ISG15 facilitates cellular antiviral response to dengue and west nile virus infection in vitro

<p>Abstract</p> <p>Background</p> <p>Dengue virus (DENV) and West Nile virus (WNV), close siblings of the <it>Flaviviridae </it>family, are the causative agents of Dengue hemorraghic shock or West Nile meningoencephalitis respectively. Vaccines against these two flaviviruses are currently unavailable. Interferon- Stimulated Gene 15 (<it>ISG15</it>), encoding an ubiquitin-like protein, is significantly induced by type I interferons or viral infections. Its roles in viral infections, however, vary with viruses, being either anti- or pro-viral. The exact roles of ISG15 in DENV and WNV infections remain unknown. In the current study, we evaluated the relevancies of ISG15 to DENV and WNV infection of a mouse macrophage cell line RAW264.7.</p> <p>Findings</p> <p>Quantitative PCR showed that mouse <it>Isg15 </it>was dramatically induced in DENV or WNV- infected RAW264.7 cells compared with non-infected cells. <it>Isg15 </it>and two other Jak-Stat related genes, <it>Socs1 </it>and <it>Socs3</it>, were silenced using siRNA mediated RNA interference. The intracellular DENV and WNV loads, as determined by quantitative PCR, were significantly higher in <it>Isg15 </it>silenced cells than control cells. The expression levels of interferon beta 1 (<it>Ifnb1</it>) were increased significantly in <it>Isg15</it>, <it>Socs1 </it>or <it>Socs3 </it>siRNA treated cells. Further investigation indicated that protein modification by ISG15, so called ISGylation, was significantly enhanced in DENV-infected cells compared to that in non-infected cells.</p> <p>Conclusions</p> <p>These findings suggest that ISG15 plays an anti-DENV/WNV function via protein ISGylation.</p

Epidemiology of acute and chronic hepatitis B virus infection in Norway, 1992-2009

<p>Abstract</p> <p>Background</p> <p>Norway is classified as a low prevalence country for hepatitis B virus infection. Vaccination is only recommended for risk groups (intravenous drug users (IDUs), Men who have Sex with Men (MSM), immigrants and contacts of known carriers). We describe the epidemiology of reported cases of hepatitis B in Norway, during the years 1992-2009 in order to assess the validity of current risk groups and recommend preventive measures.</p> <p>Methods</p> <p>We used case based data from the national surveillance system on acute and chronic hepatitis B. The Norwegian Statistics Bureau provided population and migration data and the Norwegian Institute for Alcohol and Drug Research the estimated number of active IDUs between 2002-2007. Incidence rates (IR) and incidence rate ratios (IRR) for acute hepatitis B and notification rates (NR) and notification rate ratios (NRR) for chronic hepatitis B with 95% confidence intervals were calculated.</p> <p>Results</p> <p>The annual IR of acute hepatitis B ranged from 0.7/100,000 (1992) to 10.6/100,000 (1999). Transmission occurred mainly among IDUs (64%) or through sexual contact (24%). The risk of acquiring acute hepatitis B was highest in people aged 20-29 (IRR = 6.6 [3.3-13.3]), and in males (IRR = 2.4 [1.7-3.3]). We observed two peaks of newly reported chronic hepatitis B cases in 2003 and 2009 (NR = 17.6/100,000 and 17.4/100,000, respectively). Chronic hepatitis B was more likely to be diagnosed among immigrants than among Norwegians (NRR = 93 [71.9-120.6]), and among those 20-29 compared to those 50-59 (NRR = 5.2 [3.5-7.9]).</p> <p>Conclusions</p> <p>IDUs remain the largest risk group for acute hepatitis B. The observed peaks of chronic hepatitis B are related to increased immigration from high endemic countries and screening and vaccination of these groups is important to prevent further spread of infection. Universal screening of pregnant women should be introduced. A universal vaccination strategy should be considered, given the high cost of reaching the target populations. We recommend evaluating the surveillance system for hepatitis B as well as the effectiveness of screening and vaccinating immigrant populations.</p

