Acute neuroinflammation induces AIS structural plasticity in a NOX2-dependent manner

Background Chronic microglia-mediated inflammation and oxidative stress are well-characterized underlying factors in neurodegenerative disease, whereby reactive inflammatory microglia enhance ROS production and impact neuronal integrity. Recently, it has been shown that during chronic inflammation, neuronal integrity is compromised through targeted disruption of the axon initial segment (AIS), the axonal domain critical for action potential initiation. AIS disruption was associated with contact by reactive inflammatory microglia which wrap around the AIS, increasing association with disease progression. While it is clear that chronic microglial inflammation and enhanced ROS production impact neuronal integrity, little is known about how acute microglial inflammation influences AIS stability. Here, we demonstrate that acute neuroinflammation induces AIS structural plasticity in a ROS-mediated and calpain-dependent manner. Methods C57BL/6J and NOX2−/− mice were given a single injection of lipopolysaccharide (LPS; 5 mg/kg) or vehicle (0.9% saline, 10 mL/kg) and analyzed at 6 h–2 weeks post-injection. Anti-inflammatory Didox (250 mg/kg) or vehicle (0.9% saline, 10 mL/kg) was administered beginning 24 h post-LPS injection and continued for 5 days; animals were analyzed 1 week post-injection. Microglial inflammation was assessed using immunohistochemistry (IHC) and RT-qPCR, and AIS integrity was quantitatively analyzed using ankyrinG immunolabeling. Data were statistically compared by one-way or two-way ANOVA where mean differences were significant as assessed using Tukey’s post hoc analysis. Results LPS-induced neuroinflammation, characterized by enhanced microglial inflammation and increased expression of ROS-producing enzymes, altered AIS protein clustering. Importantly, inflammation-induced AIS changes were reversed following resolution of microglial inflammation. Modulation of the inflammatory response using anti-inflammatory Didox, even after significant AIS disruption occurred, increased the rate of AIS recovery. qPCR and IHC analysis revealed that expression of microglial NOX2, a ROS-producing enzyme, was significantly increased correlating with AIS disruption. Furthermore, ablation of NOX2 prevented inflammation-induced AIS plasticity, suggesting that ROS drive AIS structural plasticity. Conclusions In the presence of acute microglial inflammation, the AIS undergoes an adaptive change that is capable of spontaneous recovery. Moreover, recovery can be therapeutically accelerated. Together, these findings underscore the dynamic capabilities of this domain in the presence of a pathological insult and provide evidence that the AIS is a viable therapeutic target

The effect of vacuum polarisation on muon-proton scattering at small energies and angles

We give a compact expression for the unpolarised differential cross section for muon-proton scattering in the one photon exchange approximation. The effect of adding the vacuum polarisation amplitude to the no-spin-flip amplitude for one photon exchange is calculated at small energies and scattering angles and is found to be negligible for present experiments.Comment: 6 pages, one figur

COMPTEL solar flare observations

COMPTEL as part of a solar target of opportunity campaign observed the sun during the period of high solar activity from 7-15 Jun. 1991. Major flares were observed on 9 and 11 Jun. Although both flares were large GOES events (greater than or = X10), they were not extraordinary in terms of gamma-ray emission. Only the decay phase of the 15 Jun. flare was observed by COMPTEL. We report the preliminary analysis of data from these flares, including the first spectroscopic measurement of solar flare neutrons. The deuterium formation line at 2.223 MeV was present in both events and for at least the 9 Jun. event, was comparable to the flux in the nuclear line region of 4-8 MeV, consistent with Solar-Maximum Mission (SSM) Observations. A clear neutron signal was present in the flare of 9 Jun. with the spectrum extending up to 80 MeV and consistent in time with the emission of gamma-rays, confirming the utility of COMPTEL in measuring the solar neutron flux at low energies. The neutron flux below 100 MeV appears to be lower than that of the 3 Jun. 1982 flare by more than an order of magnitude. The neutron signal of the 11 Jun. event is under study. Severe dead time effects resulting from the intense thermal x-rays require significant corrections to the measured flux which increase the magnitude of the associated systematic uncertainties

Transplantation of Ciliary Neurotrophic Factor-Expressing Adult Oligodendrocyte Precursor Cells Promotes Remyelination and Functional Recovery after SpinalCord Injury

Demyelination contributes to the dysfunction after traumatic spinal cord injury (SCI). We explored whether the combination of neurotrophic factors and transplantation of adult rat spinal cord oligodendrocyte precursor cells (OPCs) could enhance remyelination and functional recovery after SCI. Ciliary neurotrophic factor (CNTF) was the most effective neurotrophic factor to promote oligodendrocyte (OL) differentiation and survival of OPCs in vitro. OPCs were infected with retroviruses expressing enhanced green fluorescent protein (EGFP) or CNTF and transplanted into the contused adult thoracic spinal cord 9 d after injury. Seven weeks after transplantation, the grafted OPCs survived and integrated into the injured spinal cord. The survival of grafted CNTF-OPCs increased fourfold compared with EGFP-OPCs. The grafted OPCs differentiated into adenomatus polyposis coli (APC+) OLs, and CNTF significantly increased the percentage of APC+ OLs from grafted OPCs. Immunofluorescent and immunoelectron microscopic analyses showed that the grafted OPCs formed central myelin sheaths around the axons in the injured spinal cord. The number of OL-remyelinated axons in ventrolateral funiculus (VLF) or lateral funiculus (LF) at the injured epicenter was significantly increased in animals that received CNTF-OPC grafts compared with all other groups. Importantly, 75% of rats receiving CNTF-OPC grafts recovered transcranial magnetic motor-evoked potential and magnetic interenlargement reflex responses, indicating that conduction through the demyelinated axons in VLF or LF, respectively, was partially restored. More importantly, recovery of hindlimb locomotor function was significantly enhanced in animals receiving grafts of CNTF-OPCs. Thus, combined treatment with OPC grafts expressing CNTF can enhance remyelination and facilitate functional recovery after traumatic SCI

