Expression of Ifnlr1 on intestinal epithelial cells is critical to the antiviral effects of IFN-lambda against norovirus and reovirus

Lambda interferon (IFN-λ) has potent antiviral effects against multiple enteric viral pathogens, including norovirus and rotavirus, in both preventing and curing infection. Because the intestine includes a diverse array of cell types, however, the cell(s) upon which IFN-λ acts to exert its antiviral effects is unclear. Here, we sought to identify IFN-λ-responsive cells by generation of mice with lineage-specific deletion of the receptor for IFN-λ, Ifnlr1. We found that expression of IFNLR1 on intestinal epithelial cells (IECs) in the small intestine and colon is required for enteric IFN-λ antiviral activity. IEC Ifnlr1 expression also determines the efficacy of IFN-λ in resolving persistent murine norovirus (MNoV) infection and regulates fecal shedding and viral titers in tissue. Thus, the expression of Ifnlr1 by IECs is necessary for the response to both endogenous and exogenous IFN-λ. We further demonstrate that IEC Ifnlr1 expression is required for the sterilizing innate immune effects of IFN-λ by extending these findings in Rag1-deficient mice. Finally, we assessed whether our findings pertained to multiple viral pathogens by infecting mice specifically lacking IEC Ifnlr1 expression with reovirus. These mice phenocopied Ifnlr1-null animals, exhibiting increased intestinal tissue titers and enhanced reovirus fecal shedding. Thus, IECs are the critical cell type responding to IFN-λ to control multiple enteric viruses. This is the first genetic evidence that supports an essential role for IECs in IFN-λ-mediated control of enteric viral infection, and these findings provide insight into the mechanism of IFN-λ-mediated antiviral activity. IMPORTANCE Human noroviruses (HNoVs) are the leading cause of epidemic gastroenteritis worldwide. Type III interferons (IFN-λ) control enteric viral infections in the gut and have been shown to cure mouse norovirus, a small-animal model for HNoVs. Using a genetic approach with conditional knockout mice, we identified IECs as the dominant IFN-λ-responsive cells in control of enteric virus infection in vivo. Upon murine norovirus or reovirus infection, Ifnlr1 depletion in IECs largely recapitulated the phenotype seen in Ifnlr1(−/−) mice of higher intestinal tissue viral titers and increased viral shedding in the stool. Moreover, IFN-λ-mediated sterilizing immunity against murine norovirus requires the capacity of IECs to respond to IFN-λ. These findings clarify the mechanism of action of this cytokine and emphasize the therapeutic potential of IFN-λ for treating mucosal viral infections

Performance, Politics and Media: How the 2010 British General Election leadership debates generated ‘talk’ amongst the electorate.

During the British General Election 2010 a major innovation was introduced in part to improve engagement: a series of three live televised leadership debates took place where the leader of each of the three main parties, Labour, Liberal Democrat and Conservative, answered questions posed by members of the public and subsequently debated issues pertinent to the questions. In this study we consider these potentially ground breaking debates as the kind of event that was likely to generate discussion. We investigate various aspects of the ‘talk’ that emerged as a result of watching the debates. As an exploratory study concerned with situated accounts of the participants experiences we take an interpretive perspective. In this paper we outline the meta-narratives (of talk) associated with the viewing of the leadership debates that were identified, concluding our analysis by suggesting that putting a live debate on television and promoting and positioning it as a major innovation is likely to mean that is how the audience will make sense of it – as a media event

Automated smart home assessment to support pain management: Multiple methods analysis

©Roschelle L Fritz, Marian Wilson, Gordana Dermody, Maureen Schmitter-Edgecombe, Diane J Cook. Objective: This study aimed to determine if a smart home can detect pain-related behaviors to perform automated assessment and support intervention for persons with chronic pain.Background: Poorly managed pain can lead to substance use disorders, depression, suicide, worsening health, and increased use of health services. Most pain assessments occur in clinical settings away from patients’ natural environments. Advances in smart home technology may allow observation of pain in the home setting. Smart homes recognizing human behaviors may be useful for quantifying functional pain interference, thereby creating new ways of assessing pain and supporting people living with pain.Methods: A multiple methods, secondary data analysis was conducted using historic ambient sensor data and weekly nursing assessment data from 11 independent older adults reporting pain across 1-2 years of smart home monitoring. A qualitative approach was used to interpret sensor-based data of 27 unique pain events to support clinician-guided training of a machine learning model. A periodogram was used to calculate circadian rhythm strength, and a random forest containing 100 trees was employed to train a machine learning model to recognize pain-related behaviors. The model extracted 550 behavioral markers for each sensor-based data segment. These were treated as both a binary classification problem (event, control) and a regression problem.Results: We found 13 clinically relevant behaviors, revealing 6 pain-related behavioral qualitative themes. Quantitative results were classified using a clinician-guided random forest technique that yielded a classification accuracy of 0.70, sensitivity of 0.72, specificity of 0.69, area under the receiver operating characteristic curve of 0.756, and area under the precision-recall curve of 0.777 in comparison to using standard anomaly detection techniques without clinician guidance (0.16 accuracy achieved; P \u3c .001). The regression formulation achieved moderate correlation, with r=0.42.Conclusions: Findings of this secondary data analysis reveal that a pain-assessing smart home may recognize pain-related behaviors. Utilizing clinicians’ real-world knowledge when developing pain-assessing machine learning models improves the model’s performance. A larger study focusing on pain-related behaviors is warranted to improve and test model performance

