Characterization of distinct subpopulations of hepatic macrophages in HFD/obese mice.

The current dogma is that obesity-associated hepatic inflammation is due to increased Kupffer cell (KC) activation. However, recruited hepatic macrophages (RHMs) were recently shown to represent a sizable liver macrophage population in the context of obesity. Therefore, we assessed whether KCs and RHMs, or both, represent the major liver inflammatory cell type in obesity. We used a combination of in vivo macrophage tracking methodologies and adoptive transfer techniques in which KCs and RHMs are differentially labeled with fluorescent markers. With these approaches, the inflammatory phenotype of these distinct macrophage populations was determined under lean and obese conditions. In vivo macrophage tracking revealed an approximately sixfold higher number of RHMs in obese mice than in lean mice, whereas the number of KCs was comparable. In addition, RHMs comprised smaller size and immature, monocyte-derived cells compared with KCs. Furthermore, RHMs from obese mice were more inflamed and expressed higher levels of tumor necrosis factor-α and interleukin-6 than RHMs from lean mice. A comparison of the MCP-1/C-C chemokine receptor type 2 (CCR2) chemokine system between the two cell types showed that the ligand (MCP-1) is more highly expressed in KCs than in RHMs, whereas CCR2 expression is approximately fivefold greater in RHMs. We conclude that KCs can participate in obesity-induced inflammation by causing the recruitment of RHMs, which are distinct from KCs and are not precursors to KCs. These RHMs then enhance the severity of obesity-induced inflammation and hepatic insulin resistance

The influence of social phobia in first episode of psychosis and attentional processing and the ability to use theory of mind

Chapter One: Literature Review This chapter reviews the research surrounding the prevalence of comorbid social phobia in people diagnosed with schizophrenia. It then critically evaluates the eight studies that have specifically explored the relationships, if any, between social phobia and psychotic symptoms. The review surmises that the research findings are inconsistent, which seem to be attributable to methodological differences between all the studies in terms of participant selection, chronicity of psychotic symptoms and lack of consistent measures. Chapter Two: Research Report This study investigates attentional processing, the influence of social phobia and the ability to use Theory of Mind (ToM: the ability to infer other people's mental states and behaviour) in people diagnosed with their first episode of psychosis, when compared to healthy matched controls. The results showed that the first episode group attended towards negative evaluation, somatic sensations, physical threat, but not social situation word groups. Social phobia was highly prevalent in the first episode of psychosis cohort (37%) and this anxiety disorder was unrelated to psychotic symptoms. ToM processing was impaired in the first episode group. ToM was not related to social phobia symptoms, but was related to social functioning. Chapter Three: Critical Appraisal This section presents an overview of the experiences and personal reflections of the work that constitutes this thesis and includes the main personal learning points.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

