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

Escape Behavior of Quantum Two-Particle Systems with Coulomb Interactions

Quantum escapes of two particles with Coulomb interactions from a confined one-dimensional region to a semi-infinite lead are discussed by the probability of particles remaining in the confined region, i.e. the survival probability, in comparison with one or two free particles. For free-particle systems the survival probability decays asymptotically in power as a function of time. On the other hand, for two-particle systems with Coulomb interactions it shows an exponential decay in time. A difference of escape behaviors between Bosons and Fermions is considered as quantum effects of identical two particles such as the Pauli exclusion principle. The exponential decay in the survival probability of interacting two particles is also discussed in a viewpoint of quantum chaos based on a distribution of energy level spacings.Comment: 10 pages, 7 figure

Contact frequency determines outcome of basal insulin initiation trials in type 2 diabetes

Aims/hypothesis The aim of the present study was to investigate whether predetermined contact frequency with the study teamand endpoint insulin dose are associated with study outcomes in basal insulin initiation trials in type 2 diabetes. Methods A systematic Medline search was performed. Using data from the selected studies, contact frequency was plotted against HbA(1c) reduction and endpoint insulin dose. The importance of face-to-face vs telephone contact was also analysed. Insulin dose was plotted against HbA(1c) reduction, hypoglycaemia rate and weight gain. To investigate non-specific study effects, the relationship between contact frequency and HbA(1c) was also assessed in dipeptidyl peptidase-4 (DPP-4) inhibitor trials. Results The reduction in HbA(1c) was highly correlated with contact frequency and endpoint insulin dose (r(2)=0.751, p<0.001 and r(2)=0.433, p=0.008, respectively). However, after adjusting for contact frequency, the relationship between insulin dose and HbA(1c) reduction was no longer significant (p=0.270). The frequency of both clinical and telephone contacts were independent predictors of HbA(1c) improvement (p=0.010 and p<0.001, respectively). We found no dose response relationship between end-of-study insulin dose and hypoglycaemia or weight gain. In DPP-4 inhibitor studies, contact frequency was not positively associated with HbA(1c). Conclusions/interpretation The frequency of contact with the study team is highly correlated with the improvement in HbA(1c) achieved in basal insulin initiation trials in type 2 diabetic patients. This has important implications for trial design and interpretation, as well as for clinical car

Effects of light at night on laboratory animals and research outcomes

Light has substantial influences on the physiology and behavior of most laboratory animals. As such, lighting conditions within animal rooms are potentially significant, and often underappreciated variables within experiments. Disruption of the light/dark cycle, primarily by exposing animals to light at night (LAN), disturbs biological rhythms and has widespread physiological consequences due to mechanisms such as melatonin suppression, sympathetic stimulation, and altered circadian clock gene expression. Thus, attention to the lighting environment of laboratory animals and maintaining consistency of a light/dark cycle is imperative for study reproducibility. Light intensity as well as wavelength, photoperiod, and timing are all important variables. Although modern rodent facilities are designed to facilitate appropriate light cycling, there are simple ways to modify rooms to prevent extraneous light exposure during the dark period. Attention to lighting conditions of laboratory animals by both researchers and research care staff ensures best practices for maintaining animal welfare, as well as reproducibility of research results

Source Dimensions in Ultrarelativistic Heavy Ion Collisions

Recent experiments on pion correlations, interpreted as interferometric measurements of the collision zone, are compared with models that distinguish a prehadronic phase and a hadronic phase. The models include prehadronic longitudinal expansion, conversion to hadrons in local kinetic equilibrium, and rescattering of the produced hadrons. We find that the longitudinal and outward radii are surprisingly sensitive to the algorithm used for two-body collisions. The longitudinal radius measured in collisions of 200 GeV/u sulfur nuclei on a heavy target requires the existence of a prehadronic phase which converts to the hadronic phase at densities around 0.8-1.0 GeV/fm$^3$. The transverse radii cannot be reproduced without introducing more complex dynamics into the transverse expansion.Comment: RevTeX 3.0, 28 pages, 6 figures, not included, revised version, major change is an additional discussion of the classical two-body collision algorithm, a (compressed) postscript file of the complete paper including figures can be obtained from Authors or via anonymous ftp at ftp://ftp_int.phys.washington.edu/pub/herrmann/pisource.ps.