Noise filtering and nonparametric analysis of microarray data underscores discriminating markers of oral, prostate, lung, ovarian and breast cancer

BACKGROUND: A major goal of cancer research is to identify discrete biomarkers that specifically characterize a given malignancy. These markers are useful in diagnosis, may identify potential targets for drug development, and can aid in evaluating treatment efficacy and predicting patient outcome. Microarray technology has enabled marker discovery from human cells by permitting measurement of steady-state mRNA levels derived from thousands of genes. However many challenging and unresolved issues regarding the acquisition and analysis of microarray data remain, such as accounting for both experimental and biological noise, transcripts whose expression profiles are not normally distributed, guidelines for statistical assessment of false positive/negative rates and comparing data derived from different research groups. This study addresses these issues using Affymetrix HG-U95A and HG-U133 GeneChip data derived from different research groups. RESULTS: We present here a simple non parametric approach coupled with noise filtering to identify sets of genes differentially expressed between the normal and cancer states in oral, breast, lung, prostate and ovarian tumors. An important feature of this study is the ability to integrate data from different laboratories, improving the analytical power of the individual results. One of the most interesting findings is the down regulation of genes involved in tissue differentiation. CONCLUSIONS: This study presents the development and application of a noise model that suppresses noise, limits false positives in the results, and allows integration of results from individual studies derived from different research groups

The FLY-project: study protocol for mixed methods research to explore the complex social dynamics of sustainable food-related lifestyles in youth in practical education

Background: The present-day food system is a key driver of climate change and biodiversity loss, making it imperative for populations to shift towards more sustainable diets. The involvement of youth in this transition is vital because they are in a formative period where their identities, values, and norms, including their food behaviours, are being shaped. Special attention should be paid to youth in practical education because they are often overlooked in existing studies, yet evidence suggests they may lack the necessary resources to support dietary changes, resulting in lower levels of pro-environmental food-related behaviours. The aim of the FLY (Food-related Lifestyles in Youth) project is to study how sustainable food-related lifestyles and underlying factors develop in early adolescence, particularly in Dutch youth in practical education, how these spread in social networks, and to develop community-level intervention strategies to support youths’ transition to sustainable food-related behaviours. Methods/design: The FLY-project adopts a mixed-method approach. First, two literature reviews are conducted. A systematic review assesses how capabilities, opportunities and motivation are associated with sustainable food behaviours in youth, and how these elements interrelate in determining sustainable food-related lifestyles. A scoping review studies community-level interventions that target sustainable and healthy food-related behaviours. Second, focus groups are conducted to explore the barriers and facilitating factors concerning capabilities, opportunities, and motivations that Dutch youth in practical-level education experience to transition to more sustainable food-related lifestyles. Third, a cohort survey study is conducted to track the dynamic interplay between capabilities, opportunities, motivation, and changes in specific sustainable food behaviours over time, and to assess the diffusion of sustainable food-related lifestyles via social (media) networks. Fourth, an experimental research programme tests promising intervention approaches, some of which are co-created with youth, targeting relevant underlying factors. Discussion: This paper describes the rationale, conceptual framework, design and methods of the FLY-project. The FLY-project contributes to an understanding of underlying factors of sustainable food-related behaviours in adolescence and results in a multi-component intervention toolkit, with a particular focus on youth in practical education programmes

Arbitrage and deflators in illiquid markets

This paper presents a stochastic model for discrete-time trading in financial markets where trading costs are given by convex cost functions and portfolios are constrained by convex sets. The model does not assume the existence of a cash account/numeraire. In addition to classical frictionless markets and markets with transaction costs or bid-ask spreads, our framework covers markets with nonlinear illiquidity effects for large instantaneous trades. In the presence of nonlinearities, the classical notion of arbitrage turns out to have two equally meaningful generalizations, a marginal and a scalable one. We study their relations to state price deflators by analyzing two auxiliary market models describing the local and global behavior of the cost functions and constraints

