Rapid β-amyloid deposition and cognitive impairment after cholinergic denervation in APP/PS1 mice

Although extensive evidence supports the role of amyloid-β (Aβ) in Alzheimer disease (AD), the neurotoxic mechanisms underlying AD pathogenesis are not understood. On the other hand, neuronal loss is the pathological feature that best correlates with cognitive impairment. We hypothesized that cholinergic neurodegeneration may lead to Aβ deposition and tested this by inducing selective cholinergic lesions in APPswe/PS1dE9 mice with murine p75(NTR) saporin (mu p75-SAP). Intracerebroventricular lesions that removed ~50% of cholinergic innervation to the cortex and hippocampus were induced in animals with incipient (~3 months) and marked (~7 months of age) Aβ deposition. Cranial windows were implanted and Aβ deposition was monitored in vivo using multiphoton microscopy. Aβ deposition was increased as soon as 7 days after the lesion and this effect was maintained up to 3 months later. Postmortem studies using immunohistochemistry with an anti-Aβ antibody corroborated these findings in both cerebral cortex and hippocampus. Tau phosphorylation was also significantly increased after the lesions. Cholinergic denervation resulted in early memory impairment at 3 months of age that worsened with age (~7 months); there was a synergistic effect between cholinergic denervation and the presence of APP/PS1 transgenes. Altogether, our data suggest that cholinergic denervation may trigger Aβ deposition and synergistically contribute to cognitive impairment in AD patients

Cosmological Constraints from Measurements of Type Ia Supernovae discovered during the first 1.5 years of the Pan-STARRS1 Survey

We present griz light curves of 146 spectroscopically confirmed Type Ia Supernovae ($0.03 < z <0.65$) discovered during the first 1.5 years of the Pan-STARRS1 Medium Deep Survey. The Pan-STARRS1 natural photometric system is determined by a combination of on-site measurements of the instrument response function and observations of spectrophotometric standard stars. We find that the systematic uncertainties in the photometric system are currently 1.2\% without accounting for the uncertainty in the HST Calspec definition of the AB system. A Hubble diagram is constructed with a subset of 113 out of 146 SNe Ia that pass our light curve quality cuts. The cosmological fit to 310 SNe Ia (113 PS1 SNe Ia + 222 light curves from 197 low-z SNe Ia), using only SNe and assuming a constant dark energy equation of state and flatness, yields $w=-1.120^{+0.360}_{-0.206}\textrm{(Stat)} ^{+0.269}_{-0.291}\textrm{(Sys)}$. When combined with BAO+CMB(Planck)+$H_0$, the analysis yields $\Omega_{\rm M}=0.280^{+0.013}_{-0.012}$ and $w=-1.166^{+0.072}_{-0.069}$ including all identified systematics (see also Scolnic et al. 2014). The value of $w$ is inconsistent with the cosmological constant value of $-1$ at the 2.3$\sigma$ level. Tension endures after removing either the BAO or the $H_0$ constraint, though it is strongest when including the $H_0$ constraint. If we include WMAP9 CMB constraints instead of those from Planck, we find $w=-1.124^{+0.083}_{-0.065}$, which diminishes the discord to $<2\sigma$. We cannot conclude whether the tension with flat $\Lambda$CDM is a feature of dark energy, new physics, or a combination of chance and systematic errors. The full Pan-STARRS1 supernova sample with $\sim\!\!$3 times as many SNe should provide more conclusive results.Comment: 38 pages, 16 figures, 14 tables, ApJ in pres

Systematic Uncertainties Associated with the Cosmological Analysis of the First Pan-STARRS1 Type Ia Supernova Sample

