LRP1 Has a Predominant Role in Production over Clearance of Aβ in a Mouse Model of Alzheimer's Disease.

The low-density lipoprotein receptor-related protein-1 (LRP1) has a dual role in the metabolism of the amyloid precursor protein (APP). In cellular models, LRP1 enhances amyloid-β (Aβ) generation via APP internalization and thus its amyloidogenic processing. However, conditional knock-out studies in mice define LRP1 as an important mediator for the clearance of extracellular Aβ from brain via cellular degradation or transcytosis across the blood-brain barrier (BBB). In order to analyze the net effect of LRP1 on production and clearance of Aβ in vivo, we crossed mice with impaired LRP1 function with a mouse model of Alzheimer's disease (AD). Analysis of Aβ metabolism showed that, despite reduced Aβ clearance due to LRP1 inactivation in vivo, less Aβ was found in cerebrospinal fluid (CSF) and brain interstitial fluid (ISF). Further analysis of APP metabolism revealed that impairment of LRP1 in vivo shifted APP processing from the Aβ-generating amyloidogenic cleavage by beta-secretase to the non-amyloidogenic processing by alpha-secretase as shown by a decrease in extracellular Aβ and an increase of soluble APP-α (sAPP-α). This shift in APP processing resulted in overall lower Aβ levels and a reduction in plaque burden. Here, we present for the first time clear in vivo evidence that global impairment of LRP1's endocytosis function favors non-amyloidogenic processing of APP due to its reduced internalization and subsequently, reduced amyloidogenic processing. By inactivation of LRP1, the inhibitory effect on Aβ generation overrules the simultaneous impaired Aβ clearance, resulting in less extracellular Aβ and reduced plaque deposition in a mouse model of AD

An efficient filter for detecting gravitational wave bursts in interferometric detectors

Typical sources of gravitational wave bursts are supernovae, for which no accurate models exist. This calls for search methods with high efficiency and robustness to be used in the data analysis of foreseen interferometric detectors. A set of such filters is designed to detect gravitational wave burst signals. We first present filters based on the linear fit of whitened data to short straight lines in a given time window and combine them in a non linear filter named ALF. We study the performances and efficiencies of these filters, with the help of a catalogue of simulated supernova signals. The ALF filter is the most performant and most efficient of all filters. Its performance reaches about 80% of the Optimal Filter performance designed for the same signals. Such a filter could be implemented as an online trigger (dedicated to detect bursts of unknown waveform) in interferometric detectors of gravitational waves

The Antares Neutrino Telescope and Multi-Messenger Astronomy

Antares is currently the largest neutrino telescope operating in the Northern Hemisphere, aiming at the detection of high-energy neutrinos from astrophysical sources. Such observations would provide important clues about the processes at work in those sources, and possibly help solve the puzzle of ultra-high energy cosmic rays. In this context, Antares is developing several programs to improve its capabilities of revealing possible spatial and/or temporal correlations of neutrinos with other cosmic messengers: photons, cosmic rays and gravitational waves. The neutrino telescope and its most recent results are presented, together with these multi-messenger programs.Comment: 10 pages, 7 figures. Proceedings of the 14th Gravitational Wave Data Analysis Workshop (GWDAW-14) in Roma - January 26th-29th, 201

Detection in coincidence of gravitational wave bursts with a network of interferometric detectors (I): Geometric acceptance and timing

Detecting gravitational wave bursts (characterised by short durations and poorly modelled waveforms) requires to have coincidences between several interferometric detectors in order to reject non-stationary noise events. As the wave amplitude seen in a detector depends on its location with respect to the source direction and as the signal to noise ratio of these bursts are expected to be low, coincidences between antennas may not be so likely. This paper investigates this question from a statistical point of view by using a simple model of a network of detectors; it also estimates the timing precision of a detection in an interferometer which is an important issue for the reconstruction of the source location, based on time delays.Comment: low resolution figure 1 due to file size problem

Testing the performance of a blind burst statistic

In this work we estimate the performance of a method for the detection of burst events in the data produced by interferometric gravitational wave detectors. We compute the receiver operating characteristics in the specific case of a simulated noise having the spectral density expected for Virgo, using test signals taken from a library of possible waveforms emitted during the collapse of the core of Type II Supernovae.Comment: 8 pages, 6 figures, Talk given at the GWDAW2002 worksho

Epratuzumab (humanised anti-CD22 antibody) in primary Sjögren's syndrome: an open-label phase I/II study

