Stochastic model for nucleosome sliding in the presence of DNA ligands

Heat-induced mobility of nucleosomes along DNA is an experimentally well-studied phenomenon. A recent experiment shows that the repositioning is modified in the presence of minor-groove binding DNA ligands. We present here a stochastic three-state model for the diffusion of a nucleosome along DNA in the presence of such ligands. It allows us to describe the dynamics and the steady state of such a motion analytically. The analytical results are in excellent agreement with numerical simulations of this stochastic process.With this model, we study the response of a nucleosome to an external force and how it is affected by the presence of ligands.Comment: 10 pages, 8 figures, submitted to Eur. Phys. J.

Detection and imaging in a random medium: A matrix method to overcome multiple scattering and aberration

We present an imaging technique particularly suited to the detection of a target embedded in a strongly scattering medium. Classical imaging techniques based on the Born approximation fail in this kind of configuration because of multiply scattered echoes and aberration distortions. The experimental set up we consider uses an array of programmable transmitters/receivers. A target is placed behind a scattering medium. The impulse responses between all array elements are measured and form a matrix. The core of the method is to separate the single-scattered echo of the target from the multiple scattering background. This is possible because of a deterministic coherence along the antidiagonals of the array response matrix, which is typical of single scattering. Once this operation is performed, target detection is achieved by applying the DORT method (French acronym for decomposition of the time reversal operator). Experimental results are presented in the case of wide-band ultrasonic waves around 3 MHz. A 125-element array is placed in front of a collection of randomly distributed steel rods (diameter 0.8mm). The slab thickness is three times the scattering mean free path. The target is a larger steel cylinder (diameter 15 mm) that we try to detect and localize. The quality of detection is assessed theoretically based on random matrix theory and is shown to be significantly better than what is obtained with classical imaging methods. Aside from multiple scattering, the technique is also shown to reduce the aberrations induced by an heterogeneous layer.Comment: 48 pages, 18 figures, corrected typos, v

In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus

Hepatitis delta virus (HDV) can dramatically worsen liver disease in patients coinfected with hepatitis B virus (HBV). No effective medical therapy exists for HDV. The HDV envelope requires HBV surface antigen proteins provided by HBV. Once inside a cell, however, HDV can replicate its genome in the absence of any HBV gene products. In vitro, HDV virion assembly is critically dependent on prenyl lipid modification, or prenylation, of its nucleocapsid-like protein large delta antigen. To overcome limitations of current animal models and to test the hypothesis that pharmacologic prenylation inhibition can prevent the production of HDV virions in vivo, we established a convenient mouse-based model of HDV infection capable of yielding viremia. Such mice were then treated with the prenylation inhibitors FTI-277 and FTI-2153. Both agents were highly effective at clearing HDV viremia. As expected, HDV inhibition exhibited duration-of-treatment dependence. These results provide the first preclinical data supporting the in vivo efficacy of prenylation inhibition as a novel antiviral therapy with potential application to HDV and a wide variety of other viruses

QUBIC: The QU Bolometric Interferometer for Cosmology

One of the major challenges of modern cosmology is the detection of B-mode polarization anisotropies in the CMB. These originate from tensor fluctuations of the metric produced during the inflationary phase. Their detection would therefore constitute a major step towards understanding the primordial Universe. The expected level of these anisotropies is however so small that it requires a new generation of instruments with high sensitivity and extremely good control of systematic effects. We propose the QUBIC instrument based on the novel concept of bolometric interferometry, bringing together the sensitivity advantages of bolometric detectors with the systematics effects advantages of interferometry. Methods: The instrument will directly observe the sky through an array of entry horns whose signals will be combined together using an optical combiner. The whole set-up is located inside a cryostat. Polarization modulation will be achieved using a rotating half-wave plate and interference fringes will be imaged on two focal planes (separated by a polarizing grid) tiled with bolometers. We show that QUBIC can be considered as a synthetic imager, exactly similar to a usual imager but with a synthesized beam formed by the array of entry horns. Scanning the sky provides an additional modulation of the signal and improve the sky coverage shape. The usual techniques of map-making and power spectrum estimation can then be applied. We show that the sensitivity of such an instrument is comparable with that of an imager with the same number of horns. We anticipate a low level of beam-related systematics thanks to the fact that the synthesized beam is determined by the location of the primary horns. Other systematics should be under good control thanks to an autocalibration technique, specific to our concept, that will permit the accurate determination of most of the systematics parameters.Comment: 12 pages, 10 figures, submitted to Astronomy and Astrophysic

Cholinesterase Inhibitors and Hospitalization for Bradycardia: A Population-Based Study

Laura Park-Wyllie and colleagues examined the health records of more than 1.4 million older adults and show that initiation of cholinesterase inhibitor therapy is associated with a more than doubling of the risk of hospitalization for bradycardia

Multiple Beneficial Health Effects of Natural Alkylglycerols from Shark Liver Oil

