Monoacylglycerol lipase reprograms hepatocytes and macrophages to promote liver regeneration

Background & Aims: Liver regeneration is a repair process in which metabolic reprogramming of parenchymal and inflammatory cells plays a major role. Monoacylglycerol lipase (MAGL) is an ubiquitous enzyme at the crossroad between lipid metabolism and inflammation. It converts monoacylglycerols into free fatty acids and metabolises 2-arachidonoylglycerol into arachidonic acid, being thus the major source of pro-inflammatory prostaglandins in the liver. In this study, we investigated the role of MAGL in liver regeneration. Methods: Hepatocyte proliferation was studied in vitro in hepatoma cell lines and ex vivo in precision-cut human liver slices. Liver regeneration was investigated in mice treated with a pharmacological MAGL inhibitor, MJN110, as well as in animals globally invalidated for MAGL (MAGL-/-) and specifically invalidated in hepatocytes (MAGLHep-/-) or myeloid cells (MAGLMye-/-). Two models of liver regeneration were used: acute toxic carbon tetrachloride injection and two-thirds partial hepatectomy. MAGLMye-/- liver macrophages profiling was analysed by RNA sequencing. A rescue experiment was performed by in vivo administration of interferon receptor antibody in MAGLMye-/- mice. Results: Precision-cut human liver slices from patients with chronic liver disease and human hepatocyte cell lines exposed to MJN110 showed reduced hepatocyte proliferation. Mice with global invalidation or mice treated with MJN110 showed blunted liver regeneration. Moreover, mice with specific deletion of MAGL in either hepatocytes or myeloid cells displayed delayed liver regeneration. Mechanistically, MAGLHep-/- mice showed reduced liver eicosanoid production, in particular prostaglandin E2 that negatively impacts on hepatocyte proliferation. MAGL inhibition in macrophages resulted in the induction of the type I interferon pathway. Importantly, neutralising the type I interferon pathway restored liver regeneration of MAGLMye-/- mice. Conclusions: Our data demonstrate that MAGL promotes liver regeneration by hepatocyte and macrophage reprogramming. Impact and Implications: By using human liver samples and mouse models of global or specific cell type invalidation, we show that the monoacylglycerol pathway plays an essential role in liver regeneration. We unveil the mechanisms by which MAGL expressed in both hepatocytes and macrophages impacts the liver regeneration process, via eicosanoid production by hepatocytes and the modulation of the macrophage interferon pathway profile that restrains hepatocyte proliferation.The authors thank V. Fauveau, Institut Cochin, for help in surgery experiments; Olivier Thibaudeau of the Plateau de Morphologie Facility (INSERM UMR 1152, France) and Nicolas Sorhaindo of the Plateforme de Biochimie (CRI, INSERM UMR1149) for their help in the histology and liver function tests; and K. Bailly from the cytometry platform of Cochin Institute and H. Fohrer-Ting from the Centre de Recherche des Cordeliers, Paris University, for cell sorting analyses.Scopu

Cristaux photoniques à fente : vers une photonique silicium hybride à exaltation localisée du champ électromagnétique

Abstract : The work described in this PhD thesis brings theoretical and experimental contributions to the study of planar slot photonic crystals for a local exaltation of the electromagnetic field. The propagation of slow light in slot photonic crystal waveguides is investigated by achieving dispersion engineering and confinement of light in slotted microcavities. We have performed 3D calculations to optimize the dispersion properties of the photonic crystals by tailoring the slot itself. This allowed the observation of an enhancement of the field localization aiming at the infiltration of the slot by highly nonlinear materials. We achieved a fabrication process of slot photonic crystal waveguides in silicon on insulator (SOI) structures based on electron bearn lithography and plasma et­ ching. Slow light measurements are reported and validate the optimization method. Group indices higher than 20 have been measured in 1 mm long deviees. Slot photonic crystal microcavities with quality factors higher than 20,000 have been achieved on SOI. We have performed nonlinear optical measurements and revealed that silicon nonlinear effects in slot photonic crystal waveguides are reduced compare to standard waveguides, despite the increase of the exaltation of the electromagnetic field. Finally, we have investigated disorder-induced losses in this type of waveguides by opticallow coherence reflectrometry.Les travaux de cette thèse apportent une contribution théorique et expérimentale aux études portant sur les cristaux photoniques planaires à fente pour l'exaltation locale du champ électromagnétique. Nous avons étudié la propagation de lumière lente dans des cristaux photoniques à fente en réalisant une ingénierie de dispersion et le confinement de la lumière dans des micro-cavités à fente structurée. Nous avons pour cela effectué des calculs 3D pour optimiser les propriétés de dispersion des cristaux photoniques en structurant la fente elle-même. Cette optimisation a permis d'observer un renforcement de la localisation du champ électromagnétique dans la fente en vue d'un remplissage par des matériaux fortement non linéaires. Nous avons développé un procédé de fabrication pour les cristaux photoniques dans des structures en silicium sur isolant basé sur la lithographie électronique et la gravure plasma. Le régime de lumière lente a été caractérisé expérimentalement et nous a permis de valider la méthode d'optimisation choisie. Des facteurs de ralentissement supérieurs à 10 ont été mesurés dans des dispositifs allant jusqu'à 1 mm de long. Des micro-cavités à fente avec des facteurs de qualité supérieurs à 20000 sur substrat SOI ont été réalisées. Nous avons effectué des mesures d'optique non linéaire dans des guides à cristaux photoniques à fente et avons montré que les effets non linéaires du silicium sont réduits malgré l'exaltation du champ électromagnétique comparés à ceux présents dans des guides à cristaux photoniques standards. Nous avons enfin étudié les pertes le désordre dans ce type de structure par mesures de réflectométrie optique à faible cohérence

