Dendritic Cells Cause Bone Lesions in a New Mouse Model of Histiocytosis.

Langerhans cell histiocytosis (LCH) is a rare disease caused by the clonal accumulation of dendritic Langerhans cells, which is often accompanied by osteolytic lesions. It has been reported that osteoclast-like cells play a major role in the pathogenic bone destruction seen in patients with LCH and these cells are postulated to originate from the fusion of DCs. However, due to the lack of reliable animal models the pathogenesis of LCH is still poorly understood. In this study, we have established a mouse model of histiocytosis- recapitulating human disease for osteolytic lesions seen in LCH patients. At 12 weeks after birth, severe bone lesions were observed in our multisystem histiocytosis (Mushi) model, when CD8α conventional dendritic cells (DCs) are transformed (MuTuDC) and accumulate. Most importantly, our study demonstrates that bone loss in LCH can be accounted for the transdifferentiation of MuTuDCs into functional osteoclasts both in vivo and in vitro. Moreover, we have shown that injected MuTuDCs reverse the osteopetrotic phenotype of oc/oc mice in vivo. In conclusion, our results support a crucial role of DCs in bone lesions in histiocytosis patients. Furthermore, our new model of LCH based on adoptive transfer of MuTuDC lines, leading to bone lesions within 1-2 weeks, will be an important tool for investigating the pathophysiology of this disease and ultimately for evaluating the potential of anti-resorptive drugs for the treatment of bone lesions

Targeted knock-in mice expressing the oxidase-fixed form of xanthine oxidoreductase favor tumor growth.

Xanthine oxidoreductase has been implicated in cancer. Nonetheless, the role played by its two convertible forms, xanthine dehydrogenase (XDH) and oxidase (XO) during tumorigenesis is not understood. Here we produce XDH-stable and XO-locked knock-in (ki) mice to address this question. After tumor transfer, XO ki mice show strongly increased tumor growth compared to wild type (WT) and XDH ki mice. Hematopoietic XO expression is responsible for this effect. After macrophage depletion, tumor growth is reduced. Adoptive transfer of XO-ki macrophages in WT mice increases tumor growth. In vitro, XO ki macrophages produce higher levels of reactive oxygen species (ROS) responsible for the increased Tregs observed in the tumors. Blocking ROS in vivo slows down tumor growth. Collectively, these results indicate that the balance of XO/XDH plays an important role in immune surveillance of tumor development. Strategies that inhibit the XO form specifically may be valuable in controlling cancer growth

Seasonality modulates wind-driven mixing pathways in a large lake

Turbulent mixing controls the vertical transfer of heat, gases and nutrients in stratified water bodies, shaping their response to environmental forcing. Nevertheless, due to technical limitations, the redistribution of wind-derived energy fuelling turbulence within stratified lakes has only been mapped over short (sub-annual) timescales. Here we present a year-round observational record of energy fluxes in the large Lake Geneva. Contrary to the standing view, we show that the benthic layers are the main locus for turbulent mixing only during winter. Instead, most turbulent mixing occurs in the water-column interior during the stratified summer season, when the co-occurrence of thermal stability and lighter winds weakens near-sediment currents. Since stratified conditions are becoming more prevalent –possibly reducing turbulent fluxes in deep benthic environments–, these results contribute to the ongoing efforts to anticipate the effects of climate change on freshwater quality and ecosystem services in large lakes

Occult Hepatitis B Infection in Patients With Cryptogenic Liver Cirrhosis in Southwest of Iran

Background: Chronic hepatitis B virus (HBV) infection has a broad spectrum of manifestation, ranging from silent carrier state to advanced cirrhosis and hepatocellular carcinoma. The persistence of HBV DNA in serum and hepatocytes of the cirrhotic patient could be detected by molecular techniques in spite of negative HBV serologic markers. Objectives: This case-control study was designed to evaluate the prevalence of occult HBV infection (OBI) in patients with cryptogenic liver cirrhosis in comparison with healthy subjects. Patients and Methods: Of 165 patients with liver cirrhosis, 50 consecutive patients with cryptogenic cirrhosis and 80 healthy individual without any risk factors as a control group were enrolled in this study. Their sera were tested for HBV DNA using nested PCR method. Results: Of 50 patients with cryptogenic cirrhotic, 36 (72%) were male. The mean age of patients was 53.34 ± 14.73 years; 80 healthy subjects were selected as control group with mean age of 32.65 ± 8.51 years; 7 (14%) of the patients with cryptogenic cirrhosis showed positive HBV DNA by PCR, while HBV DNA was negative for the control group (P = 0.0001); 4 (57%) cases with positive HBV shown by PCR were negative for anti-HBc and anti-HBs tests. The mean level of transaminases was significantly higher in patients with cirrhosis. There were no significant differences in demographic parameters, transaminases level and degree of hepatic failure among cirrhotic patients with and without OBI. Conclusions: The prevalence of OBI was relatively high in patients with cryptogenic cirrhosis. OBI was found among the patients above 40 years old. Prospective cohort studies are needed to evaluate the clinical significance of OBI