Social influences on microglial reactivity and neuronal damage after cardiac arrest/cardiopulmonary resuscitation

Social isolation presents a risk factor and worsens outcome to cerebrovascular diseases; however, the underlying mechanisms remain underspecified. This study examines the effect of social environment on microglial reactivity after global cerebral ischemia, to test the hypothesis that social isolation leads to greater microglial responses. Adult female and male mice were pair-housed or socially isolated for one week prior to cardiac arrest/cardiopulmonary resuscitation (CA/CPR) or the sham procedure, and following either 2 or 24 hours of reperfusion, microglia samples were enriched and analyzed for gene expression. At the 2-hour time point, microglia from both females and males exhibited ischemia-induced inflammation, characterized by the gene expression increase of tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β) and interleukin 6 (IL-6), regardless of the housing conditions. However, at 24 hours post-ischemia, social housing attenuated microglial pro-inflammatory gene expression in a sex-specific manner. At this time point, the ischemia-induced increased expression of IL-1β and IL-6 was attenuated by social interaction in microglia from male mice, while among female mice social attenuation of the inflammatory response was observed in the microglial expression of cell surface protein major histocompatibility complex II (MHC II). A second study examined behavioral and physiological measures 96 hours after ischemic injury. At this time point, female and male mice displayed increased locomotion and exploratory behavior following CA/CPR relative to controls. Regardless of sex, ischemia also elicited neuroinflammation and neurodegeneration, both of which were modulated by the social environment. Hippocampal nitric oxide (iNOS), cortical TNF-α, and counts of Fluoro-Jade C positive stained cells in the CA1 region of the hippocampus, were increased in the isolated CA/CPR group relative to sham controls and the pair-housed CA/CPR groups. Together, these data indicate that female and male mice exhibit similar outcome measures and social modulation at 96 hours post-ischemic injury, nonetheless, that social environment influences microglial reactivity to global cerebral ischemia in a sex-specific manner

Signals from the Noise: Image Stacking for Quasars in the FIRST Survey

We present a technique to explore the radio sky into the nanoJansky regime by employing image stacking using the FIRST survey. We first discuss the non-intuitive relationship between the mean and median values of a distribution that is dominated by noise, followed by an analysis of the systematic effects present in FIRST's 20cm VLA snapshot images. Image stacking allows us to recover the properties of source populations with fluxes a factor of 30 or more below the rms noise level. Mean estimates of radio flux density, luminosity, etc., are derivable for any source class having arcsecond positional accuracy. We use this technique to compute the mean radio properties for 41,295 quasars from the SDSS DR3 catalog. There is a tight correlation between optical and radio luminosity, with the radio luminosity increasing as the 0.85 power of optical luminosity. This implies declining radio-loudness with optical luminosity: the most luminous objects (M=-28.5) have average radio-to-optical ratios 3 times lower than the least luminous objects (M=-20). There is also a striking correlation between optical color and radio loudness: quasars that are either redder or bluer than the norm are brighter radio sources, with objects 0.8 magnitudes redder than the SDSS composite spectrum having radio-loudness ratios that are higher by a factor of 10. We explore the longstanding question of whether a radio-loud/radio-quiet dichotomy exists in quasars, finding that optical selection effects probably dominate the distribution function of radio loudness, which has at most a modest (~20%) inflection between the radio-loud and radio-quiet ends of the distribution. We also find, surprisingly, that broad absorption line quasars have higher mean radio flux densities, with the greatest disparity arising in the rare low-ionization BAL subclass.Comment: 17 pages, 19 figures, accepted by ApJ; corrected error in absolute magnitude

HC4 The Potential Impact Of Recommendations Made Through The Common Drug Review Program At The Canadian Agency For Drugs And Technologies In Health

A full-length cDNA clone specifying the nuclear-encoded subunit VIb of human cytochrome c oxidase (COX) was isolated from a human skeletal muscle cDNA expression library. This was done with antiserum directed against the group of subunits VIa, b and c of bovine heart COX. A potential ribosome-binding site was located immediately upstream from the initiation codon. The predicted amino acid sequence revealed 85% similarity with the corresponding subunit of bovine heart COX. Subunit VIb lacks a cleavable presequence for mitochondrial addressing. We assume that there are no tissue-specific isoforms of subunit VIb, since (i) in a Northern blot experiment a single hybridizing band of approx. 500 nucleotides was demonstrated in RNA from liver, skeletal muscle, MOLT-4 cells and fibroblasts and (ii) a full-length cDNA clone with an identical sequence was isolated from a human liver cDNA library. Steady-state levels of the coxVIb transcript were different in the tissues examined