Mitochondrial ROS cause motor deficits induced by synaptic inactivity:implications for synapse pruning

Developmental synapse pruning refines burgeoning connectomes. The basic mechanisms of mitochondrial reactive oxygen species (ROS) production suggest they select inactive synapses for pruning: whether they do so is unknown. To begin to unravel whether mitochondrial ROS regulate pruning, we made the local consequences of neuromuscular junction (NMJ) pruning detectable as motor deficits by using disparate exogenous and endogenous models to induce synaptic inactivity en masse in developing Xenopus laevis tadpoles. We resolved whether: (1) synaptic inactivity increases mitochondrial ROS; and (2) antioxidants rescue synaptic inactivity induced motor deficits. Regardless of whether it was achieved with muscle (α-bugarotoxin), nerve (α-latrotoxin) targeted neurotoxins or an endogenous pruning cue (SPARC), synaptic inactivity increased mitochondrial ROS in vivo. The manganese porphyrins MnTE-2-PyP5+ and/or MnTnBuOE-2-PyP5+ blocked mitochondrial ROS to significantly reduce neurotoxin and endogenous pruning cue induced motor deficits. Selectively inducing mitochondrial ROS—using mitochondria-targeted Paraquat (MitoPQ)—recapitulated synaptic inactivity induced motor deficits; which were significantly reduced by blocking mitochondrial ROS with MnTnBuOE-2-PyP5+. We unveil mitochondrial ROS as synaptic activity sentinels that regulate the phenotypical consequences of forced synaptic inactivity at the NMJ. Our novel results are relevant to pruning because synaptic inactivity is one of its defining features

Supraspinal inactivation of mitochondrial superoxide dismutase is a source of peroxynitrite in the development of morphine antinociceptive tolerance.

Effective treatment of chronic pain with morphine is limited by decreases in the drug’s analgesic action with chronic administration (antinociceptive tolerance). Because opioids are mainstays of pain management, restoring their efficacy has great clinical importance. We have recently reported that formation of peroxynitrite (ONOO(−), PN) in the dorsal horn of the spinal cord plays a critical role in the development of morphine antinociceptive tolerance and have further documented that nitration and enzymatic inactivation of mitochondrial superoxide dismutase (MnSOD) at that site provides a source for this nitroxidative species. We now report for the first time that antinociceptive tolerance is also associated with the inactivation of MnSOD at supraspinal sites. Inactivation of MnSOD led to nitroxidative stress as evidenced by increased levels of products of oxidative DNA damage and activation of the nuclear factor poly (ADP-ribose) polymerase in whole brain homogenates. Co-administration of morphine with potent Mn porphyrin-based peroxynitrite scavengers, (MnTE-2-PyP(5+) and MnTnHex-2-PyP(5+)) (1) restored the enzymatic activity of MnSOD, (2) attenuated PN derived nitroxidative stress, and (3) blocked the development of morphine induced antinociceptive tolerance. The more lipophilic analogue, MnTnHex-2-PyP(5+) was able to cross the blood brain barrier at higher levels than its lipophylic counterpart MnTE-2-PyP(5+) and was about 30 fold more efficacious. Collectively, these data suggest that peroxynitrite mediated enzymatic inactivation of supraspinal MnSOD provides a source of nitroxidative stress, which in turn contributes to central sensitization associated with the development of morphine antinociceptive tolerance. These results support our general contention that PN-targeted therapeutics may have potential as adjuncts to opiates in pain management

The η\eta-3N problem with separable interactions

The $\eta$-3N-interaction is studied within the four-body Faddeev-Yakubovsky theory adopting purely separable forms for the two- and three-body subamplitudes, limiting the basic two-body interactions to s-waves only. The corresponding separable approximation for the integral kernels is obtained by using the Hilbert-Schmidt procedure. Results are presented for the $\eta$-$^3$H scattering amplitude and for the total elastic cross section for energies below the triton break-up threshold.Comment: revised version accepted for Phys. Rev. C, 16 pages revtex including 6 eps-figures, formal part shortene

Intermediate mass excess of dilepton production in heavy ion collisions at BEVALAC energies

Dielectron mass spectra are examined for various nuclear reactions recently measured by the DLS collaboration. A detailed description is given of all dilepton channels included in the transport model UrQMD 1.0, i.e. Dalitz decays of $\pi^0,\eta,\omega,\eta'$ mesons and of the $\Delta(1232)$ resonance, direct decays of vector mesons and $pn$ bremsstrahlung. The microscopic calculations reproduce data for light systems fairly well, but tend to underestimate the data in $pp$ at high energies and in $pd$ at low energies. These conventional sources, however, cannot explain the recently reported enhancement for nucleus-nucleus collisions in the mass region 0.15 GeV<$M_{ee}$<0.6 GeV. Chiral scaling and $\omega$ meson broadening in the medium are investigated as a source of this mass excess. They also cannot explain the recent DLS data.Comment: 26 pages, 9 figures, references update

