Cosmology with the Laser Interferometer Space Antenna

254 pags:, 44 figs.The Laser Interferometer Space Antenna (LISA) has two scientific objectives of cosmological focus: to probe the expansion rate of the universe, and to understand stochastic gravitational-wave backgrounds and their implications for early universe and particle physics, from the MeV to the Planck scale. However, the range of potential cosmological applications of gravitational-wave observations extends well beyond these two objectives. This publication presents a summary of the state of the art in LISA cosmology, theory and methods, and identifies new opportunities to use gravitational-wave observations by LISA to probe the universe.This work is partly supported by: A.G. Leventis Foundation; Academy of Finland Grants 328958 and 345070; Alexander S. Onassis Foundation, Scholarship ID: FZO 059-1/2018-2019; Amaldi Research Center funded by the MIUR program “Dipartimento di Eccellenza” (CUP: B81I18001170001); ASI Grants No. 2016-24-H.0 and No. 2016-24-H.1-2018; Atracción de Talento Grant 2019-T1/TIC-15784; Atracción de Talento contract no. 2019-T1/TIC-13177 granted by the Comunidad de Madrid; Ayuda ‘Beatriz Galindo Senior’ by the Spanish ‘Ministerio de Universidades’, Grant BG20/00228; Basque Government Grant (IT-979-16); Belgian Francqui Foundation; Centre national d’Etudes spatiales; Ben Gurion University Kreitman Fellowship, and the Israel Academy of Sciences and Humanities (IASH) & Council for Higher Education (CHE) Excellence Fellowship Program for International Postdoctoral Researchers; Centro de Excelencia Severo Ochoa Program SEV-2016-0597; CERCA program of the Generalitat de Catalunya; Cluster of Excellence “Precision Physics, Fundamental Interactions, and Structure of Matter” (PRISMA? EXC 2118/1); Comunidad de Madrid, Contrato de Atracción de Talento 2017-T1/TIC-5520; Czech Science Foundation GAČR, Grant No. 21-16583M; Delta ITP consortium; Department of Energy under Grant No. DE-SC0008541, DE-SC0009919 and DESC0019195; Deutsche Forschungsgemeinschaft (DFG), Project ID 438947057; Deutsche Forschungsgemeinschaft under Germany’s Excellence Strategy - EXC 2121 Quantum Universe - 390833306; European Structural and Investment Funds and the Czech Ministry of Education, Youth and Sports (Project CoGraDS - CZ.02.1.01/0.0/0.0/15 003/0000437); European Union’s H2020 ERC Consolidator Grant “GRavity from Astrophysical to Microscopic Scales” (Grant No. GRAMS-815673); European Union’s H2020 ERC, Starting Grant Agreement No. DarkGRA-757480; European Union’s Horizon 2020 programme under the Marie Sklodowska-Curie Grant Agreement 860881 (ITN HIDDeN); European Union’s Horizon 2020 Research and Innovation Programme Grant No. 796961, “AxiBAU” (K.S.); European Union’s Horizon 2020 Research Council grant 724659 MassiveCosmo ERC-2016-COG; FCT through national funds (PTDC/FIS-PAR/31938/2017) and through project “BEYLA – BEYond LAmbda” with Ref. Number PTDC/FIS-AST/0054/2021; FEDER-Fundo Europeu de Desenvolvimento Regional through COMPETE2020 - Programa Operacional Competitividade e Internacionalização (POCI-01-0145- FEDER-031938) and research Grants UIDB/04434/2020 and UIDP/04434/2020; Fondation CFM pour la Recherche in France; Foundation for Education and European Culture in Greece; French ANR project MMUniverse (ANR-19-CE31-0020); FRIA Grant No.1.E.070.19F of the Belgian Fund for Research, F.R. S.