Hepatitis C virus infection and related liver disease: the quest for the best animal model

Hepatitis C virus (HCV) is a major cause of cirrhosis and hepatocellular carcinoma (HCC) making the virus the most common cause of liver failure and transplantation. HCV is estimated to chronically affect 130 million individuals and to lead to more than 350,000 deaths per year worldwide. A vaccine is currently not available. The recently developed direct acting antivirals (DAAs) have markedly increased the efficacy of the standard of care but are not efficient enough to completely cure all chronically infected patients and their toxicity limits their use in patients with advanced liver disease, co-morbidity or transplant recipients. Because of the host restriction, which is limited to humans and non-human primates, in vivo study of HCV infection has been hampered since its discovery more than 20 years ago. The chimpanzee remains the most physiological model to study the innate and adaptive immune responses, but its use is ethically difficult and is now very restricted and regulated. The development of a small animal model that allows robust HCV infection has been achieved using chimeric liver immunodeficient mice, which are therefore not suitable for studying the adaptive immune responses. Nevertheless, these models allowed to go deeply in the comprehension of virus-host interactions and to assess different therapeutic approaches. The immunocompetent mouse models that were recently established by genetic humanization have shown an interesting improvement concerning the study of the immune responses but are still limited by the absence of the complete robust life cycle of the virus. In this review, we will focus on the relevant available animal models of HCV infection and their usefulness for deciphering the HCV life cycle and virus-induced liver disease, as well as for the development and evaluation of new therapeutics. We will also discuss the perspectives on future immunocompetent mouse models and the hurdles to their development

Inferring causative variants in microRNA target sites

MicroRNAs (miRNAs) regulate genes post transcription by pairing with messenger RNA (mRNA). Variants such as single nucleotide polymorphisms (SNPs) in miRNA regulatory regions might result in altered protein levels and disease. Genome-wide association studies (GWAS) aim at identifying genomic regions that contain variants associated with disease, but lack tools for finding causative variants. We present a computational tool that can help identifying SNPs associated with diseases, by focusing on SNPs affecting miRNA-regulation of genes. The tool predicts the effects of SNPs in miRNA target sites and uses linkage disequilibrium to map these miRNA-related variants to SNPs of interest in GWAS. We compared our predicted SNP effects in miRNA target sites with measured SNP effects from allelic imbalance sequencing. Our predictions fit measured effects better than effects based on differences in free energy or differences of TargetScan context scores. We also used our tool to analyse data from published breast cancer and Parkinson's disease GWAS and significant trait-associated SNPs from the NHGRI GWAS Catalog. A database of predicted SNP effects is available at http://www.bigr.medisin.ntnu.no/mirsnpscore/. The database is based on haplotype data from the CEU HapMap population and miRNAs from miRBase 16.0

Star Formation Under the Outflow: The Discovery of a Non-Thermal Jet from OMC-2 FIR 3 and its Relationship to the Deeply Embedded FIR 4 Protostar

We carried out multiwavelength (0.7-5 cm), multiepoch (1994-2015) Very Large Array (VLA) observations toward the region enclosing the bright far-IR sources FIR 3 (HOPS 370) and FIR 4 (HOPS 108) in OMC-2. We report the detection of 10 radio sources, seven of them identified as young stellar objects. We image a well-collimated radio jet with a thermal free-free core (VLA 11) associated with the Class I intermediate-mass protostar HOPS 370. The jet presents several knots (VLA 12N, 12C, 12S) of non-thermal radio emission (likely synchrotron from shock-accelerated relativistic electrons) at distances of ~7,500-12,500 au from the protostar, in a region where other shock tracers have been previously identified. These knots are moving away from the HOPS 370 protostar at ~ 100 km/s. The Class 0 protostar HOPS 108, which itself is detected as an independent, kinematically decoupled radio source, falls in the path of these non-thermal radio knots. These results favor the previously proposed scenario where the formation of HOPS 108 has been triggered by the impact of the HOPS 370 outflow with a dense clump. However, HOPS 108 presents a large proper motion velocity of ~ 30 km/s, similar to that of other runaway stars in Orion, whose origin would be puzzling within this scenario. Alternatively, an apparent proper motion could result because of changes in the position of the centroid of the source due to blending with nearby extended emission, variations in the source shape, and /or opacity effects.Comment: 16 pages, 4 figures, accepted for publication in The Astrophysical Journa

First detection of water vapor in a pre-stellar core

Water is a crucial molecule in molecular astrophysics as it controls much of the gas/grain chemistry, including the formation and evolution of more complex organic molecules in ices. Pre-stellar cores provide the original reservoir of material from which future planetary systems are built, but few observational constraints exist on the formation of water and its partitioning between gas and ice in the densest cores. Thanks to the high sensitivity of the Herschel Space Observatory, we report on the first detection of water vapor at high spectral resolution toward a dense cloud on the verge of star formation, the pre-stellar core L1544. The line shows an inverse P-Cygni profile, characteristic of gravitational contraction. To reproduce the observations, water vapor has to be present in the cold and dense central few thousand AU of L1544, where species heavier than Helium are expected to freeze-out onto dust grains, and the ortho:para H2 ratio has to be around 1:1 or larger. The observed amount of water vapor within the core (about 1.5x10^{-6} Msun) can be maintained by Far-UV photons locally produced by the impact of galactic cosmic rays with H2 molecules. Such FUV photons irradiate the icy mantles, liberating water wapor in the core center. Our Herschel data, combined with radiative transfer and chemical/dynamical models, shed light on the interplay between gas and solids in dense interstellar clouds and provide the first measurement of the water vapor abundance profile across the parent cloud of a future solar-type star and its potential planetary system.Comment: The Astrophysical Journal Letters, in pres