Slot Photonic Crystal Waveguides : towards a silicon photonics with a localized exaltation of the electromagnetic field

Les travaux de cette thèse apportent une contribution théorique et expérimentale aux études portant sur les cristaux photoniques planaires à fente pour l'exaltation locale du champ électromagnétique. Nous avons étudié la propagation de lumière lente dans des cristaux photoniques à fente en réalisant une ingénierie de dispersion et le confinement de la lumière dans des micro-cavités à fente structurée. Nous avons pour cela effectué des calculs 3D pour optimiser les propriétés de dispersion des cristaux photoniques en structurant la fente elle-même. Cette optimisation a permis d'observer un renforcement de la localisation du champ électromagnétique dans la fente en vue d'un remplissage par des matériaux fortement non linéaires. Nous avons développé un procédé de fabrication pour les cristaux photoniques dans des structures en silicium sur isolant basé sur la lithographie électronique et la gravure plasma. Le régime de lumière lente a été caractérisé expérimentalement et nous a permis de valider la méthode d'optimisation choisie. Des facteurs de ralentissement supérieurs à 10 ont été mesurés dans des dispositifs allant jusqu'à 1 mm de long. Des micro-cavités à fente avec des facteurs de qualité supérieurs à 20000 sur substrat SOI ont été réalisées. Nous avons effectué des mesures d'optique non linéaire dans des guides à cristaux photoniques à fente et avons montré que les effets non linéaires du silicium sont réduits malgré l'exaltation du champ électromagnétique comparés à ceux présents dans des guides à cristaux photoniques standards. Nous avons enfin étudié les pertes le désordre dans ce type de structure par mesures de réflectométrie optique à faible cohérence.Abstract : The work described in this PhD thesis brings theoretical and experimental contributions to the study of planar slot photonic crystals for a local exaltation of the electromagnetic field. The propagation of slow light in slot photonic crystal waveguides is investigated by achieving dispersion engineering and confinement of light in slotted microcavities. We have performed 3D calculations to optimize the dispersion properties of the photonic crystals by tailoring the slot itself. This allowed the observation of an enhancement of the field localization aiming at the infiltration of the slot by highly nonlinear materials. We achieved a fabrication process of slot photonic crystal waveguides in silicon on insulator (SOI) structures based on electron bearn lithography and plasma et­ ching. Slow light measurements are reported and validate the optimization method. Group indices higher than 20 have been measured in 1 mm long deviees. Slot photonic crystal microcavities with quality factors higher than 20,000 have been achieved on SOI. We have performed nonlinear optical measurements and revealed that silicon nonlinear effects in slot photonic crystal waveguides are reduced compare to standard waveguides, despite the increase of the exaltation of the electromagnetic field. Finally, we have investigated disorder-induced losses in this type of waveguides by opticallow coherence reflectrometry

Cristaux photoniques à fente (vers une photonique silicium hybride à exaltation localisée du champ électromagnétique)