Review of potential line-transect methodologies for estimating abundance of dolphin stocks in the eastern tropical Pacific

A twelve-year hiatus in fishery-independent marine mammal surveys in the eastern tropical Pacific Ocean (ETP), combined with a mandate to monitor dolphin stock status under international agreements and the need for reliable stock status information to set dolphin bycatch limits in the tuna purse-seine fishery, has renewed debate about how best to assess and monitor ETP dolphin stock status. The high cost of replicating previous ship-based surveys has intensified this debate. In this review, transect methods for estimating animal abundance from dedicated research surveys are considered, with a focus on both contemporary and potential methods suitable for surveying large areas for dolphin species that can form large, multi-species aggregations. Covered in this review are potential improvements to the previous ship-based survey methodology, other ship-based methods, alternative approaches based on high-resolution imagery and passive acoustics, and combinations of ship-based and alternative approaches. It is concluded that for immediate management needs, ship-based surveys, with some suggested modifications to improve precision, are the only reliable option despite their high cost. However, it is recommended that a top research priority should be development of composite methods. Pilot studies on the use of high-resolution imagery and passive acoustics for development of indices of relative abundance to be used in composite methods should be part of any future ship-based survey efforts

Optineurin Is Required for CYLD-Dependent Inhibition of TNFα-Induced NF-κB Activation

The nuclear factor kappa B (NF-κB) regulates genes that function in diverse cellular processes like inflammation, immunity and cell survival. The activation of NF-κB is tightly controlled and the deubiquitinase CYLD has emerged as a key negative regulator of NF-κB signalling. Optineurin, mutated in certain glaucomas and amyotrophic lateral sclerosis, is also a negative regulator of NF-κB activation. It competes with NEMO (NF-κB essential modulator) for binding to ubiquitinated RIP (receptor interacting protein) to prevent NF-κB activation. Recently we identified CYLD as optineurin-interacting protein. Here we have analysed the functional significance of interaction of optineurin with CYLD. Our results show that a glaucoma-associated mutant of optineurin, H486R, is altered in its interaction with CYLD. Unlike wild-type optineurin, the H486R mutant did not inhibit tumour necrosis factor α (TNFα)-induced NF-κB activation. CYLD mediated inhibition of TNFα-induced NF-κB activation was abrogated by expression of the H486R mutant. Upon knockdown of optineurin, CYLD was unable to inhibit TNFα-induced NF-κB activation and showed drastically reduced interaction with ubiquitinated RIP. The level of ubiquitinated RIP was increased in optineurin knockdown cells. Deubiquitination of RIP by over-expressed CYLD was abrogated in optineurin knockdown cells. These results suggest that optineurin regulates NF-κB activation by mediating interaction of CYLD with ubiquitinated RIP thus facilitating deubiquitination of RIP

CONQUER Scleroderma: Association of Gastrointestinal Tract Symptoms in Early Disease With Resource Utilization

OBJECTIVES: SSc is associated with increased health-care resource utilization and economic burden. The Collaborative National Quality and Efficacy Registry (CONQUER) is a US-based collaborative that collects longitudinal follow-up data on SSc patients withparticipants. METHODS: CONQUER participants who had completed a baseline and 12-month Gastrointestinal Tract Questionnaire (GIT 2.0) and a Resource Utilization Questionnaire (RUQ) were included in this analysis. Patients were categorized by total GIT 2.0 severity: none-to-mild (0-0.49); moderate (0.50-1.00), and severe-to-very severe (1.01-3.00). Clinical features and medication exposures were examined in each of these categories. The 12-month RUQ responses were summarized by GIT 2.0 score categories at 12 months. RESULTS: Among the 211 CONQUER participants who met the inclusion criteria, most (64%) had mild GIT symptoms, 26% had moderate symptoms, and 10% severe GIT symptoms at 12 months. The categorization of GIT total severity score by RUQ showed that more upper endoscopy procedures and inpatient hospitalization occurred in the CONQUER participants with severe GIT symptoms. These patients with severe GIT symptoms also reported the use of more adaptive equipment. CONCLUSION: This report from the CONQUER cohort suggests that severe GIT symptoms result in more resource utilization. It is especially important to understand resource utilization in early disease cohorts when disease activity, rather than damage, primarily contributes to health-related costs of SSc