Serotype-specific differences in inhibition of reovirus infectivity by human-milk glycans are determined by viral attachment protein σ1

AbstractHuman milk contains many bioactive components, including secretory IgA, oligosaccharides, and milk-associated proteins. We assessed the antiviral effects of several components of milk against mammalian reoviruses. We found that glucocerebroside (GCB) inhibited the infectivity of reovirus strain type 1 Lang (T1L), whereas gangliosides GD3 and GM3 and 3′-sialyllactose (3SL) inhibited the infectivity of reovirus strain type 3 Dearing (T3D). Agglutination of erythrocytes mediated by T1L and T3D was inhibited by GD3, GM3, and bovine lactoferrin. Additionally, α-sialic acid, 3SL, 6′-sialyllactose, sialic acid, human lactoferrin, osteopontin, and α-lactalbumin inhibited hemagglutination mediated by T3D. Using single-gene reassortant viruses, we found that serotype-specific differences segregate with the gene encoding the viral attachment protein. Furthermore, GD3, GM3, and 3SL inhibit T3D infectivity by blocking binding to host cells, whereas GCB inhibits T1L infectivity post-attachment. These results enhance an understanding of reovirus cell attachment and define a mechanism for the antimicrobial activity of human milk

Chikungunya virus vaccine candidates with decreased mutational robustness are attenuated in vivo and have compromised transmissibility

Chikungunya virus (CHIKV) is a reemerged arbovirus, a member of the Togaviridae family. It circulates through mosquito vectors mainly of the Aedes family and a mammalian host. CHIKV causes chikungunya fever, a mild to severe disease characterized by arthralgia, with some fatal outcomes described. In the past years, several outbreaks mainly caused by enhanced adaptation of the virus to the vector and ineffective control of the contacts between infected mosquito populations and the human host have been reported. Vaccines represent the best solution for the control of insect-borne viruses, including CHIKV, but are often unavailable. We designed live attenuated CHIKVs by applying a rational genomic design based on multiple replacements of synonymous codons. In doing so, the virus mutational robustness (capacity to maintain phenotype despite introduction of mutations to genotype) is decreased, driving the viral population toward deleterious evolutionary trajectories. When the candidate viruses were tested in the insect and mammalian hosts, we observed overall strong attenuation in both and greatly diminished signs of disease. Moreover, we found that the vaccine candidates elicited protective immunity related to the production of neutralizing antibodies after a single dose. During an experimental transmission cycle between mosquitoes and naive mice, vaccine candidates could be transmitted by mosquito bite, leading to asymptomatic infection in mice with compromised dissemination. Using deep-sequencing technology, we observed an increase in detrimental (stop) codons, which confirmed the effectiveness of this genomic design. Because the approach involves hundreds of synonymous modifications to the genome, the reversion risk is significantly reduced, rendering the viruses promising vaccine candidates

Reovirus-Induced Apoptosis in the Intestine Limits Establishment of Enteric Infection

Several viruses induce intestinal epithelial cell death during enteric infection. However, it is unclear whether proapoptotic capacity promotes or inhibits replication in this tissue. We infected mice with two reovirus strains that infect the intestine but differ in the capacity to alter immunological tolerance to new food antigen. Infection with reovirus strain T1L, which induces an inflammatory immune response to fed antigen, is prolonged in the intestine, whereas T3D-RV, which does not induce this response, is rapidly cleared from the intestine. Compared with T1L, T3D-RV infection triggered apoptosis of intestinal epithelial cells and subsequent sloughing of dead cells into the intestinal lumen. We conclude that the infection advantage of T1L derives from its capacity to subvert host restriction by epithelial cell apoptosis, providing a possible mechanism by which T1L enhances inflammatory signals during antigen feeding. Using a panel of T1L × T3D-RV reassortant viruses, we identified the viral M1 and M2 gene segments as determinants of reovirus-induced apoptosis in the intestine. Expression of the T1L M1 and M2 genes in a T3D-RV background was sufficient to limit epithelial cell apoptosis and enhance viral infection to levels displayed by T1L. These findings define additional reovirus gene segments required for enteric infection of mice and illuminate the antiviral effect of intestinal epithelial cell apoptosis in limiting enteric viral infection. Viral strain-specific differences in the capacity to infect the intestine may be useful in identifying viruses capable of ameliorating tolerance to fed antigen in autoimmune conditions like celiac disease