Monocyte dysfunction in decompensated cirrhosis is mediated by the prostaglandin E2-EP4 pathway

Background & Aims: Infection is a major problem in advanced liver disease secondary to monocyte dysfunction. Elevated prostaglandin (PG)E2 is a mediator of monocyte dysfunction in cirrhosis; thus, we examined PGE2 signalling in outpatients with ascites and in patients hospitalised with acute decompensation to identify potential therapeutic targets aimed at improving monocyte dysfunction. Methods: Using samples from 11 outpatients with ascites and 28 patients hospitalised with decompensated cirrhosis, we assayed plasma levels of PGE2 and lipopolysaccharide (LPS); performed quantitative real-time PCR on monocytes; and examined peripheral blood monocyte function. We performed western blotting and immunohistochemistry for PG biosynthetic machinery expression in liver tissue. Finally, we investigated the effect of PGE2 antagonists in whole blood using polychromatic flow cytometry and cytokine production. Results: We show that hepatic production of PGE2 via the cyclo-oxygenase 1–microsomal PGE synthase 1 pathway, and circulating monocytes contributes to increased plasma PGE2 in decompensated cirrhosis. Transjugular intrahepatic sampling did not reveal whether hepatic or monocytic production was larger. Blood monocyte numbers increased, whereas individual monocyte function decreased as patients progressed from outpatients with ascites to patients hospitalised with acute decompensation, as assessed by Human Leukocyte Antigen (HLA)–DR isotype expression and tumour necrosis factor alpha and IL6 production. PGE2 mediated this dysfunction via its EP4 receptor. Conclusions: PGE2 mediates monocyte dysfunction in decompensated cirrhosis via its EP4 receptor and dysfunction was worse in hospitalised patients compared with outpatients with ascites. Our study identifies a potential drug target and therapeutic opportunity in these outpatients with ascites to reverse this process to prevent infection and hospital admission. Lay summary: Patients with decompensated cirrhosis (jaundice, fluid build-up, confusion, and vomiting blood) have high infection rates that lead to high mortality rates. A white blood cell subset, monocytes, function poorly in these patients, which is a key factor underlying their sensitivity to infection. We show that monocyte dysfunction in decompensated cirrhosis is mediated by a lipid hormone in the blood, prostaglandin E2, which is present at elevated levels, via its EP4 pathway. This dysfunction worsens when patients are hospitalised with complications of cirrhosis compared with those in the outpatients setting, which supports the EP4 pathway as a potential therapeutic target for patients to prevent infection and hospitalisation

Older LGBT+ health inequalities in the UK: setting a research agenda

Lesbian, gay, bisexual and trans+ (LGBT+) people report poorer health than the general population and worse experiences of healthcare particularly cancer, palliative/end-of-life, dementia and mental health provision. This is attributable to: (a) social inequalities, including ‘minority stress’; (b) associated health-risk behaviours (eg, smoking, excessive drug/alcohol use, obesity); (c) loneliness and isolation, affecting physical/mental health and mortality; (d) anticipated/experienced discrimination and (e) inadequate understandings of needs among healthcare providers. Older LGBT+ people are particularly affected, due to the effects of both cumulative disadvantage and ageing. There is a need for greater and more robust research data to support growing international and national government initiatives aimed at addressing these health inequalities. We identify seven key research strategies: (1) Production of large data sets; (2) Comparative data collection; (3) Addressing diversity and intersectionality among LGBT+ older people; (4) Investigation of healthcare services’ capacity to deliver LGBT+ affirmative healthcare and associated education and training needs; (5) Identification of effective health promotion and/or treatment interventions for older LGBT+ people, and subgroups within this umbrella category; (6) Development of an (older) LGBT+ health equity model; (7) Utilisation of social justice concepts to ensure meaningful, change-orientated data production which will inform and support government policy, health promotion and healthcare interventions