We probe the systematic uncertainties from 113 Type Ia supernovae (SNIa) in the Pan-STARRS1 (PS1) sample along with 197 SN Ia from a combination of low-redshift surveys. The companion paper by Rest et al. (2013) describes the photometric measurements and cosmological inferences from the PS1 sample. The largest systematic uncertainty stems from the photometric calibration of the PS1 and low-z samples. We increase the sample of observed Calspec standards from 7 to 10 used to define the PS1 calibration system. The PS1 and SDSS-II calibration systems are compared and discrepancies up to ~0.02 mag are recovered. We find uncertainties in the proper way to treat intrinsic colors and reddening produce differences in the recovered value of w up to 3%. We estimate masses of host galaxies of PS1 supernovae and detect an insignificant difference in distance residuals of the full sample of 0.037\pm0.031 mag for host galaxies with high and low masses. Assuming flatness in our analysis of only SNe measurements, we find $w = {-1.120^{+0.360}_{-0.206}\textrm{(Stat)} ^{+0.269}_{-0.291}\textrm{(Sys)}}$. With additional constraints from BAO, CMB(Planck) and H0 measurements, we find $w = -1.166^{+0.072}_{-0.069}$ and $\Omega_M=0.280^{+0.013}_{-0.012}$ (statistical and systematic errors added in quadrature). Significance of the inconsistency with $w=-1$ depends on whether we use Planck or WMAP measurements of the CMB: $w_{\textrm{BAO+H0+SN+WMAP}}=-1.124^{+0.083}_{-0.065}$.Comment: 24 pages, 20 figures. Accepted by Ap

Discovery of Very High Energy Gamma Rays from 1ES 1440+122

The BL Lacertae object 1ES 1440+122 was observed in the energy range from 85 GeV to 30 TeV by the VERITAS array of imaging atmospheric Cherenkov telescopes. The observations, taken between 2008 May and 2010 June and totalling 53 hours, resulted in the discovery of $\gamma$-ray emission from the blazar, which has a redshift $z$=0.163. 1ES 1440+122 is detected at a statistical significance of 5.5 standard deviations above the background with an integral flux of (2.8$\pm0.7_{\mathrm{stat}}\pm0.8_{\mathrm{sys}}$) $\times$ 10$^{-12}$ cm$^{-2}$ s$^{-1}$ (1.2\% of the Crab Nebula's flux) above 200 GeV. The measured spectrum is described well by a power law from 0.2 TeV to 1.3 TeV with a photon index of 3.1 $\pm$ 0.4$_{\mathrm{stat}}$ $\pm$ 0.2$_{\mathrm{sys}}$. Quasi-simultaneous multi-wavelength data from the Fermi Large Area Telescope (0.3--300 GeV) and the Swift X-ray Telescope (0.2--10 keV) are additionally used to model the properties of the emission region. A synchrotron self-Compton model produces a good representation of the multi-wavelength data. Adding an external-Compton or a hadronic component also adequately describes the data.Comment: 8 pages, 4 figures. Accepted for publication in MNRA

ALA and ALA hexyl ester induction of porphyrins after their systemic administration to tumour bearing mice

The use of synthetic lipophilic molecules derived from 5-aminolevulinic acid (ALA) is currently under investigation to enhance cellular ALA penetration. In this work we studied the effect of systemic administration to mice of the hexyl ester of ALA (He-ALA) on porphyrin tissue synthesis as compared to ALA. In most normal tissues as well as in tumour, He-ALA induced less porphyrin synthesis than ALA after its systemic administration either intravenous or intraperitoneal, although explant organ cultures exposed to either ALA or He-ALA revealed equally active esterases. The only tissue that accumulated higher porphyrin levels from He-ALA (seven times more than ALA) was the brain, and this correlated well with a rapid increase in ALA/He-ALA content in brain after administration of He-ALA. This may be ascribed to a differential permeability to lipophilic substances controlled by the blood–brain barrier, a feature which could be further exploited to treat brain tumours

A Pair of Dopamine Neurons Target the D1-Like Dopamine Receptor DopR in the Central Complex to Promote Ethanol-Stimulated Locomotion in Drosophila