-FNRS Fundação para a Ciência e a Tecnologia (FCT) through Contract No. DL 57/2016/CP1364/ CT0001; Fundação para a Ciência e a Tecnologia (FCT) through Grants UIDB/04434/2020, UIDP/04434/ 2020, PTDC/FIS-OUT/29048/2017, CERN/FIS-PAR/0037/2019 and “CosmoTests – Cosmological tests of gravity theories beyond General Relativity” CEECIND/00017/2018; Generalitat Valenciana Grant PROMETEO/2021/083; Grant No. 758792, project GEODESI; Government of Canada through the Department of Innovation, Science and Economic Development and Province of Ontario through the Ministry of Colleges and Universities; Grants-in-Aid for JSPS Overseas Research Fellow (No. 201960698); I?D Grant PID2020-118159GB-C41 of the Spanish Ministry of Science and Innovation; INFN iniziativa specifica TEONGRAV; Israel Science Foundation (Grant No. 2562/20); Japan Society for the Promotion of Science (JSPS) KAKENHI Grant Nos. 20H01899 and 20H05853; IFT Centro de Excelencia Severo Ochoa Grant SEV-2; Kavli Foundation and its founder Fred Kavli; Minerva Foundation; Ministerio de Ciencia e Innovacion Grant PID2020-113644GB-I00; NASA Grant 80NSSC19K0318; NASA Hubble Fellowship grants No. HST-HF2-51452.001-A awarded by the Space Telescope Science Institute with NASA contract NAS5-26555; Netherlands Organisation for Science and Research (NWO) Grant Number 680-91-119; new faculty seed start-up grant of the Indian Institute of Science, Bangalore, the Core Research Grant CRG/2018/002200 of the Science and Engineering; NSF Grants PHY-1820675, PHY-2006645 and PHY-2011997; Polish National Science Center Grant 2018/31/D/ ST2/02048; Polish National Agency for Academic Exchange within the Polish Returns Programme under Agreement PPN/PPO/2020/1/00013/U/00001; Pró-Reitoria de Pesquisa of Universidade Federal de Minas Gerais (UFMG) under Grant No. 28359; Ramón y Cajal Fellowship contract RYC-2017-23493; Research Project PGC2018-094773-B-C32 [MINECO-FEDER]; Research Project PGC2018-094773-B-C32 [MINECO-FEDER]; ROMFORSK Grant Project. No. 302640; Royal Society Grant URF/R1/180009 and ERC StG 949572: SHADE; Shota Rustaveli National Science Foundation (SRNSF) of Georgia (Grant FR/18-1462); Simons Foundation/SFARI 560536; SNSF Ambizione grant; SNSF professorship Grant (No. 170547); Spanish MINECO’s “Centro de Excelencia Severo Ochoa” Programme Grants SEV-2016- 0597 and PID2019-110058GB-C22; Spanish Ministry MCIU/AEI/FEDER Grant (PGC2018-094626-BC21); Spanish Ministry of Science and Innovation (PID2020-115845GB-I00/AEI/10.13039/ 501100011033); Spanish Proyectos de I?D via Grant PGC2018-096646-A-I00; STFC Consolidated Grant ST/T000732/1; STFC Consolidated Grants ST/P000762/1 and ST/T000791/1; STFC Grant ST/ S000550/1; STFC Grant ST/T000813/1; STFC Grants ST/P000762/1 and ST/T000791/1; STFC under the research Grant ST/P000258/1; Swiss National Science Foundation (SNSF), project The Non-Gaussian Universe and Cosmological Symmetries, Project Number: 200020-178787; Swiss National Science Foundation Professorship Grants No. 170547 and No. 191957; SwissMap National Center for Competence in Research; “The Dark Universe: A Synergic Multi-messenger Approach” Number 2017X7X85K under the MIUR program PRIN 2017; UK Space Agency; UKSA Flagship Project, Euclid.Peer reviewe