Lagrangian Diffusion Properties of a Free Shear Turbulent Jet

A Lagrangian experimental study of an axisymmetric turbulent water jet is performed to investigate the highly anisotropic and inhomogeneous flow field. Measurements are conducted within a Lagrangian exploration module, an icosahedron apparatus, to facilitate optical access of three cameras. Stereoscopic particle tracking velocimetry results in three-component tracks of position, velocity and acceleration of the tracer particles within the vertically oriented jet with a Taylor-based Reynolds number Reλ≃230. Analysis is performed at seven locations from 15 diameters up to 45 diameters downstream. Eulerian analysis is first carried out to obtain critical parameters of the jet and relevant scales, namely the Kolmogorov and large (integral) scales as well as the energy dissipation rate. Lagrangian statistical analysis is then performed on velocity components stationarised following methods inspired by Batchelor (J. Fluid Mech., vol. 3, 1957, pp. 67–80), which aim to extend stationary Lagrangian theory of turbulent diffusion by Taylor to the case of self-similar flows. The evolution of typical Lagrangian scaling parameters as a function of the developing jet is explored and results show validation of the proposed stationarisation. The universal scaling constant C0 (for the Lagrangian second-order structure function), as well as Eulerian and Lagrangian integral time scales, are discussed in this context. Constant C0 is found to converge to a constant value (of the order of C0=3) within 30 diameters downstream of the nozzle. Finally, the occurrence of finite particle size effects is investigated through consideration of acceleration-dependent quantities

The principle of relative locality

We propose a deepening of the relativity principle according to which the invariant arena for non-quantum physics is a phase space rather than spacetime. Descriptions of particles propagating and interacting in spacetimes are constructed by observers, but different observers, separated from each other by translations, construct different spacetime projections from the invariant phase space. Nonetheless, all observers agree that interactions are local in the spacetime coordinates constructed by observers local to them. This framework, in which absolute locality is replaced by relative locality, results from deforming momentum space, just as the passage from absolute to relative simultaneity results from deforming the linear addition of velocities. Different aspects of momentum space geometry, such as its curvature, torsion and non-metricity, are reflected in different kinds of deformations of the energy-momentum conservation laws. These are in principle all measurable by appropriate experiments. We also discuss a natural set of physical hypotheses which singles out the cases of momentum space with a metric compatible connection and constant curvature.Comment: 12 pages, 3 figures; in version 2 one reference added and some minor modifications in sects. II and III mad

Differential and shared genetic effects on kidney function between diabetic and non-diabetic individuals

Reduced glomerular filtration rate (GFR) can progress to kidney failure. Risk factors include genetics and diabetes mellitus (DM), but little is known about their interaction. We conducted genome-wide association meta-analyses for estimated GFR based on serum creatinine (eGFR), separately for individuals with or without DM (nDM = 178,691, nnoDM = 1,296,113). Our genome-wide searches identified (i) seven eGFR loci with significant DM/noDM-difference, (ii) four additional novel loci with suggestive difference and (iii) 28 further novel loci (including CUBN) by allowing for potential difference. GWAS on eGFR among DM individuals identified 2 known and 27 potentially responsible loci for diabetic kidney disease. Gene prioritization highlighted 18 genes that may inform reno-protective drug development. We highlight the existence of DM-only and noDM-only effects, which can inform about the target group, if respective genes are advanced as drug targets. Largely shared effects suggest that most drug interventions to alter eGFR should be effective in DM and noDM

Torcetrapib impairs endothelial function in hypertension

Aims A marked increase in HDL notwithstanding, the cholesterol ester transfer protein (CETP) inhibitor torcetrapib was associated with an increase in all-cause mortality in the ILLUMINATE trial. As underlying mechanisms remain elusive, the present study was designed to delineate potential off-target effects of torcetrapib. Methods and results Spontaneously hypertensive rats (SHRs) and Wistar-Kyoto (WKY) rats were treated with torcetrapib (100 mg/kg/day; SHR-T and WKY-T) or placebo (SHR-P and WKY-P) for 3 weeks. Blood pressure transiently increased during the first 3 days of torcetrapib administration in SHRs and returned to baseline thereafter despite continued drug administration. Acetylcholine-induced endothelium-dependent relaxations of aortic rings were markedly impaired, and endothelial nitric oxide synthase (eNOS) mRNA and protein were down-regulated after 3 weeks of torcetrapib treatment in SHR (P < 0.0001, <0.01, and <0.05, resp. vs. SHR-P). Torcetrapib reduced NO release in cultured aortic endothelial cells (P < 0.01 vs. vehicle-treated cells) and increased generation of reactive oxygen species in aortas of SHR-T (P < 0.05, vs. SHR-P). Vascular reactivity to endothelin-1 (ET-1) and aortic ET-1 tissue content were increased in SHR-T (P < 0.05 vs. SHR-P). Importantly, the ET-1 receptor A/B (ETA/B) antagonist bosentan normalized endothelial function in SHR-T (P < 0.05). Conclusion Torcetrapib induces a sustained impairment of endothelial function, decreases eNOS mRNA, protein as well as NO release, stimulates vascular ROS and ET production, an effect that is prevented by chronic ETA/B-receptor blockade. These unexpected off-target effects of torcetrapib need to be ruled out in the clinical development of novel CETP inhibitors, particularly before a large patient population at increased cardiovascular risk is exposed to these compound