Les travaux de cette thèse apportent une contribution théorique et expérimentale aux études portant sur les cristaux photoniques planaires à fente pour l'exaltation locale du champ électromagnétique. Nous avons étudié la propagation de lumière lente dans des cristaux photoniques à fente en réalisant une ingénierie de dispersion et le confinement de la lumière dans des micro-cavités à fente structurée. Nous avons pour cela effectué des calculs 3D pour optimiser les propriétés de dispersion des cristaux photoniques en structurant la fente elle-même. Cette optimisation a permis d'observer un renforcement de la localisation du champ électromagnétique dans la fente en vue d'un remplissage par des matériaux fortement non linéaires. Nous avons développé un procédé de fabrication pour les cristaux photoniques dans des structures en silicium sur isolant basé sur la lithographie électronique et la gravure plasma. Le régime de lumière lente a été caractérisé expérimentalement et nous a permis de valider la méthode d'optimisation choisie. Des facteurs de ralentissement supérieurs à 10 ont été mesurés dans des dispositifs allant jusqu'à 1 mm de long. Des micro-cavités à fente avec des facteurs de qualité supérieurs à 20000 sur substrat SOI ont été réalisées. Nous avons effectué des mesures d'optique non linéaire dans des guides à cristaux photoniques à fente et avons montré que les effets non linéaires du silicium sont réduits malgré l'exaltation du champ électromagnétique comparés à ceux présents dans des guides à cristaux photoniques standards. Nous avons enfin étudié les pertes le désordre dans ce type de structure par mesures de réflectométrie optique à faible cohérence.Abstract : The work described in this PhD thesis brings theoretical and experimental contributions to the study of planar slot photonic crystals for a local exaltation of the electromagnetic field. The propagation of slow light in slot photonic crystal waveguides is investigated by achieving dispersion engineering and confinement of light in slotted microcavities. We have performed 3D calculations to optimize the dispersion properties of the photonic crystals by tailoring the slot itself. This allowed the observation of an enhancement of the field localization aiming at the infiltration of the slot by highly nonlinear materials. We achieved a fabrication process of slot photonic crystal waveguides in silicon on insulator (SOI) structures based on electron bearn lithography and plasma et ching. Slow light measurements are reported and validate the optimization method. Group indices higher than 20 have been measured in 1 mm long deviees. Slot photonic crystal microcavities with quality factors higher than 20,000 have been achieved on SOI. We have performed nonlinear optical measurements and revealed that silicon nonlinear effects in slot photonic crystal waveguides are reduced compare to standard waveguides, despite the increase of the exaltation of the electromagnetic field. Finally, we have investigated disorder-induced losses in this type of waveguides by opticallow coherence reflectrometry.PARIS11-SCD-Bib. électronique (914719901) / SudocSudocFranceF

RELATIONS THERMODYNAMIQUES ENTRE LA CRISTALLISATION DES ALLIAGES AMORPHES (Fe, B) ET LEUR PREPARATION PAR TREMPE DEPUIS L'ETAT LIQUIDE

Our experimental study is based on the enthalpic analysis of the crystallisation of fourteen Fe(1-x) Bx amorphous alloys with 0.125 ≤ x ≤ 0.25. We show that this system, though it is out of equilibrium, exhibits characteristics of thermodynamical reversibility. We point out the existence of a biphased domain formed from the undercooled liquid during the glass transition. We calculate the free enthalpy of the liquid from data of the phase diagram and from some thermodynamical properties of the solid phases. In order to account for our observations, we propose a simplified model of associations in the liquid phase.Notre étude expérimentale repose sur l'analyse enthalpique de la cristallisation de quatorze alliages amorphes Fe(1 - x) Bx pour 0,125 ≤ x ≤ 0,25. Nous montrons que ce système bien que hors d'équilibre présente les caractères de réversibilité thermodynamique. Nous mettons en évidence l'existence d'un domaine biphasé issu du liquide surfondu figé au moment de la transition vitreuse. Nous calculons l'enthalpie libre de la phase liquide à partir d'informations contenues dans le diagramme de phase et de certaines grandeurs de formation des phases solides. Pour rendre compte de nos observations, nous proposons un modèle simplifié d'associations en phase liquide

Detection of Onchocerca volvulus (Nematoda: Onchocercidae) infection in vectors from Amazonian Brazil following mass Mectizan distribution

Detection of Onchocerca volvulus in Simulium populations is of primary importance in the assessment of the effectiveness of onchocerciasis control programs. In Brazil, the main focus of onchocerciasis is in the Amazon region, in a Yanomami reserve. The main onchocerciasis control strategy in Brazil is the semi-annually mass distribution of the microfilaricide ivermectin. In accordance with the control strategy for the disease, polymerase chain reaction (PCR) was applied in pools of simuliids from the area to detect the helminth infection in the vectors, as recommended by the Onchocerciasis Elimination Program for the Americas and the World Health Organization. Systematic sampling was performed monthly from September 1998 to October 1999, and a total of 4942 blackflies were collected from two sites (2576 from Balawaú and 2366 from Toototobi). The molecular methodology was found to be highly sensitive and specific for the detection of infected and/or infective blackflies in pools of 50 blackflies. The results from the material collected under field conditions showed that after the sixth cycle of distribution of ivermectin, the prevalence of infected blackflies with O. volvulus had decreased from 8.6 to 0.3% in Balawaú and from 4 to 0.1% in Toototobi

