The BACE1 product sAPPβ induces ER stress and inflammation and impairs insulin signaling

Objective β-secretase/β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1) is a key enzyme involved in Alzheimer's disease that has recently been implicated in insulin-independent glucose uptake in myotubes. However, it is presently unknown whether BACE1 and the product of its activity, soluble APPβ (sAPPβ), contribute to lipid-induced inflammation and insulin resistance in skeletal muscle cells. Materials/Methods Studies were conducted in mouse C2C12 myotubes, skeletal muscle from Bace1−/−mice and mice treated with sAPPβ and adipose tissue and plasma from obese and type 2 diabetic patients. Results We show that BACE1 inhibition or knockdown attenuates palmitate-induced endoplasmic reticulum (ER) stress, inflammation, and insulin resistance and prevents the reduction in Peroxisome Proliferator-Activated Receptor γ Co-activator 1α (PGC-1α) and fatty acid oxidation caused by palmitate in myotubes. The effects of palmitate on ER stress, inflammation, insulin resistance, PGC-1α down-regulation, and fatty acid oxidation were mimicked by soluble APPβ in vitro. BACE1 expression was increased in subcutaneous adipose tissue of obese and type 2 diabetic patients and this was accompanied by a decrease in PGC-1α mRNA levels and by an increase in sAPPβ plasma levels of obese type 2 diabetic patients compared to obese non-diabetic subjects. Acute sAPPβ administration to mice reduced PGC-1α levels and increased inflammation in skeletal muscle and decreased insulin sensitivity. Conclusions Collectively, these findings indicate that the BACE1 product sAPPβ is a key determinant in ER stress, inflammation and insulin resistance in skeletal muscle and gluconeogenesis in liver

A search of the Orion spur for continuous gravitational waves using a "loosely coherent" algorithm on data from LIGO interferometers

We report results of a wideband search for periodic gravitational waves from isolated neutron stars within the Orion spur towards both the inner and outer regions of our Galaxy. As gravitational waves interact very weakly with matter, the search is unimpeded by dust and concentrations of stars. One search disk (A) is $6.87^\circ$ in diameter and centered on $20^\textrm{h}10^\textrm{m}54.71^\textrm{s}+33^\circ33'25.29"$, and the other (B) is $7.45^\circ$ in diameter and centered on $8^\textrm{h}35^\textrm{m}20.61^\textrm{s}-46^\circ49'25.151"$. We explored the frequency range of 50-1500 Hz and frequency derivative from $0$ to $-5\times 10^{-9}$ Hz/s. A multi-stage, loosely coherent search program allowed probing more deeply than before in these two regions, while increasing coherence length with every stage. Rigorous followup parameters have winnowed initial coincidence set to only 70 candidates, to be examined manually. None of those 70 candidates proved to be consistent with an isolated gravitational wave emitter, and 95% confidence level upper limits were placed on continuous-wave strain amplitudes. Near $169$ Hz we achieve our lowest 95% CL upper limit on worst-case linearly polarized strain amplitude $h_0$ of $6.3\times 10^{-25}$, while at the high end of our frequency range we achieve a worst-case upper limit of $3.4\times 10^{-24}$ for all polarizations and sky locations.Comment: Fixed minor typo - duplicate name in the author lis

Search of the Orion spur for continuous gravitational waves using a loosely coherent algorithm on data from LIGO interferometers

We report results of a wideband search for periodic gravitational waves from isolated neutron stars within the Orion spur towards both the inner and outer regions of our Galaxy. As gravitational waves interact very weakly with matter, the search is unimpeded by dust and concentrations of stars. One search disk (A) is 6.87° in diameter and centered on 20h10m54.71s+33°33′25.29′′, and the other (B) is 7.45° in diameter and centered on 8h35m20.61s-46°49′25.151′′. We explored the frequency range of 50-1500 Hz and frequency derivative from 0 to -5×10-9 Hz/s. A multistage, loosely coherent search program allowed probing more deeply than before in these two regions, while increasing coherence length with every stage. Rigorous follow-up parameters have winnowed the initial coincidence set to only 70 candidates, to be examined manually. None of those 70 candidates proved to be consistent with an isolated gravitational-wave emitter, and 95% confidence level upper limits were placed on continuous-wave strain amplitudes. Near 169 Hz we achieve our lowest 95% C.L. upper limit on the worst-case linearly polarized strain amplitude h0 of 6.3×10-25, while at the high end of our frequency range we achieve a worst-case upper limit of 3.4×10-24 for all polarizations and sky locations. © 2016 American Physical Society

Beam test performance of a prototype module with Short Strip ASICs for the CMS HL-LHC tracker upgrade