V-band Doppler backscattering diagnostic in the TCV tokamak

A variable configuration V-band heterodyne Doppler back-scattering diagnostic has been recently made operational in the tokamak a configuration variable. This article describes the hardware setup options, flexible quasi-optical launcher antenna, data-analysis techniques, and first data. The diagnostic uses a fast arbitrary waveform generator as the main oscillator and commercial vector network analyzer extension modules as the main mm-wave hardware. It allows sweepable single or multi-frequency operation. A flexible quasi-optical launcher antenna allows 3D poloidal (10 degrees - 58 degrees) and toroidal (-180 degrees to 180 degrees) steering of the beam with 0.2 degrees accuracy. A pair of fast HE11 miter-bend polarizers allow flexible coupling to either O or X mode and programmable polarization changes during the shot. These have been used to measure the magnetic-field pitch angle in the edge of the plasma by monitoring the backscattered signal power. Ray-tracing simulations reveal an available k(perpendicular to) range between 3 and 16 cm(-1) with a resolution of 2-4 cm(-1). Perpendicular rotation velocity estimates compare well against ExB plasma poloidal rotation estimates from charge exchange recombination spectroscopy

Targeted hepatitis C antibody testing interventions: a systematic review and meta-analysis

Testing for hepatitis C virus (HCV) infection may reduce the risk of liver-related morbidity, by facilitating earlier access to treatment and care. This review investigated the effectiveness of targeted testing interventions on HCV case detection, treatment uptake, and prevention of liver-related morbidity. A literature search identified studies published up to 2013 that compared a targeted HCV testing intervention (targeting individuals or groups at increased risk of HCV) with no targeted intervention, and results were synthesised using meta-analysis. Exposure to a targeted testing intervention, compared to no targeted intervention, was associated with increased cases detected [number of studies (n) = 14; pooled relative risk (RR) 1.7, 95 % CI 1.3, 2.2] and patients commencing therapy (n = 4; RR 3.3, 95 % CI 1.1, 10.0). Practitioner-based interventions increased test uptake and cases detected (n = 12; RR 3.5, 95 % CI 2.5, 4.8; and n = 10; RR 2.2, 95 % CI 1.4, 3.5, respectively), whereas media/information-based interventions were less effective (n = 4; RR 1.5, 95 % CI 0.7, 3.0; and n = 4; RR 1.3, 95 % CI 1.0, 1.6, respectively). This meta-analysis provides for the first time a quantitative assessment of targeted HCV testing interventions, demonstrating that these strategies were effective in diagnosing cases and increasing treatment uptake. Strategies involving practitioner-based interventions yielded the most favourable outcomes. It is recommended that testing should be targeted at and offered to individuals who are part of a population with high HCV prevalence, or who have a history of HCV risk behaviour

Bidirectional lipid droplet velocities are controlled by differential binding strengths of HCV Core DII protein

Host cell lipid droplets (LD) are essential in the hepatitis C virus (HCV) life cycle and are targeted by the viral capsid core protein. Core-coated LDs accumulate in the perinuclear region and facilitate viral particle assembly, but it is unclear how mobility of these LDs is directed by core. Herein we used two-photon fluorescence, differential interference contrast imaging, and coherent anti-Stokes Raman scattering microscopies, to reveal novel core-mediated changes to LD dynamics. Expression of core protein’s lipid binding domain II (DII-core) induced slower LD speeds, but did not affect directionality of movement on microtubules. Modulating the LD binding strength of DII-core further impacted LD mobility, revealing the temporal effects of LD-bound DII-core. These results for DII-core coated LDs support a model for core-mediated LD localization that involves core slowing down the rate of movement of LDs until localization at the perinuclear region is accomplished where LD movement ceases. The guided localization of LDs by HCV core protein not only is essential to the viral life cycle but also poses an interesting target for the development of antiviral strategies against HCV