Alkylglycerols (alkyl-Gro) are ether lipids abundant in the liver of some elasmobranch fish species such as ratfishes and some sharks. Shark liver oil from Centrophorus squamosus (SLO), or alkyl-Gro mix from this source, have several in vivo biological activities including stimulation of hematopoiesis and immunological defences, sperm quality improvement, or anti-tumor and anti-metastasis activities. Several mechanisms are suggested for these multiple activities, resulting from incorporation of alkyl-Gro into membrane phospholipids, and lipid signaling interactions. Natural alkyl-Gro mix from SLO contains several alkyl-Gro, varying by chain length and unsaturation. Six prominent constituents of natural alkyl-Gro mix, namely 12:0, 14:0, 16:0, 18:0, 16:1 n-7, and 18:1 n-9 alkyl-Gro, were synthesized and tested for anti-tumor and anti-metastatic activities on a model of grafted tumor in mice (3LL cells). 16:1 and 18:1 alkyl-Gro showed strong activity in reducing lung metastasis number, while saturated alkyl- Gro had weaker (16:0) or no (12:0, 14:0, 18:0) effect. Multiple compounds and mechanisms are probably involved in the multiple activities of natural alkyl-Gro

QUBIC: The Q&U Bolometric Interferometer for Cosmology - A novel way to look at the polarized Cosmic Microwave Background

In this paper we describe QUBIC, an experiment that takes up the challenge posed by the detection of primordial gravitational waves with a novel approach, that combines the sensitivity of state-of-the art bolometric detectors with the systematic effects control typical of interferometers. The so-called "self-calibration" is a technique deeply rooted in the interferometric nature of the instrument and allows us to clean the measured data from instrumental effects. The first module of QUBIC is a dual band instrument (150 GHz and 220 GHz) that will be deployed in Argentina during the Fall 2018.Fil: Mennella, Aniello. University of Milan; ItaliaFil: Ade, P. A. R.. Cardiff University; Reino UnidoFil: Aumont, J.. Institut d'Astrophysique Spatiale; FranciaFil: Banfie, S.. Istituto Nazionale Di Fisica Nucleare; ItaliaFil: Battaglia, P.. Università degli Studi di Trieste; ItaliaFil: Battistelli, E. S.. Università degli Studi di Roma "La Sapienza"; ItaliaFil: Baùe, F.. Istituto Nazionale Di Fisica Nucleare; ItaliaFil: Buzi, D.. Università degli Studi di Roma "La Sapienza"; ItaliaFil: Columbro, F.. Università degli Studi di Roma "La Sapienza"; ItaliaFil: Bélie, B.. Institute of Fundamental Electronics; FranciaFil: Bennett, D.. Maynooth University; IrlandaFil: Bergé, L.. Centre de Sciences Nucléaires et de Sciences de la Matière; FranciaFil: Bernard, J. Ph.. Institut de Recherche en Astrophysique et Planétologie; FranciaFil: Bersanelli, M.. University of Milan; ItaliaFil: Bigot Sazy, M. A.. APC; FranciaFil: Bleurvacq, N.. APC; FranciaFil: Bordier, G.. APC; FranciaFil: Brossard, J.. APC; FranciaFil: Bunn, E. F.. Richmond University; Estados UnidosFil: Burke, D. P.. Maynooth University; IrlandaFil: Buzi, D.. Università degli Studi di Roma "La Sapienza"; ItaliaFil: Buzzelli, A.. Universita Tor Vergata; ItaliaFil: Cammilleri, D.. APC; FranciaFil: Cavaliere, F.. University of Milan; ItaliaFil: Chanial, P.. APC; FranciaFil: Etchegoyen, Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaFil: Harari, Diego Dario. Comisión Nacional de Energía Atómica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Medina, Maria Clementina. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Argentino de Radioastronomía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Argentino de Radioastronomía; ArgentinaFil: Romero, Gustavo Esteban. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Argentino de Radioastronomía. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Argentino de Radioastronomía; ArgentinaFil: Suarez, Federico. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Tecnología en Detección y Astropartículas. Comisión Nacional de Energía Atómica. Instituto de Tecnología en Detección y Astropartículas. Universidad Nacional de San Martín. Instituto de Tecnología en Detección y Astropartículas; ArgentinaThe European Physical Society Conference on High Energy PhysicsVeneciaItaliaEuropean Physical Societ

Partitioning the Proteome: Phase Separation for Targeted Analysis of Membrane Proteins in Human Post-Mortem Brain

Neuroproteomics is a powerful platform for targeted and hypothesis driven research, providing comprehensive insights into cellular and sub-cellular disease states, Gene × Environmental effects, and cellular response to medication effects in human, animal, and cell culture models. Analysis of sub-proteomes is becoming increasingly important in clinical proteomics, enriching for otherwise undetectable proteins that are possible markers for disease. Membrane proteins are one such sub-proteome class that merit in-depth targeted analysis, particularly in psychiatric disorders. As membrane proteins are notoriously difficult to analyse using traditional proteomics methods, we evaluate a paradigm to enrich for and study membrane proteins from human post-mortem brain tissue. This is the first study to extensively characterise the integral trans-membrane spanning proteins present in human brain. Using Triton X-114 phase separation and LC-MS/MS analysis, we enriched for and identified 494 membrane proteins, with 194 trans-membrane helices present, ranging from 1 to 21 helices per protein. Isolated proteins included glutamate receptors, G proteins, voltage gated and calcium channels, synaptic proteins, and myelin proteins, all of which warrant quantitative proteomic investigation in psychiatric and neurological disorders. Overall, our sub-proteome analysis reduced sample complexity and enriched for integral membrane proteins by 2.3 fold, thus allowing for more manageable, reproducible, and targeted proteomics in case vs. control biomarker studies. This study provides a valuable reference for future neuroproteomic investigations of membrane proteins, and validates the use Triton X-114 detergent phase extraction on human post mortem brain