Alphacoronavirus protein 7 modulates host innate immune response

Innate immune response is the first line of antiviral defense resulting, in most cases, in pathogen clearance with minimal clinical consequences. Viruses have developed diverse strategies to subvert host defense mechanisms and increase their survival. In the transmissible gastroenteritis virus (TGEV) as a model, we previously reported that accessorygene 7 counteracts the host antiviral response by associating with the catalytic subunit of protein phosphatase 1 (PP1c). In the present work, the effect of the absence of gene 7on the host cell, during infection, was further analyzed by transcriptomic analysis. The pattern of gene expression of cells infected with a recombinant mutant TGEV, lacking gene7 expression (rTGEV-δ7), was compared to that of cells infected with the parental virus (rTGEV-wt). Genes involved in the immune response, the interferon response, and inflammation were upregulated during TGEV infection in the absence of gene 7. An exacerbated innate immune response during infection with rTGEV-δ7 virus was observed both in vitro and invivo. An increase in macrophage recruitment and activation in lung tissues infected with rTGEV-δ7 virus was observed compared to cells infected with the parental virus. In summary, the absence of protein 7 both in vitro and in vivo led to increased proinflammatory responses and acute tissue damage after infection. In a porcine animal model, which is immunologically similar to humans, we present a novel example of how viral proteins counteract host antiviral pathways to determine the infection outcome and pathogenesis

The measurement programme at the neutron time-of-flight facility n-TOF at CERN

Neutron-induced reaction cross sections are important for a wide variety of research fields ranging from the study of nuclear level densities, nucleosynthesis to applications of nuclear technology like design, and criticality and safety assessment of existing and future nuclear reactors, radiation dosimetry, medical applications, nuclear waste transmutation, accelerator-driven systems and fuel cycle investigations. Simulations and calculations of nuclear technology applications largely rely on evaluated nuclear data libraries. The evaluations in these libraries are based both on experimental data and theoretical models. CERN’s neutron time-of-flight facility n_TOF has produced a considerable amount of experimental data since it has become fully operational with the start of its scientific measurement programme in 2001. While for a long period a single measurement station (EAR1) located at 185 m from the neutron production target was available, the construction of a second beam line at 20 m (EAR2) in 2014 has substantially increased the measurement capabilities of the facility. An outline of the experimental nuclear data activities at n_TOF will be presented

Present Status and Future Programs of the n_TOF Experiment

This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial License 3.0, which permits unrestricted use, distribution, and reproduction in any noncommercial medium, provided the original work is properly citedThe neutron time-of-flight facility n_TOF at CERN, Switzerland, operational since 2001, delivers neutrons using the Proton Synchrotron (PS) 20 GeV/c proton beam impinging on a lead spallation target. The facility combines a very high instantaneous neutron flux, an excellent time of flight resolution due to the distance between the experimental area and the production target (185 meters), a low intrinsic background and a wide range of neutron energies, from thermal to GeV neutrons. These characteristics provide a unique possibility to perform neutron-induced capture and fission cross-section measurements for applications in nuclear astrophysics and in nuclear reactor technology.The most relevant measurements performed up to now and foreseen for the future will be presented in this contribution. The overall efficiency of the experimental program and the range of possible measurements achievable with the construction of a second experimental area (EAR-2), vertically located 20 m on top of the n_TOF spallation target, might offer a substantial improvement in measurement sensitivities. A feasibility study of the possible realisation of the installation extension will be also presented

Measurement of the α ratio and (n, γ) cross section of 235U from 0.2 to 200 eV at n_TOF

We measured the neutron capture-to-fission cross-section ratio (α ratio) and the capture cross section of 235U between 0.2 and 200 eV at the n_TOF facility at CERN. The simultaneous measurement of neutron-induced capture and fission rates was performed by means of the n_TOF BaF2 Total Absorption Calorimeter (TAC), used for detection of γ rays, in combination with a set of micromegas detectors used as fission tagging detectors. The energy dependence of the capture cross section was obtained with help of the 6 Li(n,t) standard reaction determining the n_TOF neutron fluence; the well-known integral of the 235U(n, f ) cross section between 7.8 and 11 eV was then used for its absolute normalization. The α ratio, obtained with slightly higher statistical fluctuations, was determined directly, without need for any reference cross section. To perform the analysis of this measurement we developed a new methodology to correct the experimentally observed effect that the probabilities of detecting a fission reaction in the TAC and the micromegas detectors are not independent. The results of this work have been used in a new evaluation of 235U performed within the scope of the Collaborative International Evaluated Library Organisation (CIELO) Project, and are consistent with the ENDF/B-VIII.0 and JEFF-3.3 capture cross sections below 4 eV and above 100 eV. However, the measured capture cross section is on average 10% larger between 4 and 100 eV.This work was supported in part by the Spanish national company for radioactive waste management, ENRESA, through the CIEMAT-ENRESA agreements on “Transmutación de radionucleidos de vida larga como soporte a la gestión de residuos radioactivos de alta actividad”; by the Spanish Ministerio de Economía, Industria y Competitividad, through the projects FPA2014-53290-C2-1, FPA2016-76765- P, and FPA2017-82647-P; and by the European Commission 7th Framework Programme project CHANDA (Grant No. FP7-605203)