The Short Strip ASIC (SSA) is one of the four front-end chips designed for the upgrade of the CMS Outer Tracker for the High Luminosity LHC. Together with the Macro-Pixel ASIC (MPA) it will instrument modules containing a strip and a macro-pixel sensor stacked on top of each other. The SSA provides both full readout of the strip hit information when triggered, and, together with the MPA, correlated clusters called stubs from the two sensors for use by the CMS Level-1 (L1) trigger system. Results from the first prototype module consisting of a sensor and two SSA chips are presented. The prototype module has been characterized at the Fermilab Test Beam Facility using a 120 GeV proton beam

Searches for continuous gravitational waves from nine young supernova remnants

We describe directed searches for continuous gravitational waves in data from the sixth LIGO science data run. The targets were nine young supernova remnants not associated with pulsars; eight of the remnants are associated with non-pulsing suspected neutron stars. One target's parameters are uncertain enough to warrant two searches, for a total of ten. Each search covered a broad band of frequencies and first and second frequency derivatives for a fixed sky direction. The searches coherently integrated data from the two LIGO interferometers over time spans from 5.3-25.3 days using the matched-filtering F-statistic. We found no credible gravitational-wave signals. We set 95% confidence upper limits as strong (low) as $4\times10^{-25}$ on intrinsic strain, $2\times10^{-7}$ on fiducial ellipticity, and $4\times10^{-5}$ on r-mode amplitude. These beat the indirect limits from energy conservation and are within the range of theoretical predictions for neutron-star ellipticities and r-mode amplitudes.Comment: Science summary available at http://www.ligo.org/science/Publication-S6DirectedSNR/index.ph

Multimessenger Search for Sources of Gravitational Waves and High-Energy Neutrinos: Results for Initial LIGO-Virgo and IceCube

We report the results of a multimessenger search for coincident signals from the LIGO and Virgo gravitational-wave observatories and the partially completed IceCube high-energy neutrino detector, including periods of joint operation between 2007-2010. These include parts of the 2005-2007 run and the 2009-2010 run for LIGO-Virgo, and IceCube's observation periods with 22, 59 and 79 strings. We find no significant coincident events, and use the search results to derive upper limits on the rate of joint sources for a range of source emission parameters. For the optimistic assumption of gravitational-wave emission energy of $10^{-2}$\,M$_\odot$c$^2$ at $\sim 150$\,Hz with $\sim 60$\,ms duration, and high-energy neutrino emission of $10^{51}$\,erg comparable to the isotropic gamma-ray energy of gamma-ray bursts, we limit the source rate below $1.6 \times 10^{-2}$\,Mpc$^{-3}$yr$^{-1}$. We also examine how combining information from gravitational waves and neutrinos will aid discovery in the advanced gravitational-wave detector era

Test beam performance of a CBC3-based mini-module for the Phase-2 CMS Outer Tracker before and after neutron irradiation

The Large Hadron Collider (LHC) at CERN will undergo major upgrades to increase the instantaneous luminosity up to 5–7.5×10$^{34}$ cm$^{-2}$s$^{-1}$. This High Luminosity upgrade of the LHC (HL-LHC) will deliver a total of 3000–4000 fb-1 of proton-proton collisions at a center-of-mass energy of 13–14 TeV. To cope with these challenging environmental conditions, the strip tracker of the CMS experiment will be upgraded using modules with two closely-spaced silicon sensors to provide information to include tracking in the Level-1 trigger selection. This paper describes the performance, in a test beam experiment, of the first prototype module based on the final version of the CMS Binary Chip front-end ASIC before and after the module was irradiated with neutrons. Results demonstrate that the prototype module satisfies the requirements, providing efficient tracking information, after being irradiated with a total fluence comparable to the one expected through the lifetime of the experiment

The pervasive effects of recombinant Fasciola gigantica Ras-related protein Rab10 on the functions of goat peripheral blood mononuclear cells