Inhibition of Interferon Induction and Action by the Nairovirus Nairobi Sheep Disease Virus/Ganjam Virus

The Nairoviruses are an important group of tick-borne viruses that includes pathogens of man (Crimean Congo hemorrhagic fever virus) and livestock animals (Dugbe virus, Nairobi sheep disease virus (NSDV)). NSDV is found in large parts of East Africa and the Indian subcontinent (where it is known as Ganjam virus). We have investigated the ability of NSDV to antagonise the induction and actions of interferon. Both pathogenic and apathogenic isolates could actively inhibit the induction of type 1 interferon, and also blocked the signalling pathways of both type 1 and type 2 interferons. Using transient expression of viral proteins or sections of viral proteins, these activities all mapped to the ovarian tumour-like protease domain (OTU) found in the viral RNA polymerase. Virus infection, or expression of this OTU domain in transfected cells, led to a great reduction in the incorporation of ubiquitin or ISG15 protein into host cell proteins. Point mutations in the OTU that inhibited the protease activity also prevented it from antagonising interferon induction and action. Interestingly, a mutation at a peripheral site, which had little apparent effect on the ability of the OTU to inhibit ubiquitination and ISG15ylation, removed the ability of the OTU to block the induction of type 1 and the action of type 2 interferons, but had a lesser effect on the ability to block type 1 interferon action, suggesting that targets other than ubiquitin and ISG15 may be involved in the actions of the viral OTU

Genetic Risk Can Be Decreased: Quitting Smoking Decreases and Delays Lung Cancer for Smokers With High and Low CHRNA5 Risk Genotypes - A Meta-analysis.

BACKGROUND: Recent meta-analyses show that individuals with high risk variants in CHRNA5 on chromosome 15q25 are likely to develop lung cancer earlier than those with low-risk genotypes. The same high-risk genetic variants also predict nicotine dependence and delayed smoking cessation. It is unclear whether smoking cessation confers the same benefits in terms of lung cancer risk reduction for those who possess CHRNA5 risk variants versus those who do not. METHODS: Meta-analyses examined the association between smoking cessation and lung cancer risk in 15 studies of individuals with European ancestry who possessed varying rs16969968 genotypes (N=12,690 ever smokers, including 6988 cases of lung cancer and 5702 controls) in the International Lung Cancer Consortium. RESULTS: Smoking cessation (former vs. current smokers) was associated with a lower likelihood of lung cancer (OR=0.48, 95%CI=0.30-0.75, p=0.0015). Among lung cancer patients, smoking cessation was associated with a 7-year delay in median age of lung cancer diagnosis (HR=0.68, 95%CI=0.61-0.77, p=4.9∗10(-10)). The CHRNA5 rs16969968 risk genotype (AA) was associated with increased risk and earlier diagnosis for lung cancer, but the beneficial effects of smoking cessation were very similar in those with and without the risk genotype. CONCLUSION: We demonstrate that quitting smoking is highly beneficial in reducing lung cancer risks for smokers regardless of their CHRNA5 rs16969968 genetic risk status. Smokers with high-risk CHRNA5 genotypes, on average, can largely eliminate their elevated genetic risk for lung cancer by quitting smoking- cutting their risk of lung cancer in half and delaying its onset by 7years for those who develop it. These results: 1) underscore the potential value of smoking cessation for all smokers, 2) suggest that CHRNA5 rs16969968 genotype affects lung cancer diagnosis through its effects on smoking, and 3) have potential value for framing preventive interventions for those who smoke

