Increased liver stiffness promotes hepatitis B progression by impairing innate immunity in CCl4-induced fibrotic HBV\u3csup\u3e+\u3c/sup\u3e transgenic mice

Background: Hepatitis B virus (HBV) infection develops as an acute or chronic liver disease, which progresses from steatosis, hepatitis, and fibrosis to end-stage liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). An increased stromal stiffness accompanies fibrosis in chronic liver diseases and is considered a strong predictor for disease progression. The goal of this study was to establish the mechanisms by which enhanced liver stiffness regulates HBV infectivity in the fibrotic liver tissue. Methods: For in vitro studies, HBV-transfected HepG2.2.15 cells were cultured on polydimethylsiloxane gels coated by polyelectrolyte multilayer films of 2 kPa (soft) or 24 kPa (stiff) rigidity mimicking the stiffness of the healthy or fibrotic liver. For in vivo studies, hepatic fibrosis was induced in C57Bl/6 parental and HBV+ transgenic (HBVTg) mice by injecting CCl4 twice a week for 6 weeks. Results: We found higher levels of HBV markers in stiff gel-attached hepatocytes accompanied by up-regulated OPN content in cell supernatants as well as suppression of anti-viral interferon-stimulated genes (ISGs). This indicates that pre-requisite “fibrotic” stiffness increases osteopontin (OPN) content and releases and suppresses anti-viral innate immunity, causing a subsequent rise in HBV markers expression in hepatocytes. In vitro results were corroborated by data from HBVTg mice administered CCl4 (HBVTg CCl4). These mice showed higher HBV RNA, DNA, HBV core antigen (HBcAg), and HBV surface antigen (HBsAg) levels after liver fibrosis induction as judged by a rise in Col1a1, SMA, MMPs, and TIMPs mRNAs and by increased liver stiffness. Importantly, CCl4-induced the pro-fibrotic activation of liver cells, and liver stiffness was higher in HBVTg mice compared with control mice. Elevation of HBV markers and OPN levels corresponded to decreased ISG activation in HBVTg CCl4 mice vs HBVTg control mice. Conclusion: Based on our data, we conclude that liver stiffness enhances OPN levels to limit anti-viral ISG activation in hepatocytes and promote an increase in HBV infectivity, thereby contributing to end-stage liver disease progression

Morphological variation and sensitivity to frequency of forms among native speakers of Czech

This article looks at inter-speaker variation in two environments: the genitive and locative singular cases of masculine ‘hard inanimate’ nouns in Czech, using a large-scale survey of native speakers that used two tasks to test their preferences for certain forms (acceptability) and their choices (gap filling). Our hypothesis that such variation exists was upheld, but only within limited parameters. Most biographical data (age, gender, education) played no role in respondents’ choices or preferences. Their region of origin played a small but significant role, although not the one expected. Relating the two types of tasks to each other, we found that respondents’ use of the ratings scale did not correlate to their choice of forms, but their overall strength of preference for one form over another did correlate with their choices. Inter-speaker variation does thus go some way to explaining the persistent diversity in this paradigm and arguably may contribute to its maintenance

Increased liver stiffness promotes hepatitis B progression by impairing innate immunity in CCl4-induced fibrotic HBV+ transgenic mice

BackgroundHepatitis B virus (HBV) infection develops as an acute or chronic liver disease, which progresses from steatosis, hepatitis, and fibrosis to end-stage liver diseases such as cirrhosis and hepatocellular carcinoma (HCC). An increased stromal stiffness accompanies fibrosis in chronic liver diseases and is considered a strong predictor for disease progression. The goal of this study was to establish the mechanisms by which enhanced liver stiffness regulates HBV infectivity in the fibrotic liver tissue.MethodsFor in vitro studies, HBV-transfected HepG2.2.15 cells were cultured on polydimethylsiloxane gels coated by polyelectrolyte multilayer films of 2 kPa (soft) or 24 kPa (stiff) rigidity mimicking the stiffness of the healthy or fibrotic liver. For in vivo studies, hepatic fibrosis was induced in C57Bl/6 parental and HBV+ transgenic (HBVTg) mice by injecting CCl4 twice a week for 6 weeks.ResultsWe found higher levels of HBV markers in stiff gel-attached hepatocytes accompanied by up-regulated OPN content in cell supernatants as well as suppression of anti-viral interferon-stimulated genes (ISGs). This indicates that pre-requisite “fibrotic” stiffness increases osteopontin (OPN) content and releases and suppresses anti-viral innate immunity, causing a subsequent rise in HBV markers expression in hepatocytes. In vitro results were corroborated by data from HBVTg mice administered CCl4 (HBVTg CCl4). These mice showed higher HBV RNA, DNA, HBV core antigen (HBcAg), and HBV surface antigen (HBsAg) levels after liver fibrosis induction as judged by a rise in Col1a1, SMA, MMPs, and TIMPs mRNAs and by increased liver stiffness. Importantly, CCl4-induced the pro-fibrotic activation of liver cells, and liver stiffness was higher in HBVTg mice compared with control mice. Elevation of HBV markers and OPN levels corresponded to decreased ISG activation in HBVTg CCl4 mice vs HBVTg control mice.ConclusionBased on our data, we conclude that liver stiffness enhances OPN levels to limit anti-viral ISG activation in hepatocytes and promote an increase in HBV infectivity, thereby contributing to end-stage liver disease progression