Métabolisme du resvératrol par les cytochromes P450 et étude de leur inhibition par le resvératrol et les polyphénols de boissons alcoolisées

La première partie de notre étude a porté sur le métabolisme du resvératrol (trans-3,5,4'-trihydroxystilbène) par les cytochromes P450 et l'identification des isoformes de cytochromes P450 humains (CYP) impliquées dans sa transformation hépatique. Le resvératrol est hydroxylé en picéatannol (3,5,3',4'-tétrahydroxystilbène) et en tétrahydroxystilbène X non identifié. A l'aide de moyens actuellement bien codifiés, nous avons montré que le CYP1A2 contenu dans les microsomes hépatiques humains est l'enzyme qui catalyse majoritairement la biotransformation du resvératrol en picéatannol et en tétrahydroxystilbène X. La formation de ces métabolites est également catalysée par les CYP1A1, CYP1A2 et CYP1B1 recombinants humains. La seconde partie de notre étude s'est intéressée à l'effet inhibiteur du resvératrol, de son dimère (l's-viniférine) et des polyphénols de boissons alcoolisées sur les activités enzymatiques des CYP1A1, CYP1A2, CYP1B1, CYP2A6, CYP2E1, CYP3A4 et CYP4A. L'inhibition de l's-viniférine est plus forte que celle du resvératrol pour toutes les activités CYP testées. Le resvératrol et l's-viniférine inhibent tous les CYP testés selon un mode mixte sauf pour le CYP2E1 (mode non-compétitif). Si le mode d'inhibition de 1's-viniférine n'est pas basé sur un mécanisme catalytique pour aucun des CYP étudiés, l'effet inhibiteur du resvératrol fait intervenir un mécanisme catalytique lors de l'inhibition des CYP1A2 et CYP3A4 chez l'homme. L'inhibition des activités CYP, obtenue avec les polyphénols de vin rouge ou de CognacR, montre que ni le resvératrol ni l's-viniférine ne peuvent expliquer à eux seuls ces effets inhibiteurs. La dernière partie de notre étude a concerné les effets in vivo du resvératrol et de 1'c-viniférine sur les cytochromes P450. Chez les rats traités à la dose de 100 mg/Kg/jour, en intrapéritonéal pendant trois jours, nous avons observé au niveau du foie et du rein des différences significatives parmi les activités enzymatiques CYP, assorties parfois de modifications de leur taux de protéines.BREST-BU Médecine-Odontologie (290192102) / SudocSudocFranceF

Identification et dosage de dérivés oxydés d'acides gras polyinsaturés dans les milieux biologiques par une approche métabolomique ciblée

Les oxylipides/oxylipines, dérivés oxydés d'acides gras polyinsaturés, jouent un rôle important dans la signalisation lipidique, en réponse à un stress biotique ou abiotique, chez les animaux comme chez les végétaux. Nous avons mis au point des méthodes spécifiques de dosage des oxylipides dans des échantillons biologiques d'origine humaine et phycologique (algues). Ces méthodes font appel à la spectrométrie de masse couplée à la chromatographie en phase gazeuse ou liquide (GC/MS/NCI et LC/MS). Ainsi, nous avons : -établi une méthode de dosage des EETs dans le sang humain par GC/MS/NCI. Ces métabolites époxydés de l'acide arachidonique (AA) par les cytochromes P450 ont des propriétés de vasorelaxation. -mis en évidence la production de 20-HETE, métabolite de l'AA, par le CYFP dans une lignée hépatomateuse humaine, HepaRG. -étudié la formation des énantiomères du 19,20-époxyde de l'acide docosahaénoïque (DHA) après incubation de cytochromes P450 recombinants humains avec du [14C]-DHA, ainsi que leur séparation sur colonne chirale. -identifié une signature oxylipidique de la réponse de l'algue brune Laminaria digitata au stress induit par le cuivre, révélant des voies de synthèse enzymatique et chimique ainsi qu'un nouveau composé : l'acide 18-hydroxy, 17-oxo-eicosatétranoïque. -mis en évidence l'émission d'aldéhydes polyinsaturés par les algues en réponse à un stress. Ces composés sont impliqués dans la communication interplante menant à une potentialisation des défenses face au stress biotique mimé par les oligoguluronates. Ces résultats devraient contribuer à une meilleure compréhension du rôle des oxylipides chez l'homme comme chez l'algue.Oxylipids/oxylipins, oxidized derivatives of polyunsaturated fatty acids, play a major role in lipid signalization, during biotic or abiotic stress, in both mammals ans in higher plants. We established specific methods for quantifying oxylipids in biological samples of human or phycologic (algae) origin. These methods are based on mass spectrometry coupled with gas or liquid chromatography (GC/MS/NCI and LC/MS). Thus, we have : -established a quantification method of EETs from human blood by GC/MS/NCI. These arachidonic acid (AA) metabolites by the action of cytochromes P450, have vasorelaxation properties. -highlighted the specific production of 20-HETE, an AA metabolite, by the CYP4F3B in a human hepatoma cell line, HepaRG. -studied the formation of docosahexaenoic acid (DHA) 19,20-epoxide enantiomers after incubation of recombinant human cytochromes P450 with [14C]-DHA and their separation on a chiral column. -identified an oxylipin signature of the response of the brown marine alga Laminaria digitata during abiotic stress, induced by copper, revealing enzymatic and chemical synthesis pathways. The presence of a new compound, the 18-hydroxy, 17-oxo-eicosatetraenoic acid has been described. -highlighted the polyinsaturated aldehyde emission in response to stress in this alga. These compounds are involved in distance signaling and inter-plant communication leading to a priming of defenses during a biotic stress mimicked by oligoguluronates. These results could allow a better comprehension of the oxylipid role in man as algae.BREST-BU Médecine-Odontologie (290192102) / SudocSudocFranceF

n-3 long chain polyunsaturated fatty acids: a nutritional tool to prevent insulin resistance associated to type 2 diabetes and obesity?

