Early neuronal accumulation of DNA double strand breaks in Alzheimer's disease.

The maintenance of genomic integrity is essential for normal cellular functions. However, it is difficult to maintain over a lifetime in postmitotic cells such as neurons, in which DNA damage increases with age and is exacerbated by multiple neurological disorders, including Alzheimer's disease (AD). Here we used immunohistochemical staining to detect DNA double strand breaks (DSBs), the most severe form of DNA damage, in postmortem brain tissues from patients with mild cognitive impairment (MCI) or AD and from cognitively unimpaired controls. Immunostaining for γH2AX-a post-translational histone modification that is widely used as a marker of DSBs-revealed increased proportions of γH2AX-labeled neurons and astrocytes in the hippocampus and frontal cortex of MCI and AD patients, as compared to age-matched controls. In contrast to the focal pattern associated with DSBs, some neurons and glia in humans and mice showed diffuse pan-nuclear patterns of γH2AX immunoreactivity. In mouse brains and primary neuronal cultures, such pan-nuclear γH2AX labeling could be elicited by increasing neuronal activity. To assess whether pan-nuclear γH2AX represents DSBs, we used a recently developed technology, DNA damage in situ ligation followed by proximity ligation assay, to detect close associations between γH2AX sites and free DSB ends. This assay revealed no evidence of DSBs in neurons or astrocytes with prominent pan-nuclear γH2AX labeling. These findings suggest that focal, but not pan-nuclear, increases in γH2AX immunoreactivity are associated with DSBs in brain tissue and that these distinct patterns of γH2AX formation may have different causes and consequences. We conclude that AD is associated with an accumulation of DSBs in vulnerable neuronal and glial cell populations from early stages onward. Because of the severe adverse effects this type of DNA damage can have on gene expression, chromatin stability and cellular functions, DSBs could be an important causal driver of neurodegeneration and cognitive decline in this disease

The AGASA/SUGAR Anisotropies and TeV Gamma Rays from the Galactic Center: A Possible Signature of Extremely High-energy Neutrons

Recent analysis of data sets from two extensive air shower cosmic ray detectors shows tantalizing evidence of an anisotropic overabundance of cosmic rays towards the Galactic Center (GC) that ``turns on'' around $10^{18}$ eV. We demonstrate that the anisotropy could be due to neutrons created at the Galactic Center through charge-exchange in proton-proton collisions, where the incident, high energy protons obey an $\sim E^{-2}$ power law associated with acceleration at a strong shock. We show that the normalization supplied by the gamma-ray signal from EGRET GC source 3EG J1746-2851 -- ascribed to pp induced neutral pion decay at GeV energies -- together with a very reasonable spectral index of 2.2, predicts a neutron flux at $\sim 10^{18}$ eV fully consistent with the extremely high energy cosmic ray data. Likewise, the normalization supplied by the very recent GC data from the HESS air-Cerenkov telescope at \~TeV energies is almost equally-well compatible with the $\sim 10^{18}$ eV cosmic ray data. Interestingly, however, the EGRET and HESS data appear to be themselves incompatible. We consider the implications of this discrepancy. We discuss why the Galactic Center environment can allow diffusive shock acceleration at strong shocks up to energies approaching the ankle in the cosmic ray spectrum. Finally, we argue that the shock acceleration may be occuring in the shell of Sagittarius A East, an unusual supernova remnant located very close to the Galactic Center. If this connection between the anisotropy and Sagittarius A East could be firmly established it would be the first direct evidence for a particular Galactic source of cosmic rays up to energies near the ankle.Comment: 57 pages, 2 figure

Astrocytic gap junctional communication is reduced in amyloid-β-treated cultured astrocytes, but not in Alzheimer's disease transgenic mice

Alzheimer's disease is characterized by accumulation of amyloid deposits in brain, progressive cognitive deficits and reduced glucose utilization. Many consequences of the disease are attributed to neuronal dysfunction, but roles of astrocytes in its pathogenesis are not well understood. Astrocytes are extensively coupled via gap junctions, and abnormal trafficking of metabolites and signalling molecules within astrocytic syncytia could alter functional interactions among cells comprising the neurovascular unit. To evaluate the influence of amyloid-β on astrocyte gap junctional communication, cultured astrocytes were treated with monomerized amyloid-β1–40 (1 μmol/l) for intervals ranging from 2 h to 5 days, and the areas labelled by test compounds were determined by impaling a single astrocyte with a micropipette and diffusion of material into coupled cells. Amyloid-β-treated astrocytes had rapid, sustained 50–70% reductions in the area labelled by Lucifer Yellow, anionic Alexa Fluor® dyes and energy-related compounds, 6-NBDG (a fluorescent glucose analogue), NADH and NADPH. Amyloid-β treatment also caused a transient increase in oxidative stress. In striking contrast with these results, spreading of Lucifer Yellow within astrocytic networks in brain slices from three regions of 8.5–14-month-old control and transgenic Alzheimer's model mice was variable, labelling 10–2000 cells; there were no statistically significant differences in the number of dye-labelled cells among the groups or with age. Thus amyloid-induced dysfunction of gap junctional communication in cultured astrocytes does not reflect the maintenance of dye transfer through astrocytic syncytial networks in transgenic mice; the pathophysiology of Alzheimer's disease is not appropriately represented by the cell culture system