Genetic association of CDC2 with cerebrospinal fluid tau in Alzheimer's disease

We have recently reported that a polymorphism in the cell division cycle (CDC2) gene, designated Ex6 + 7I/D, is associated with Alzheimer's disease (AD). The CDC2 gene is located on chromosome 10q21.1 close to the marker D10S1225 linked to AD. Active cdc2 accumulates in neurons containing neurofibrillary tangles (NFT), a process that can precede the formation of NFT. Therefore, CDC2 is a promising candidate susceptibility gene for AD. We investigated the possible effects of the CDC2 polymorphism on cerebrospinal fluid (CSF) biomarkers in AD patients. CDC2 genotypes were evaluated in relation to CSF protein levels of total tau, phospho-tau and beta-amyloid (1-42) in AD patients and control individuals, and in relation to the amount of senile plaques and NFT in the frontal cortex and in the hippocampus in patients with autopsy-proven AD and controls. The CDC2 Ex6 + 7I allele was associated with a gene dose-dependent increase of CSF total tau levels (F-2,F- 626 = 7.0, p = 0.001) and the homozygous CDC2Ex6 +7II genotype was significantly more frequent among AD patients compared to controls (p = 0.006, OR = 1.57, 95% CI 1.13-2.17). Our results provide further evidence for an involvement of cdc2 in the pathogenesis of AD. Copyright (C) 2005 S. Karger AG, Basel

The source ambiguity problem: Distinguishing the effects of grammar and processing on acceptability judgments

Judgments of linguistic unacceptability may theoretically arise from either grammatical deviance or significant processing difficulty. Acceptability data are thus naturally ambiguous in theories that explicitly distinguish formal and functional constraints. Here, we consider this source ambiguity problem in the context of Superiority effects: the dispreference for ordering a wh-phrase in front of a syntactically “superior” wh-phrase in multiple wh-questions, e.g., What did who buy? More specifically, we consider the acceptability contrast between such examples and so-called D-linked examples, e.g., Which toys did which parents buy? Evidence from acceptability and self-paced reading experiments demonstrates that (i) judgments and processing times for Superiority violations vary in parallel, as determined by the kind of wh-phrases they contain, (ii) judgments increase with exposure, while processing times decrease, (iii) reading times are highly predictive of acceptability judgments for the same items, and (iv) the effects of the complexity of the wh-phrases combine in both acceptability judgments and reading times. This evidence supports the conclusion that D-linking effects are likely reducible to independently motivated cognitive mechanisms whose effects emerge in a wide range of sentence contexts. This in turn suggests that Superiority effects, in general, may owe their character to differential processing difficulty

The impact of sound field systems on learning and attention in elementary school classrooms

Purpose: An evaluation of the installation and use of sound field systems (SFS) was carried out to investigate their impact on teaching and learning in elementary school classrooms. Methods: The evaluation included acoustic surveys of classrooms, questionnaire surveys of students and teachers and experimental testing of students with and without the use of SFS. Students ’ perceptions of classroom environments and objective data evaluating change in performance on cognitive and academic assessments with amplification over a six month period are reported. Results: Teachers were positive about the use of SFS in improving children’s listening and attention to verbal instructions. Over time students in amplified classrooms did not differ from those in nonamplified classrooms in their reports of listening conditions, nor did their performance differ in measures of numeracy, reading or spelling. Use of SFS in the classrooms resulted in significantly larger gains in performance in the number of correct items on the nonverbal measure of speed of processing and the measure of listening comprehension. Analysis controlling for classroom acoustics indicated that students ’ listening comprehension score

Exploring marine ecosystems with elementary school Portuguese children: inquiry-based project activities focused on ‘real-life’ contexts

The purpose of the study was to investigate how young students engage in an inquirybased project driven by real-life contexts. Elementary school children were engaged in a small inquiry project centred on marine biodiversity and species adaptations. All activities included the exploration of an out-of-school setting as a learning context. A total of 49 students and 2 teachers were involved in the activities. The research methods included observation, document analysis and content analysis of the answers to a questionnaire and an interview. The results revealed that most of the students acquired scientific knowledge related to biological diversity and adaptations to habitat. Moreover, students progressively demonstrate greater autonomy, argumentative ability and decision-making. One implication of the present study is that elementary science curriculum could be better managed with inquiry projectbased activities that explore different types of resources and out-of-school settings.info:eu-repo/semantics/publishedVersio

Managing the Marine Aquarium Trade: Revealing the Data Gaps Using Ornamental Polychaetes

The marine aquarium industry has great potential to generate jobs in low-income coastal communities creating incentives for the maintenance of a healthy coral reef, if effectively managed. In the absence of current monitoring or legislation to govern the trade, baseline information regarding the species, number and source location of animals traded is missing despite being critical for its successful management and sustainability. An industry assessment to establish the number and provenance of species of ornamental polychaetes (sabellids and serpulids) traded was undertaken across UK wholesalers and retailers. Six geographical regions exporting fan worms were identified. Singapore contributed the highest percentage of imports, but of only one worm “type” whereas Bali, the second largest source, supplied five different worm “types”. Over 50% of UK retailers were supplied by one wholesaler while the remainder were stocked by a mixture of one other wholesaler and/or direct imports from the source country. We estimate that up to 18,500 ornamental polychaetes (16,980 sabellids and 1,018 serpulids) are sold annually in the UK revealing a drastic underestimation of currently accepted trade figures. Incorrect identification (based on exporting region or visual characteristics) of traded animals exacerbates the inaccuracy in market quantification, although identification of preserved sabellids using published keys proved just as inconclusive with high within-species variability and the potential for new or cryptic species. A re-description of the polychaete groups traded using a combination of molecular and morphological techniques is necessary for effective identification and market quantification. This study provides the first assessment of ornamental polychaetes but more importantly highlights the issues surrounding the collection of baseline information necessary to manage the aquarium trade. We recommend that future management should be community based and site-specific with financial and educational support from NGOs, local governments and industry members