The nucleon-nucleon interaction

We review the major progress of the past decade concerning our understanding of the nucleon-nucleon interaction. The focus is on the low-energy region (below pion production threshold), but a brief outlook towards higher energies is also given. The items discussed include charge-dependence, the precise value of the $\pi NN$ coupling constant, phase shift analysis and high-precision NN data and potentials. We also address the issue of a proper theory of nuclear forces. Finally, we summarize the essential open questions that future research should be devoted to.Comment: 42 pages, 12 figures, iopart.cls style; Topical Review prepared for J. Phys. G: Nucl. Part. Phy

Redox Proteomic Identification of HNE-Bound Mitochondrial Proteins in Cardiac Tissues Reveals a Systemic Effect on Energy Metabolism After Doxorubicin Treatment

Doxorubicin (DOX), one of the most effective anticancer drugs, is known to generate progressive cardiac damage, which is due, in part, to DOX-induced reactive oxygen species (ROS). The elevated ROS often induce oxidative protein modifications that result in alteration of protein functions. This study demonstrates that the level of proteins adducted by 4-hydroxy-2-nonenal (HNE), a lipid peroxidation product, is significantly increased in mouse heart mitochondria after DOX treatment. A redox proteomics method involving two-dimensional electrophoresis followed by mass spectrometry and investigation of protein databases identified several HNE-modified mitochondrial proteins, which were verified by HNE-specific immunoprecipitation in cardiac mitochondria from the DOX-treated mice. The majority of the identified proteins are related to mitochondrial energy metabolism. These include proteins in the citric acid cycle and electron transport chain. The enzymatic activities of the HNE-adducted proteins were significantly reduced in DOX-treated mice. Consistent with the decline in the function of the HNE-adducted proteins, the respiratory function of cardiac mitochondria as determined by oxygen consumption rate was also significantly reduced after DOX treatment. Treatment with Mn(III) meso-tetrakis(N-n-butoxyethylpyridinium-2-yl)porphyrin, an SOD mimic, averted the doxorubicin-induced mitochondrial dysfunctions as well as the HNE–protein adductions. Together, the results demonstrate that free radical-mediated alteration of energy metabolism is an important mechanism mediating DOX-induced cardiac injury, suggesting that metabolic intervention may represent a novel approach to preventing cardiac injury after chemotherapy

Electromagnetic Meson Production in the Nucleon Resonance Region

Recent experimental and theoretical advances in investigating electromagnetic meson production reactions in the nucleon resonance region are reviewed.Comment: 75 pages, 42 figure

2-Hydroxyglutarate Production, but Not Dominant Negative Function, Is Conferred by Glioma-Derived NADP+-Dependent Isocitrate Dehydrogenase Mutations

Gliomas frequently contain mutations in the cytoplasmic NADP(+)-dependent isocitrate dehydrogenase (IDH1) or the mitochondrial NADP(+)-dependent isocitrate dehydrogenase (IDH2). Several different amino acid substitutions recur at either IDH1 R132 or IDH2 R172 in glioma patients. Genetic evidence indicates that these mutations share a common gain of function, but it is unclear whether the shared function is dominant negative activity, neomorphic production of (R)-2-hydroxyglutarate (2HG), or both.We show by coprecipitation that five cancer-derived IDH1 R132 mutants bind IDH1-WT but that three cancer-derived IDH2 R172 mutants exert minimal binding to IDH2-WT. None of the mutants dominant-negatively lower isocitrate dehydrogenase activity at physiological (40 µM) isocitrate concentrations in mammalian cell lysates. In contrast to this, all of these mutants confer 10- to 100-fold higher 2HG production to cells, and glioma tissues containing IDH1 R132 or IDH2 R172 mutations contain high levels of 2HG compared to glioma tissues without IDH mutations (54.4 vs. 0.1 mg 2HG/g protein).Binding to, or dominant inhibition of, WT IDH1 or IDH2 is not a shared feature of the IDH1 and IDH2 mutations, and thus is not likely to be important in cancer. The fact that the gain of the enzymatic activity to produce 2HG is a shared feature of the IDH1 and IDH2 mutations suggests that this is an important function for these mutants in driving cancer pathogenesis

P-wave excited baryons from pion- and photo-induced hyperon production

We report evidence for $N(1710)P_{11}$, $N(1875)P_{11}$, $N(1900)P_{13}$, $\Delta(1600)P_{33}$, $\Delta(1910)P_{31}$, and $\Delta(1920)P_{33}$, and find indications that $N(1900)P_{13}$ might have a companion state at 1970\,MeV. The controversial $\Delta(1750)P_{31}$ is not seen. The evidence is derived from a study of data on pion- and photo-induced hyperon production, but other data are included as well. Most of the resonances reported here were found in the Karlsruhe-Helsinki (KH84) and the Carnegie-Mellon (CM) analyses but were challenged recently by the Data Analysis Center at GWU. Our analysis is constrained by the energy independent $\pi N$ scattering amplitudes from either KH84 or GWU. The two $\pi N$ amplitudes from KH84 or GWU, respectively, lead to slightly different $\pi N$ branching ratios of contributing resonances but the debated resonances are required in both series of fits.Comment: 22 pages, 28 figures. Some additional sets of data are adde