bcl-xL's direct interaction with the F1F0 ATP synthase and/or regulation of cellular redox status. These lead-induced alterations in photoreceptor synaptic terminal mitochondria likely underlie the persistent scotopic and mesopic deficits in lead-exposed children, workers, and experimental animals. Our findings stress the clinical and scientific importance of examining synaptic dysfunction following injury or disease during development, and developing therapeutic treatments that prevent synaptic degeneration in retinal and neurodegenerative disorders even when apoptosis is blocked

Summary of Pressure Gain Combustion Research at NASA

NASA has undertaken a systematic exploration of many different facets of pressure gain combustion over the last 25 years in an effort to exploit the inherent thermodynamic advantage of pressure gain combustion over the constant pressure combustion process used in most aerospace propulsion systems. Applications as varied as small-scale UAV's, rotorcraft, subsonic transports, hypersonics and launch vehicles have been considered. In addition to studying pressure gain combustor concepts such as wave rotors, pulse detonation engines, pulsejets, and rotating detonation engines, NASA has studied inlets, nozzles, ejectors and turbines which must also process unsteady flow in an integrated propulsion system. Other design considerations such as acoustic signature, combustor material life and heat transfer that are unique to pressure gain combustors have also been addressed in NASA research projects. In addition to a wide range of experimental studies, a number of computer codes, from 0-D up through 3-D, have been developed or modified to specifically address the analysis of unsteady flow fields. Loss models have also been developed and incorporated into these codes that improve the accuracy of performance predictions and decrease computational time. These codes have been validated numerous times across a broad range of operating conditions, and it has been found that once validated for one particular pressure gain combustion configuration, these codes are readily adaptable to the others. All in all, the documentation of this work has encompassed approximately 170 NASA technical reports, conference papers and journal articles to date. These publications are very briefly summarized herein, providing a single point of reference for all of NASA's pressure gain combustion research efforts. This documentation does not include the significant contributions made by NASA research staff to the programs of other agencies, universities, industrial partners and professional society committees through serving as technical advisors, technical reviewers and research consultants

Perturbation Theory for Path Integrals of Stiff Polymers

The wormlike chain model of stiff polymers is a nonlinear $\sigma$-model in one spacetime dimension in which the ends are fluctuating freely. This causes important differences with respect to the presently available theory which exists only for periodic and Dirichlet boundary conditions. We modify this theory appropriately and show how to perform a systematic large-stiffness expansions for all physically interesting quantities in powers of $L/\xi$, where $L$ is the length and $\xi$ the persistence length of the polymer. This requires special procedures for regularizing highly divergent Feynman integrals which we have developed in previous work. We show that by adding to the unperturbed action a correction term ${\cal A}^{\rm corr}$, we can calculate all Feynman diagrams with Green functions satisfying Neumann boundary conditions. Our expansions yield, order by order, properly normalized end-to-end distribution function in arbitrary dimensions $d$, its even and odd moments, and the two-point correlation function

Optical Absorption of CuO3_3 antiferromagnetic chains at finite temperatures

We use a high-statistic quantum Monte Carlo and Maximum Entropy regularization method to compute the dynamical energy correlation function (DECF) of the one-dimensional (1D) $S=1/2$ antiferromagnetic Heisenberg model at finite temperatures. We also present a finite temperature analytical ansatz for the DECF which is in very good agreement with the numerical data in all the considered temperature range. From these results, and from a finite temperature generalisation of the mechanism proposed by Lorenzana and Sawatsky [Phys. Rev. Lett. {\bf 74}, 1867 (1995)], we compute the line shape for the optical absorption spectra of multimagnon excitations assisted by phonons for quasi 1D compounds. The line shape has two contributions analogous to the Stokes and anti-Stokes process of Raman scattering. Our low temperature data is in good agreement with optical absorption experiments of CuO$_3$ chains in Sr$_2$CuO$_3$. Our finite temperature results provide a non trivial prediction on the dynamics of the Heisenberg model at finite temperatures that is easy to verify experimentally.Comment: 7 pages, 5 figure

An R^4 non-renormalisation theorem in N=4 supergravity

We consider the four-graviton amplitudes in CHL constructions providing four-dimensional N=4 models with various numbers of vector multiplets. We show that in these models the two-loop amplitude has a prefactor of d^2R^4. This implies a non-renormalisation theorem for the R^4 term, which forbids the appearance of a three-loop ultraviolet divergence in four dimensions in the four-graviton amplitude. We connect the special nature of the R^4 term to the U(1) anomaly of pure N=4 supergravity.Comment: v2: added comments about one-loop UV divergences. Assorted stylistic corrections. Added references. v3: Eq. III.21 corrected and assorted minor corrections and clarifications. Version to be published. v4: minor corrections. 18 pages. one figur

Pion-Muon Asymmetry Revisited

Long ago an unexpected and unexplainable phenomena was observed. The distribution of muons from positive pion decay at rest was anisotropic with an excess in the backward direction relative to the direction of the proton beam from which the pions were created. Although this effect was observed by several different groups with pions produced by different means, the result was not accepted by the physics community, because it is in direct conflict with a large set of other experiments indicating that the pion is a pseudoscalar particle. It is possible to satisfy both sets of experiments if helicity-zero vector particles exist and the pion is such a particle. Helicity-zero vector particles have direction but no net spin. For the neutral pion to be a vector particle requires an additional modification to conventional theory as discussed herein. An experiment is proposed which can prove that the asymmetry in the distribution of muons from pion decay is a genuine physical effect because the asymmetry can be modified in a controllable manner. A positive result will also prove that the pion is NOT a pseudoscalar particle.Comment: 9 pages, 3 figure