Background: Fasciola gigantica-induced immunomodulation is a major hurdle faced by the host for controlling infection. Here, we elucidated the role of F. gigantica Ras-related protein Rab10 (FgRab10) in the modulation of key functions of peripheral blood mononuclear cells (PBMCs) of goats.Methods: We cloned and expressed recombinant FgRab10 (rFgRab10) protein and examined its effects on several functions of goat PBMCs. Protein interactors of rFgRab10 were predicted in silico by querying the databases Intact, String, BioPlex and BioGrid. In addition, a total energy analysis of each of the identified interactions was also conducted. Gene Ontology (GO) enrichment analysis was carried out using FuncAssociate 3.0.Results: The FgRab10 gene (618 bp), encodes 205-amino-acid residues with a molecular mass of ~23 kDa, had complete nucleotide sequence homology with F. hepatica Ras family protein gene (PIS87503.1). The rFgRab10 protein specifically cross-reacted with anti-Fasciola antibodies as shown by Western blot and immunofluorescence analysis. This protein exhibited multiple effects on goat PBMCs, including increased production of cytokines [interleukin-2 (IL-2), IL-4, IL-10, transforming growth factor beta (TGF-β) and interferon gamma (IFN-γ)] and total nitric oxide (NO), enhancing apoptosis and migration of PBMCs, and promoting the phagocytic ability of monocytes. However, it significantly inhibited cell proliferation. Homology modelling revealed 63% identity between rFgRab10 and human Rab10 protein (Uniprot ID: P61026). Protein interaction network analysis revealed more stabilizing interactions between Rab proteins geranylgeranyltransferase component A 1 (CHM) and Rab proteins geranylgeranyltransferase component A 2 (CHML) and rFgRab10 protein. Gene Ontology analysis identified RabGTPase mediated signaling as the most represented pathway.Conclusions: rFgRab10 protein exerts profound influences on various functions of goat PBMCs. This finding may help explain why F. gigantica is capable of provoking recognition by host immune cells, less capable of destroying this successful parasite

Search of the Orion spur for continuous gravitational waves using a loosely coherent algorithm on data from LIGO interferometers

We report results of a wideband search for periodic gravitational waves from isolated neutron stars within the Orion spur towards both the inner and outer regions of our Galaxy. As gravitational waves interact very weakly with matter, the search is unimpeded by dust and concentrations of stars. One search disk (A) is 6.87° in diameter and centered on 20[superscript h]10[superscript m]54.71[superscript s] + 33°33[superscript ′]25.29[superscript ′′], and the other (B) is 7.45° in diameter and centered on 8[superscript h]35[superscript m]20.61[superscript s] - 46°49[superscript ′]25.151[superscript ′′]. We explored the frequency range of 50–1500 Hz and frequency derivative from 0 to -5 × 10[superscript -9]  Hz/s. A multistage, loosely coherent search program allowed probing more deeply than before in these two regions, while increasing coherence length with every stage. Rigorous follow-up parameters have winnowed the initial coincidence set to only 70 candidates, to be examined manually. None of those 70 candidates proved to be consistent with an isolated gravitational-wave emitter, and 95% confidence level upper limits were placed on continuous-wave strain amplitudes. Near 169 Hz we achieve our lowest 95% C.L. upper limit on the worst-case linearly polarized strain amplitude h[subscript 0] of 6.3 × 10[superscript -25], while at the high end of our frequency range we achieve a worst-case upper limit of 3.4 × 10[superscript -24] for all polarizations and sky locations.National Science Foundation (U.S.)United States. National Aeronautics and Space AdministrationCarnegie TrustDavid & Lucile Packard FoundationAlfred P. Sloan Foundatio

First low frequency all-sky search for continuous gravitational wave signals

In this paper we present the results of the first low frequency all-sky search of continuous gravitational wave signals conducted on Virgo VSR2 and VSR4 data. The search covered the full sky, a frequency range between 20 and 128 Hz with a range of spin-down between −1.0×10−10 and +1.5×10−11  Hz/s, and was based on a hierarchical approach. The starting point was a set of short fast Fourier transforms, of length 8192 s, built from the calibrated strain data. Aggressive data cleaning, in both the time and frequency domains, has been done in order to remove, as much as possible, the effect of disturbances of instrumental origin. On each data set a number of candidates has been selected, using the FrequencyHough transform in an incoherent step. Only coincident candidates among VSR2 and VSR4 have been examined in order to strongly reduce the false alarm probability, and the most significant candidates have been selected. The criteria we have used for candidate selection and for the coincidence step greatly reduce the harmful effect of large instrumental artifacts. Selected candidates have been subject to a follow-up by constructing a new set of longer fast Fourier transforms followed by a further incoherent analysis, still based on the FrequencyHough transform. No evidence for continuous gravitational wave signals was found, and therefore we have set a population-based joint VSR2-VSR4 90% confidence level upper limit on the dimensionless gravitational wave strain in the frequency range between 20 and 128 Hz. This is the first all-sky search for continuous gravitational waves conducted, on data of ground-based interferometric detectors, at frequencies below 50 Hz. We set upper limits in the range between about 10−24 and 2×10−23 at most frequencies. Our upper limits on signal strain show an improvement of up to a factor of ∼2 with respect to the results of previous all-sky searches at frequencies below 80 H