ELGAR—a European Laboratory for Gravitation and Atom-interferometric Research

Gravitational waves (GWs) were observed for the first time in 2015, one century after Einstein predicted their existence. There is now growing interest to extend the detection bandwidth to low frequency. The scientific potential of multi-frequency GW astronomy is enormous as it would enable to obtain a more complete picture of cosmic events and mechanisms. This is a unique and entirely new opportunity for the future of astronomy, the success of which depends upon the decisions being made on existing and new infrastructures. The prospect of combining observations from the future space-based instrument LISA together with third generation ground based detectors will open the way toward multi-band GW astronomy, but will leave the infrasound (0.1–10 Hz) band uncovered. GW detectors based on matter wave interferometry promise to fill such a sensitivity gap. We propose the European Laboratory for Gravitation and Atom-interferometric Research (ELGAR), an underground infrastructure based on the latest progress in atomic physics, to study space–time and gravitation with the primary goal of detecting GWs in the infrasound band. ELGAR will directly inherit from large research facilities now being built in Europe for the study of large scale atom interferometry and will drive new pan-European synergies from top research centers developing quantum sensors. ELGAR will measure GW radiation in the infrasound band with a peak strain sensitivity of $3.3{\times}1{0}^{-22}/\sqrt{\text{Hz}}$ at 1.7 Hz. The antenna will have an impact on diverse fundamental and applied research fields beyond GW astronomy, including gravitation, general relativity, and geology.AB acknowledges support from the ANR (project EOSBECMR), IdEx Bordeaux—LAPHIA (project OE-TWR), theQuantERA ERA-NET (project TAIOL) and the Aquitaine Region (projets IASIG3D and USOFF).XZ thanks the China Scholarships Council (No. 201806010364) program for financial support. JJ thanks ‘AssociationNationale de la Recherche et de la Technologie’ for financial support (No. 2018/1565).SvAb, NG, SL, EMR, DS, and CS gratefully acknowledge support by the German Space Agency (DLR) with funds provided by the Federal Ministry for Economic Affairs and Energy (BMWi) due to an enactment of the German Bundestag under Grants No. DLR∼50WM1641 (PRIMUS-III), 50WM1952 (QUANTUS-V-Fallturm), and 50WP1700 (BECCAL), 50WM1861 (CAL), 50WM2060 (CARIOQA) as well as 50RK1957 (QGYRO)SvAb, NG, SL, EMR, DS, and CS gratefully acknowledge support by ‘Niedersächsisches Vorab’ through the ‘Quantum- and Nano-Metrology (QUANOMET)’ initiative within the project QT3, and through ‘Förderung von Wissenschaft und Technik in Forschung und Lehre’ for the initial funding of research in the new DLR-SI Institute, the CRC 1227 DQ-mat within the projects A05 and B07DS gratefully acknowledges funding by the Federal Ministry of Education and Research (BMBF) through the funding program Photonics Research Germany under contract number 13N14875.RG acknowledges Ville de Paris (Emergence programme HSENS-MWGRAV), ANR (project PIMAI) and the Fundamental Physics and Gravitational Waves (PhyFOG) programme of Observatoire de Paris for support. We also acknowledge networking support by the COST actions GWverse CA16104 and AtomQT CA16221 (Horizon 2020 Framework Programme of the European Union).The work was also supported by the German Space Agency (DLR) with funds provided by the Federal Ministry for Economic Affairs and Energy (BMWi) due to an enactment of the German Bundestag under Grant Nos.∼50WM1556, 50WM1956 and 50WP1706 as well as through the DLR Institutes DLR-SI and DLR-QT.PA-S, MN, and CFS acknowledge support from contracts ESP2015-67234-P and ESP2017-90084-P from the Ministry of Economy and Business of Spain (MINECO), and from contract 2017-SGR-1469 from AGAUR (Catalan government).SvAb, NG, SL, EMR, DS, and CS gratefully acknowledge support by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—EXC-2123 QuantumFrontiers—390837967 (B2) andCRC1227 ‘DQ-mat’ within projects A05, B07 and B09.LAS thanks Sorbonne Universités (Emergence project LORINVACC) and Conseil Scientifique de l'Observatoire de Paris for funding.This work was realized with the financial support of the French State through the ‘Agence Nationale de la Recherche’ (ANR) in the frame of the ‘MRSEI’ program (Pre-ELGAR ANR-17-MRS5-0004-01) and the ‘Investissement d'Avenir’ program (Equipex MIGA: ANR-11-EQPX-0028, IdEx Bordeaux—LAPHIA: ANR-10-IDEX-03-02).Peer Reviewe

Euclid Near Infrared Spectrometer and Photometer instrument concept and first test results obtained for different breadboards models at the end of phase C

The Euclid mission objective is to understand why the expansion of the Universe is accelerating through by mapping the geometry of the dark Universe by investigating the distance-redshift relationship and tracing the evolution of cosmic structures. The Euclid project is part of ESA's Cosmic Vision program with its launch planned for 2020 (ref [1]). The NISP (Near Infrared Spectrometer and Photometer) is one of the two Euclid instruments and is operating in the near-IR spectral region (900- 2000nm) as a photometer and spectrometer. The instrument is composed of: - a cold (135K) optomechanical subsystem consisting of a Silicon carbide structure, an optical assembly (corrector and camera lens), a filter wheel mechanism, a grism wheel mechanism, a calibration unit and a thermal control system - a detection subsystem based on a mosaic of 16 HAWAII2RG cooled to 95K with their front-end readout electronic cooled to 140K, integrated on a mechanical focal plane structure made with molybdenum and aluminum. The detection subsystem is mounted on the optomechanical subsystem structure - a warm electronic subsystem (280K) composed of a data processing / detector control unit and of an instrument control unit that interfaces with the spacecraft via a 1553 bus for command and control and via Spacewire links for science data This presentation describes the architecture of the instrument at the end of the phase C (Detailed Design Review), the expected performance, the technological key challenges and preliminary test results obtained for different NISP subsystem breadboards and for the NISP Structural and Thermal model (STM)