Towards the high-accuracy determination of the 238U fission cross section at the threshold region at CERN - N-TOF

The 238U fission cross section is an international standard beyond 2 MeV where the fission plateau starts. However, due to its importance in fission reactors, this cross-section should be very accurately known also in the threshold region below 2 MeV. The 238U fission cross section has been measured relative to the 235U fission cross section at CERN - n-TOF with different detection systems. These datasets have been collected and suitably combined to increase the counting statistics in the threshold region from about 300 keV up to 3 MeV. The results are compared with other experimental data, evaluated libraries, and the IAEA standards

Measurement of the Ge 70 (n,γ) cross section up to 300 keV at the CERN n-TOF facility

©2019 American Physical Society.Neutron capture data on intermediate mass nuclei are of key importance to nucleosynthesis in the weak component of the slow neutron capture processes, which occurs in massive stars. The (n,γ) cross section on Ge70, which is mainly produced in the s process, was measured at the neutron time-of-flight facility n-TOF at CERN. Resonance capture kernels were determined up to 40 keV neutron energy and average cross sections up to 300 keV. Stellar cross sections were calculated from kT=5 keV to kT=100 keV and are in very good agreement with a previous measurement by Walter and Beer (1985) and recent evaluations. Average cross sections are in agreement with Walter and Beer (1985) over most of the neutron energy range covered, while they are systematically smaller for neutron energies above 150 keV. We have calculated isotopic abundances produced in s-process environments in a 25 solar mass star for two initial metallicities (below solar and close to solar). While the low metallicity model reproduces best the solar system germanium isotopic abundances, the close to solar model shows a good global match to solar system abundances in the range of mass numbers A=60-80.Peer reviewedFinal Published versio

Impaired LXRa phosphorylation attenuates progression of fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a very common indication for liver transplantation. How fat-rich diets promote progression from fatty liver to more damaging inflammatory and fibrotic stages is poorly understood. Here, we show that disrupting phosphorylation at Ser196 (S196A) in the liver X receptor alpha (LXRα, NR1H3) retards NAFLD progression in mice on a high-fat-high-cholesterol diet. Mechanistically, this is explained by key histone acetylation (H3K27) and transcriptional changes in pro-fibrotic and pro-inflammatory genes. Furthermore, S196A-LXRα expression reveals the regulation of novel diet-specific LXRα-responsive genes, including the induction of Ces1f, implicated in the breakdown of hepatic lipids. This involves induced H3K27 acetylation and altered LXR and TBLR1 cofactor occupancy at the Ces1f gene in S196A fatty livers. Overall, impaired Ser196-LXRα phosphorylation acts as a novel nutritional molecular sensor that profoundly alters the hepatic H3K27 acetylome and transcriptome during NAFLD progression placing LXRα phosphorylation as an alternative anti-inflammatory or anti-fibrotic therapeutic target

Changes In LXRα Phosphorylation Promote A Novel Diet-Induced Transcriptome That Alters The Transition From Fatty Liver To Steatohepatitis

Understanding the transition from fatty liver or steatosis to more advanced inflammatory and fibrotic stages of non-alcoholic fatty liver disease (steatohepatitis), is key to define strategies that alter or even reverse the progression of this pathology. The Liver X Receptor alpha (LXRα) controls hepatic lipid homeostasis and inflammation. Here we show that mice carrying a mutation that abolishes phosphorylation at Ser196 (S196A) in LXRα exhibit reduced hepatic inflammation and fibrosis when challenged with a high fat-high cholesterol diet, despite displaying enhanced hepatic lipid accumulation. This protective effect is associated with reduced cholesterol accumulation, a key promoter of lipid-mediated hepatic damage. Reduced steatohepatitis in S196A mice involves the reprogramming of the liver transcriptome by promoting diet-induced changes in the expression of genes involved in endoplasmic reticulum stress, extracellular matrix remodelling, inflammation and lipid metabolism. Unexpectedly, changes in LXRα phosphorylation uncover novel diet-specific target genes, whose regulation does not simply mirror ligand-induced LXR activation. These unique LXRα phosphorylation-sensitive, diet-responsive target genes are revealed by promoting LXR occupancy and cofactor recruitment in the context of a cholesterol-rich diet. Therefore, LXRα phosphorylation at Ser196 critically acts as a novel nutritional sensor that promotes a unique diet-induced transcriptome thereby modulating metabolic, inflammatory and fibrotic responses important in the transition to steatohepatitis