Integrating III-V, Si, and polymer waveguides for optical interconnects: RAPIDO

We present a vision for the hybrid integration of advanced transceivers at 1.3 μm wavelength, and the progress done towards this vision in the EU-funded RAPIDO project. The final goal of the project is to make five demonstrators that show the feasibility of the proposed concepts to make optical interconnects and packet-switched optical networks that are scalable to Pb/s systems in data centers and high performance computing. Simplest transceivers are to be made by combining directly modulated InP VCSELs with 12 μm SOI multiplexers to launch, for example, 200 Gbps data into a single polymer waveguide with 4 channels to connect processors on a single line card. For more advanced transceivers we develop novel dilute nitride amplifiers and modulators that are expected to be more power-efficient and temperatureinsensitive than InP devices. These edge-emitting III-V chips are flip-chip bonded on 3 μm SOI chips that also have polarization and temperature independent multiplexers and low-loss coupling to the 12 μm SOI interposers, enabling to launch up to 640 Gbps data into a standard single mode (SM) fiber. In this paper we present a number of experimental results, including low-loss multiplexers on SOI, zero-birefringence Si waveguides, micron-scale mirrors and bends with 0.1 dB loss, direct modulation of VCSELs up to 40 Gbps, ±0.25μm length control for dilute nitride SOA, strong band edge shifts in dilute nitride EAMs and SM polymer waveguides with 0.4 dB/cm loss

Monolithically Integrated CMOS-Compatible III-V on Silicon Lasers

CMOS-compatible III–V lasers integrated on silicon are a crucial step to reduce power consumption and cost for next-generation optical transceivers. Here, we demonstrate a concept to co-integrate III-V lasers into a CMOS Silicon Photonics platform, in which lasers, photonics, and electronic circuitry share the same back end of line. Based on a bonded III–V epitaxial layer stack, ultra-thin laser devices, optically pumped lasing and coupling to silicon are demonstrated. Furthermore, we present all building blocks for electrically pumped laser devices.ISSN:1077-260

TREM-1+ Macrophages Define a Pathogenic Cell Subset in the Intestine of Crohn's Disease Patients

This work was funded by grants to M.J.W. from the Swedish Cancer Society [CAN2015/463 and CAN 2018/372] and to E.B.L. from the Swedish Government under the ALF agreement [ALFGBG-784211]. Publisher Copyright: © The Author(s) 2021. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.BACKGROUND AND AIMS: Uncontrolled activation of intestinal mononuclear phagocytes [MNPs] drives chronic inflammation in inflammatory bowel disease [IBD]. Triggering receptor expressed on myeloid cells 1 [TREM-1] has been implicated in the pathogenesis of IBD. However, the role of TREM-1+ cell subsets in driving IBD pathology and the link with clinical parameters are not understood. We investigated TREM-1 expression in human intestinal MNP subsets and examined blocking TREM-1 as a potential IBD therapy. METHODS: TREM-1 gene expression was analysed in intestinal mucosa, enriched epithelial and lamina propria [LP] layers, and purified cells from controls and IBD patients. TREM-1 protein on immune cells was assessed by flow cytometry and immunofluorescence microscopy. Blood monocyte activation was examined by large-scale gene expression using a TREM-1 agonist or LP conditioned media [LP-CM] from patients in the presence or absence of TREM-1 and tumour necrosis factor [TNF] antagonist antibodies. RESULTS: TREM-1 gene expression increases in intestinal mucosa from IBD patients and correlates with disease score. TREM-1+ cells, which are mainly immature macrophages and CD11b+ granulocytes, increase among LP cells from Crohn's disease patients and their frequency correlates with inflammatory molecules in LP-CM. LP-CM from Crohn's disease patients induces an inflammatory transcriptome in blood monocytes, including increased IL-6 expression, which is reduced by simultaneous blocking of TREM-1 and TNF. CONCLUSIONS: High intestinal TREM-1 expression, reflecting a high frequency of TREM-1+ immature macrophages and TREM-1+CD11b+ granulocytes, is linked to the deleterious inflammatory microenvironment in IBD patients. Therefore, blocking the TREM-1 pathway, especially simultaneously with anti-TNF therapy, has potential as a new IBD therapy.Peer reviewe

T Cell–Derived IL-22 Amplifies IL-1β–Driven Inflammation in Human Adipose Tissue: Relevance to Obesity and Type 2 Diabetes

International audienc