Dopamine is a mediator of the stimulant properties of drugs of abuse, including ethanol, in mammals and in the fruit fly Drosophila. The neural substrates for the stimulant actions of ethanol in flies are not known. We show that a subset of dopamine neurons and their targets, through the action of the D1-like dopamine receptor DopR, promote locomotor activation in response to acute ethanol exposure. A bilateral pair of dopaminergic neurons in the fly brain mediates the enhanced locomotor activity induced by ethanol exposure, and promotes locomotion when directly activated. These neurons project to the central complex ellipsoid body, a structure implicated in regulating motor behaviors. Ellipsoid body neurons are required for ethanol-induced locomotor activity and they express DopR. Elimination of DopR blunts the locomotor activating effects of ethanol, and this behavior can be restored by selective expression of DopR in the ellipsoid body. These data tie the activity of defined dopamine neurons to D1-like DopR-expressing neurons to form a neural circuit that governs acute responding to ethanol

Selecting superluminous supernovae in faint galaxies from the first year of the Pan-STARRS1 Medium Deep Survey

The Pan-STARRS1 (PS1) survey has obtained imaging in 5 bands (grizy_P1) over 10 Medium Deep Survey (MDS) fields covering a total of 70 square degrees. This paper describes the search for apparently hostless supernovae (SNe) within the first year of PS1 MDS data with an aim of discovering new superluminous supernovae (SLSNe). A total of 249 hostless transients were discovered down to a limiting magnitude of M_AB ~ 23.5, of which 76 were classified as Type Ia SNe. There were 57 SNe with complete light curves that are likely core-collapse SNe (CCSNe) or SLSNe and 12 of these have had spectra taken. Of these 12 hostless, non-Type Ia SNe, 7 were SLSNe of Type Ic at redshifts between 0.5-1.4. This illustrates that the discovery rate of Type Ic SLSNe can be maximised by concentrating on hostless transients and removing normal SNe Ia. We present data for two new possible SLSNe; PS1-10pm (z = 1.206) and PS1-10ahf (z = 1.1), and estimate the rate of SLSNe-Ic to be between 3^{+3}_{-2} * 10^{-5} and 8^{+2}_{-1} * 10^{-5} of the CCSNe rate within 0.3 <= z <= 1.4 by applying a Monte-Carlo technique. The rate of slowly evolving, SN2007bi-like explosions is estimated as a factor of 10 lower than this range.Comment: 26 pages, 16 figures, Accepted for publication in MNRA

Lipocalin-2 Deficiency Attenuates Insulin Resistance Associated With Aging and Obesity

OBJECTIVE - The proinflammatory cytokines/adipokines produced from adipose tissue act in an autocrine and/or endocrine manner to perpetuate local inflammation and to induce peripheral insulin resistance. The present study investigates whether lipocalin-2 deficiency or replenishment with this adipokine has any impact on systemic insulin sensitivity and the underlying mechanisms. METHODS AND RESULTS - Under conditions of aging or dietary-/genetic-induced obesity, lipocalin-2 knockout (Lcn2-KO) mice show significantly decreased fasting glucose and insulin levels and improved insulin sensitivity compared with their wild-type littermates. Despite enlarged fat mass, inflammation and the accumulation of lipid peroxidation products are significantly attenuated in the adipose tissues of Lcn2-KO mice. Adipose fatty acid composition of these mice varies significantly from that in wild-type animals. The amounts of arachidonic acid (C20:4 n6) are elevated by aging and obesity and are paradoxically further increased in adipose tissue, but not skeletal muscle and liver of Lcn2-KO mice. On the other hand, the expression and activity of 12-lipoxygenase, an enzyme responsible for metabolizing arachidonic acid, and the production of tumor necrosis factor-α (TNF-α), a critical insulin resistance-inducing factor, are largely inhibited by lipocalin-2 deficiency. Lipocalin-2 stimulates the expression and activity of 12-lipoxygenase and TNF-α production in fat tissues. Cinnamyl-3,4- dihydroxy-α-cyanocinnamate (CDC), an arachidonate lipoxygenase inhibitor, prevents TNF-α expression induced by lipocalin-2. Moreover, treatment with TNF-α neutralization antibody or CDC significantly attenuated the differences of insulin sensitivity between wild-type and Lcn2-KO mice. CONCLUSIONS - Lipocalin-2 deficiency protects mice from developing aging- and obesity-induced insulin resistance largely by modulating 12-lipoxygenase and TNF-α levels in adipose tissue. © 2010 by the American Diabetes Association.link_to_OA_fulltex