n-3 long chain polyunsaturated fatty acids (n-3 LC-PUFA), mainly eicosapentaenoic acid (EPA, 20:5 n-3) and docosahexaenoic acid (DHA, 22:6 n-3), are present in mammal tissues both from endogenous synthesis from desaturation and elongation of 18:3 n-3 and/or from dietary origin (marine products and fish oils). In rodents in vivo, n-3 LC-PUFA have a protective effect against high fat diet induced insulin resistance. Such an effect is explained at the molecular level by the prevention of many alterations of insulin signaling induced by a high fat diet. Indeed, the protective effect of n-3 LC-PUFA results from the following: (a) the prevention of the decrease of phosphatidyl inositol 3’ kinase (PI3 kinase) activity and of the depletion of the glucose transporter protein GLUT4 in the muscle; (b) the prevention of the decreased expression of GLUT4 in adipose tissue. In addition, n-3 LC-PUFA inhibit both the activity and expression of liver glucose-6-phosphatase which could explain the protective effect with respect to the excessive hepatic glucose output induced by a high fat diet. n-3 LC-PUFA also decrease muscle intramyofibrillar triglycerides and liver steatosis. This last effect results on the one hand, from a decreased expression of lipogenesis enzymes and of delta 9 desaturase (via a depleting effect on sterol response element binding protein 1c (SREBP-1c). On the other hand, n-3 LC-PUFA stimulate fatty acid oxidation in the liver (via the activation of peroxisome proliferator activated receptor $\alpha$ (PPAR-$\alpha$)). In patients with type 2 diabetes, fish oil dietary supplementation fails to reverse insulin resistance for unclear reasons, but systematically decreases plasma triglycerides. Conversely, in healthy humans, fish oil has many physiological effects. Indeed, fish oil reduces insulin response to oral glucose without altering the glycaemic response, abolishes extraggression at times of mental stress, decreases the activation of sympathetic activity during mental stress and also decreases plasma triglycerides. These effects are encouraging in the perspective of prevention of insulin resistance but further clinical and basic studies must be designed to confirm and complete our knowledge in this field

Functions of Anti-MAGE T-Cells Induced in Melanoma Patients under Different Vaccination Modalities.

Tumor regressions have been observed in a small proportion of melanoma patients vaccinated with a MAGE-A3 peptide presented by HLA-A1, administered as peptide, ALVAC canarypox virus containing a MAGE-A3 minigene, or peptide-pulsed dendritic cells (DC). There was a correlation between tumor regression and the detection of anti-MAGE-3.A1 CTL responses. These responses were monoclonal and often of a very low magnitude after vaccination with peptide or ALVAC, and usually polyclonal and of a higher magnitude after DC vaccination. These results suggested that, at least in some patients, surprisingly few anti-MAGE-3.A1 T-cells could initiate a tumor regression process. To understand the role of these T cells, we carried out a functional analysis of anti-MAGE-3.A1 CTL clones derived from vaccinated patients who displayed tumor regression. The functional avidities of these CTL clones, evaluated in lysis assays, were surprisingly low, suggesting that high avidity was not part of the putative capability of these CTL to trigger tumor rejection. Most anti-MAGE-3.A1 CTL clones obtained after DC vaccination, but not after peptide or ALVAC vaccination, produced interleukin 10. Transcript profiling confirmed these results and indicated that approximately 20 genes, including CD40L, prostaglandin D2 synthase, granzyme K, and granzyme H, were highly differentially expressed between the anti-MAGE-3.A1 CTL clones derived from patients vaccinated with either peptide-ALVAC or peptide-pulsed DC. These results indicate that the modality of vaccination with a tumor-specific antigen influences the differentiation pathway of the antivaccine CD8 T-cells, which may have an effect on their capacity to trigger a tumor rejection response. [Cancer Res 2008;68(10):3931-40]