EGRET Observations of the Extragalactic Gamma Ray Emission

The all-sky survey in high-energy gamma rays (E$>$30 MeV) carried out by the Energetic Gamma Ray Experiment Telescope (EGRET) aboard the Compton Gamma-Ray Observatory provides a unique opportunity to examine in detail the diffuse gamma-ray emission. The observed diffuse emission has a Galactic component arising from cosmic-ray interactions with the local interstellar gas and radiation as well an almost uniformly distributed component that is generally believed to originate outside the Galaxy. Through a careful study and removal of the Galactic diffuse emission, the flux, spectrum and uniformity of the extragalactic emission is deduced. The analysis indicates that the extragalactic emission is well described by a power law photon spectrum with an index of -(2.10+-0.03) in the 30 MeV to 100 GeV energy range. No large scale spatial anisotropy or changes in the energy spectrum are observed in the deduced extragalactic emission. The most likely explanation for the origin of this extragalactic high-energy gamma-ray emission is that it arises primarily from unresolved gamma-ray-emitting blazars.Comment: 19 pages latex, 10 figures, accepted for publication in Ap

EGRET Spectral Index and the Low-Energy Peak Position in the Spectral Energy Distribution of EGRET-Detected Blazars

In current theoretical models of the blazar subclass of active galaxies, the broadband emission consists of two components: a low-frequency synchrotron component with a peak in the IR to X-ray band, and a high-frequency inverse Compton component with a peak in the gamma-ray band. In such models, the gamma-ray spectral index should be correlated with the location of the low-energy peak, with flatter gamma-ray spectra expected for blazars with synchrotron peaks at higher photon energies and vice versa. Using the EGRET-detected blazars as a sample, we examine this correlation and possible uncertainties in its construction.Comment: 17 pages including 1 figure, accepted for publication in The Astrophysical Journa

Inclusive meson production in peripheral collisions of ultrarelativistic heavy ions

There exist several proposals to use Weizs\"{a}cker-Williams photons generated by ultrarelativistic heavy ions to produce exotic particles in $\gamma\gamma$ fusion reactions. To estimate the background conditions for such reactions we analyze various mechanisms of meson production in very peripheral collisions of ultrarelativistic heavy ions at RHIC and LHC energies. Besides $\gamma\gamma$ fusion they include also electromagnetic $\gamma A$ interactions and strong nucleon-nucleon interactions in grazing $AA$ collisions. All these processes are characterised by low multiplicities of produced particles. $\gamma A$ and $AA$ events are simulated by corresponding Monte Carlo codes, RELDIS and FRITIOF. In each of these processes a certain fraction of pions is produced close to the mid-rapidity region that gives a background for the $\gamma\gamma$ events. The possibility of selecting mesons produced in $\gamma\gamma$ fusion events via different $p_t$ cut procedures is demonstrated.Comment: 27 pages with 4 eps-figures included, uses axodraw.sty Tab.2 and 3 correcte

Early postpartum resting‐state functional connectivity for mothers receiving buprenorphine treatment for opioid use disorder: A pilot study

Between 1999 and 2014, the prevalence of opioid use disorder (OUD) among pregnant women quadrupled in the USA. The standard treatment for peripartum women with OUD is buprenorphine. However, the maternal behavior neurocircuit that regulates maternal behavior and mother‐infant bonding has not been previously studied for human mothers receiving buprenorphine treatment for OUD (BT). Rodent research shows opioid effects on reciprocal inhibition between maternal care and defence maternal brain subsystems: the hypothalamus and periaqueductal gray, respectively. We conducted a longitudinal functional magnetic resonance imaging (fMRI) pilot study in humans to specifically examine resting‐state functional connectivity (rs‐FC) between the periaqueductal gray and hypothalamus, as well as to explore associations with maternal bonding for BT. We studied 32 mothers who completed fMRI scans at 1 month (T1) and 4 months postpartum (T2), including seven mothers receiving buprenorphine for OUD and 25 non‐OUD mothers as a comparison group (CG). The participants underwent a 6‐minute resting‐state fMRI scan at each time point. We measured potential bonding impairments using the Postpartum Bonding Questionnaire to explore how rs‐FC with periaqueductal gray is associated with bonding impairments. Compared to CG, BT mothers differed in periaqueductal gray‐dependent rs‐FC with the hypothalamus, amygdala, insular cortex and other brain regions at T1, with many of these differences disappearing at T2, suggesting potential therapeutic effects of continuing buprenorphine treatment. In contrast, the “rejection and pathological anger” subscale of the Postpartum Bonding Questionnaire at T1 and T2 was associated with the T1‐to‐T2 increases in periaqueductal gray‐dependent rs‐FC with the hypothalamus and amygdala. Preliminary evidence links maternal bonding problems for mothers with OUD early in the postpartum to connectivity between specific care and defence maternal brain circuits, which may be mitigated by buprenorphine treatment. This exploratory study supports a potential mechanism for investigating both the therapeutic benefits and risks of opioids for maternal care and bonding with infants.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/151866/1/jne12770.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/151866/2/jne12770_am.pd

Photoionization Dynamics of the Tetraoxo Complexes OsO4 and RuO4

The photoionization dynamics of OsO4 and RuO4, chosen as model systems of small-size mononuclear heavy-metal complexes, has been theoretically studied by the time-dependent density functional theory (TDDFT). Accurate experimental measurements of photoionization dynamics as a benchmarking test for the theory are reported for the photoelectron asymmetry parameters of outer valence ionizations of OsO4, measured in the 17-90 eV photon energy range. The theoretical results are in good agreement with the available experimental data. The observed dynamical behavior of partial cross sections and asymmetry parameters has been related to both the coupling to the continuum of discrete excited states, giving strong modulations in the photon energy dependency, and the atomic composition of the initial ionized states, which determines the rate of decay of ionization probability for increasing excitation energies. Overall, an extensive analysis of the photoionization dynamics for valence and core orbitals is presented, showing good agreement with all the available experimental data. This provides confidence for the validity of the TDDFT approach in describing photoionization of heavy transition element compounds, with the perspective of being used for larger systems. Further experimental work is suggested for RuO4 to gather evidence of the sensitivity of the theoretical method to the nature of the metal atom