This open-label, phase I/II study investigated the safety and efficacy of epratuzumab, a humanised anti-CD22 monoclonal antibody, in the treatment of patients with active primary Sjögren's syndrome (pSS). Sixteen Caucasian patients (14 females/2 males, 33–72 years) were to receive 4 infusions of 360 mg/m(2 )epratuzumab once every 2 weeks, with 6 months of follow-up. A composite endpoint involving the Schirmer-I test, unstimulated whole salivary flow, fatigue, erythrocyte sedimentation rate (ESR), and immunoglobulin G (IgG) was devised to provide a clinically meaningful assessment of response, defined as a ≥20% improvement in at least two of the aforementioned parameters, with ≥20% reduction in ESR and/or IgG considered as a single combined criterion. Fourteen patients received all infusions without significant reactions, 1 patient received 3, and another was discontinued due to a mild acute reaction after receiving a partial infusion. Three patients showed moderately elevated levels of Human anti-human (epratuzumab) antibody not associated with clinical manifestations. B-cell levels had mean reductions of 54% and 39% at 6 and 18 weeks, respectively, but T-cell levels, immunoglobulins, and routine safety laboratory tests did not change significantly. Fifty-three percent achieved a clinical response (at ≥20% improvement level) at 6 weeks, with 53%, 47%, and 67% responding at 10, 18, and 32 weeks, respectively. Approximately 40%–50% responded at the ≥30% level, while 10%–45% responded at the ≥50% level for 10–32 weeks. Additionally, statistically significant improvements were observed in fatigue, and patient and physician global assessments. Further, we determined that pSS patients have a CD22 over-expression in their peripheral B cells, which was downregulated by epratuzumab for at least 12 weeks after the therapy. Thus, epratuzumab appears to be a promising therapy in active pSS, suggesting that further studies be conducted

Joint searches between gravitational-wave interferometers and high-energy neutrino telescopes: science reach and analysis strategies

Many of the astrophysical sources and violent phenomena observed in our Universe are potential emitters of gravitational waves (GWs) and high-energy neutrinos (HENs). A network of GW detectors such as LIGO and Virgo can determine the direction/time of GW bursts while the IceCube and ANTARES neutrino telescopes can also provide accurate directional information for HEN events. Requiring the consistency between both, totally independent, detection channels shall enable new searches for cosmic events arriving from potential common sources, of which many extra-galactic objects.Comment: 4 pages. To appear in the Proceedings of the 2d Heidelberg Workshop: "High-Energy Gamma-rays and Neutrinos from Extra-Galactic Sources", Heidelberg (Germany), January 13-16, 200

Gravity Wave and Neutrino Bursts from Stellar Collapse: A Sensitive Test of Neutrino Masses

New methods are proposed with the goal to determine absolute neutrino masses from the simultaneous observation of the bursts of neutrinos and gravitational waves emitted during a stellar collapse. It is shown that the neutronization electron neutrino flash and the maximum amplitude of the gravitational wave signal are tightly synchronized with the bounce occuring at the end of the core collapse on a timescale better than 1 ms. The existing underground neutrino detectors (SuperKamiokande, SNO, ...) and the gravity wave antennas soon to operate (LIGO, Virgo, ...) are well matched in their performance for detecting galactic supernovae and for making use of the proposed approach. Several methods are described, which apply to the different scenarios depending on neutrino mixing. Given the present knowledge on neutrino oscillations, the methods proposed are sensitive to a mass range where neutrinos would essentially be mass-degenerate. The 95 % C.L. upper limit which can be achieved varies from 0.75 eV/c2 for large electron neutrino survival probabilities to 1.1 eV/c2 when in practice all electron neutrinos convert into muon or tau neutrinos. The sensitivity is nearly independent of the supernova distance.Comment: 17 pages, 4 figure

On line power spectra identification and whitening for the noise in interferometric gravitational wave detectors

In this paper we address both to the problem of identifying the noise Power Spectral Density of interferometric detectors by parametric techniques and to the problem of the whitening procedure of the sequence of data. We will concentrate the study on a Power Spectral Density like the one of the Italian-French detector VIRGO and we show that with a reasonable finite number of parameters we succeed in modeling a spectrum like the theoretical one of VIRGO, reproducing all its features. We propose also the use of adaptive techniques to identify and to whiten on line the data of interferometric detectors. We analyze the behavior of the adaptive techniques in the field of stochastic gradient and in the Least Squares ones.Comment: 28 pages, 21 figures, uses iopart.cls accepted for pubblication on Classical and Quantum Gravit