On the importance of fat cell size, location and signaling in insulin resistance

Obesity has reached epidemic proportions worldwide and is associated with insulin resistance, type 2 diabetes and cardiovascular disease. During the past decades, substantial evidence has demonstrated that not only the amount of adipose tissue constitutes a major determinant in the development of metabolic disorders, but also the distribution. The visceral adipose tissue has shown to be stronger correlated with insulin resistance, type 2 diabetes and cardiovascular disease than the subcutaneous depot. When we measured the activity of the nuclear receptor PPARγ in visceral and subcutaneous adipocytes, we found considerably lower activity in fat cells obtained from the visceral portion. This finding provides additional evidence to the unfavorable consequences of visceral obesity. The common PPARγ polymorphism Pro12Ala was studied in type 2 diabetic patients. We found that men with the Ala isoform exhibited higher sagittal abdominal diameter, waist circumference and body weight compared with homozygotes for the Pro isoform. However, no differences in either gender with regard to blood pressure or markers of cardiovascular disease and organ damage could be observed. In addition to an excessive visceral adipose tissue mass, obese subjects with enlarged adipocytes display an increased risk for developing metabolic disorders compared with individuals exhibiting smaller fat cells but a similar degree of adiposity. The insulin responsiveness in small and large adipocytes obtained from the same subject was examined. Upon insulin stimulation, we found approximately a 2 fold increase of GLUT4 at the plasma membrane in small adipocytes, whereas the large fat cells were refractory to insulin induced GLUT4 translocation. This finding demonstrates a causal relationship between the accumulation of large fat cells in obese subjects and reduced insulin responsiveness. Caloric restriction in humans ameliorates insulin responsiveness in liver and muscle prior to any substantial weight loss. By combining gene expression profiles of adipose tissue and adipocytes from human subjects undergoing either caloric restriction or overfeeding, we identified genes regulated by changes in caloric intake independent of weight loss per se. We found several genes under the control of mTOR and SREBP1 as well as genes involved in β-oxidation, liberation of fatty acids and glyceroneogenesis to be regulated during the interventions. These genes may indicate pathways and mechanisms mediating the effects of nutrient deprivation and obesity on morbidity and mortality

and signaling in insulin resistance

On the importance of fat cell size, locatio

*Corresponding author:

Distinct parts of leukotriene C-4 synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protei

Distinct parts of leukotriene C-4 synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein

Leukotriene C-4 is a potent inflammatory mediator formed from arachidonic acid and glutathione. 5-Lipoxygenase (5-LO), 5-lipoxygenase activating protein (FLAP) and leukotriene C-4 synthase (LTC4S) participate in its biosynthesis. We report evidence that LTC4S interacts in vitro with both FLAP and 5-LO and that these interactions involve distinct parts of LTC4S. FLAP bound to the N-terminal part/first hydrophobic region of LTC4S. This part did not bind 5-LO which bound to the second hydrophilic loop of LTC4S. Fluorescent FLAP- and LTC4S-fusion proteins co-localized at the nuclear envelope. Furthermore, GFP-FLAP and GFP-LTC4S co-localized with a fluorescent ER marker. In testing HEK293/T or COS-7 cells GFP-5-LO was found mainly in the nuclear matrix. Upon stimulation with calcium ionophore, GFP-5-LO translocated to the nuclear envelope allowing it to interact with FLAP and LTC4S. Direct interaction of 5-LO and LTC4S in ionophore-stimulated (but not un-stimulated) cells was demonstrated by BRET using GFP-5-LO and Rluc-LTC4S.Original Publication: Tobias Strid, Jesper Svartz, Niclas Franck, Elisabeth Hallin, Björn Ingelsson, Mats Söderström and Sven Hammarström, Distinct parts of leukotriene C-4 synthase interact with 5-lipoxygenase and 5-lipoxygenase activating protein, 2009, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, (381), 4, 518-522. http://dx.doi.org/10.1016/j.bbrc.2009.02.074 Copyright: Elsevier Science B.V., Amsterdam http://www.elsevier.com/</p