Under-ice convection dynamics in a boreal lake

We investigated radiatively driven under-ice convection in Lake Onego (Russia) during 3 consecutive late winters. In ice-covered lakes, where the temperature of water is below the temperature of maximum density, radiatively driven heating in the upper water column induces unstable density distributions leading to gravitational convection. In this work, we quantified the key parameters to characterise the radiatively driven under-ice convection: (1) the effective buoyancy flux, B∗ (driver), and its vertical distribution; (2) the convective mixed-layer thickness, hCML (depth scale); and (3) the convective velocity,w∗(kinematic scale). We compared analytical w∗ scaling estimates to in situ observations from high-resolution acoustic Doppler current profilers. The results show a robust correlation between w∗and the direct observations, except during the onset and decay of the solar radiation. Our results highlight the importance of accurately defining the upper limit of hCML in highly turbid water and the need for spectrally resolving solar radiation measurements and their attenuation for accurate B∗ estimates. Uncertainties in the different parameters were also investigated. We finally examined the implications of under-ice convection for the growth rate of nonmotile phytoplankton and provide a simple heuristic model as a function of easily measurable parameters

Activation of ERAD Pathway by Human Hepatitis B Virus Modulates Viral and Subviral Particle Production

Hepatitis B virus (HBV) belongs to the Hepadnaviridae family of enveloped DNA viruses. It was previously shown that HBV can induce endoplasmic reticulum (ER) stress and activate the IRE1-XBP1 pathway of the unfolded protein response (UPR), through the expression of the viral regulatory protein X (HBx). However, it remained obscure whether or not this activation had any functional consequences on the target genes of the UPR pathway. Of these targets, the ER degradation-enhancing, mannosidase-like proteins (EDEMs) are thought to play an important role in relieving the ER stress during UPR, by recognizing terminally misfolded glycoproteins and delivering them to the ER-associated degradation (ERAD). In this study, we investigated the role of EDEMs in the HBV life-cycle. We found that synthesis of EDEMs (EDEM1 and its homologues, EDEM2 and EDEM3) is significantly up-regulated in cells with persistent or transient HBV replication. Co-expression of the wild-type HBV envelope proteins with EDEM1 resulted in their massive degradation, a process reversed by EDEM1 silencing. Surprisingly, the autophagy/lysosomes, rather than the proteasome were involved in disposal of the HBV envelope proteins. Importantly, inhibition of the endogenous EDEM1 expression in HBV replicating cells significantly increased secretion of both, enveloped virus and subviral particles. This is the first report showing that HBV activates the ERAD pathway, which, in turn, reduces the amount of envelope proteins, possibly as a mechanism to control the level of virus particles in infected cells and facilitate the establishment of chronic infections

The prevalence of HBV infection in the cohort of IDPs of war against terrorism in Malakand Division of Northern Pakistan

<p>Abstract</p> <p>Background</p> <p>Hepatitis B is an important public health problem in the Pakistani population and is the major cause of chronic hepatitis, cirrhosis, fibrosis and hepatocellular carcinoma. High prevalence of HBV infections has been observed especially in areas of low economic status. In spite of effective immunization programs, no significant change has been observed in the epidemiology of HBV in the rural areas of Pakistan (~67.5% of the total population) mainly due to lack of interest from government authorities and poor hygienic measures. The current study was aimed at estimating the prevalence and risk factors associated with HBV infection within internally displaced persons (IDPs) due to war against terrorism in the Malakand Division of Northern Pakistan.</p> <p>Methods</p> <p>Blood samples from 950 IDPs suspected with HBV infection (including both males and females) were collected and processed with commercial ELISA kits for HBsAg, Anti HBs, HBeAg, Anti HBe antibodies. The samples positive by ELISA were confirmed for HBV DNA by real-time PCR analysis.</p> <p>Results</p> <p>The overall prevalence of HBV observed was 21.05% of which 78.5% were males and 21.5% were females. Most confirmed HBV patients belong to the Malakand and Dir (lower) district. High-risk of infection was found in the older subjects 29.13% (46-60 years), while a lower incidence (11.97%) was observed in children aged <15 years. Lack of awareness, socioecomic conditions, sexual activities and sharing of razor blades, syringes and tattooing needles were the most common risk factors of HBV infection observed during the cohort of patients.</p> <p>Conclusion</p> <p>The present study, revealed for the first time a high degree of prevalence of HBV infection in rural areas of Northern Pakistan. The noticed prevalence is gender- and age-dependent that might be due to their high exposures to the common risk factors. To avoid the transmission of HBV infection proper awareness about the possible risk factors and extension of immunization to the rural areas are recommended.</p