Adsorption dynamics of hydrophobically modified polymers at an air-water interface

The adsorption dynamics of a series of hydrophobically modified polymers, PAAαCn, at the air-water interface is studied by measuring the dynamic surface tension. The PAAαCn are composed of a poly(acrylic acid) backbone grafted with a percentage α of C8 or C12 alkyl moieties, at pH conditions where the PAA backbone is not charged. The observed adsorption dynamics is very slow and follows a logarithmic behavior at long times indicating the building of an energy barrier which grows over time. After comparison of our experimental results to models from the literature, a new model which accounts for both the deformation of the incoming polymer coils as well as the deformation of the adsorbed pseudo-brush is described. This model enables to fit very well the experimental data. The two fitting parameters give expected values for the monomer size and for the area per adsorbed polymer chain.This article is uploaded in "arXiv.org" https://arxiv.org/abs/1706.0710

Investigating Population Genetic Structure in a Highly Mobile Marine Organism: The Minke Whale Balaenoptera acutorostrata acutorostrata in the North East Atlantic

Inferring the number of genetically distinct populations and their levels of connectivity is of key importance for the sustainable management and conservation of wildlife. This represents an extra challenge in the marine environment where there are few physical barriers to gene-flow, and populations may overlap in time and space. Several studies have investigated the population genetic structure within the North Atlantic minke whale with contrasting results. In order to address this issue, we analyzed ten microsatellite loci and 331 bp of the mitochondrial D-loop on 2990 whales sampled in the North East Atlantic in the period 2004 and 2007–2011. The primary findings were: (1) No spatial or temporal genetic differentiations were observed for either class of genetic marker. (2) mtDNA identified three distinct mitochondrial lineages without any underlying geographical pattern. (3) Nuclear markers showed evidence of a single panmictic population in the NE Atlantic according STRUCTURE's highest average likelihood found at K = 1. (4) When K = 2 was accepted, based on the Evanno's test, whales were divided into two more or less equally sized groups that showed significant genetic differentiation between them but without any sign of underlying geographic pattern. However, mtDNA for these individuals did not corroborate the differentiation. (5) In order to further evaluate the potential for cryptic structuring, a set of 100 in silico generated panmictic populations was examined using the same procedures as above showing genetic differentiation between two artificially divided groups, similar to the aforementioned observations. This demonstrates that clustering methods may spuriously reveal cryptic genetic structure. Based upon these data, we find no evidence to support the existence of spatial or cryptic population genetic structure of minke whales within the NE Atlantic. However, in order to conclusively evaluate population structure within this highly mobile species, more markers will be required

A20 (Tnfaip3) Deficiency in Myeloid Cells Protects against Influenza A Virus Infection

The innate immune response provides the first line of defense against viruses and other pathogens by responding to specific microbial molecules. Influenza A virus (IAV) produces double-stranded RNA as an intermediate during the replication life cycle, which activates the intracellular pathogen recognition receptor RIG-I and induces the production of proinflammatory cytokines and antiviral interferon. Understanding the mechanisms that regulate innate immune responses to IAV and other viruses is of key importance to develop novel therapeutic strategies. Here we used myeloid cell specific A20 knockout mice to examine the role of the ubiquitin-editing protein A20 in the response of myeloid cells to IAV infection. A20 deficient macrophages were hyperresponsive to double stranded RNA and IAV infection, as illustrated by enhanced NF-κB and IRF3 activation, concomitant with increased production of proinflammatory cytokines, chemokines and type I interferon. In vivo this was associated with an increased number of alveolar macrophages and neutrophils in the lungs of IAV infected mice. Surprisingly, myeloid cell specific A20 knockout mice are protected against lethal IAV infection. These results challenge the general belief that an excessive host proinflammatory response is associated with IAV-induced lethality, and suggest that under certain conditions inhibition of A20 might be of interest in the management of IAV infections