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

In vitro efficacy of tavaborole topical solution, 5% after penetration through nail polish on ex vivo human fingernails

This document is the Accepted Manuscript of the following article: Aditya K. Gupta, et al, 'In vitro efficacy of tavaborole topical solution, 5% after penetration through nail polish on ex vivo human fingernails', Journal of Dermatological Treatment, Jan 2018. Under embargo until 10 January 2019. The final, published version is available online at doi: https://doi.org/10.1080/09546634.2017.1422078.Background: Topical antifungal treatments for onychomycosis are applied to clean, unpolished nails for 48 weeks or longer. Patients often wish to mask their infection with nail polish yet there is no evidence to suggest antifungal efficacy in the presence of nail polish. Objective: To determine if tavaborole retains the ability to penetrate the nail plate and inhibit fungal growth in the presence of nail polish. Method: Tavaborole was applied to human fingernails painted with 2 or 4 coats of nail polish, and unpainted nails in an ex vivo model. Nails were mounted on TurChub ® chambers seeded with Trichophyton rubrum and allowed to incubate for 7 days. Antifungal activity was assessed by measuring zones of inhibition. Results and conclusion: Tavaborole exhibited antifungal activity in all experimental groups. The zones of inhibition of T. rubrum for all experimental groups (2 or 4 coats of polish, unpolished) were greater than infected controls (polished and unpolished), p s <.001. Tavaborole penetrates polished nails and kills T. rubrum in this ex vivo model.Peer reviewe

An Evaluation of Hand-Held Infrared Thermography for Determining Velvet Antler Growth Rates in Red Deer Stags

Last updated: 6/12/200

Who is to blame? The relationship between ingroup identification and relative deprivation is moderated by ingroup attributions

Contradictory evidence can be found in the literature about whether ingroup identification and perceived relative deprivation are positively or negatively related. Indeed, theoretical arguments can be made for both effects. It was proposed that the contradictory findings can be explained by considering a hitherto unstudied moderator: The extent to which deprivation is attributed to the ingroup. It was hypothesised that identification would only have a negative impact on deprivation, and that deprivation would only have a negative impact on identification, if ingroup attributions are high. To test this, attributions to the ingroup were experimentally manipulated among British student participants (N = 189) who were asked about their perceived deprivation vis-à-vis German students, yield ing support for the hypotheses

Identifying Prevalent Mathematical Pathways to Engineering in South Carolina

National data indicate that initial mathematics course placement in college is a strong predictor of persistence to degree in engineering, with students placed in calculus persisting at nearly twice the rate of those placed below calculus. Within the state of South Carolina, approximately 95% of engineering-intending students who initially place below calculus are from in-state. In order to make systemic change, we are first analyzing system-wide data to identify prevalent educational pathways within the state, and the mathematical milestones along those pathways taken by students in engineering and engineering-related fields. This paper reports preliminary analysis of that data to understand trends in major selection and mathematics preparation within the state

An assessment of the aquaculture potential of indigenous freshwater food fish of Fiji, Papua New Guinea, Vanuatu, Solomon Islands, Samoa and Tonga as alternatives to farming of tilapia

An important driver behind introductions for aquaculture of alien fish species into Pacific Island Countries and Territories (PICTs) is a lack of knowledge about domestication suitability and specific culture requirements of indigenous taxa. Introductions may be appropriate in some circumstances, but in other circumstances, the associated risks may outweigh the benefits, so greater understanding of indigenous species' aquaculture potential is important. This review summarises literature for indigenous freshwater food fish species from Papua New Guinea, Fiji, Vanuatu, the Solomon Islands, Samoa and Tonga, and evaluates their aquaculture potential for food security and/or small-scale livelihoods. A species selection criteria incorporating economic, social, biological and environmental spheres was used to score 62 candidate species. Tilapia (Oreochromis mossambicus and O. niloticus) now established in PICTs were evaluated for comparison. Results show that 13 species belonging to the families Mugilidae (Mullets), Terapontidae (Grunters), Kuhliidae (Flagtails) and Scatophagidae (Scats) have the highest culture potential according to selection criteria. These feed at a relatively low trophic level (are herbivores/detritivores), have comparatively fast growth rates and overall possess characteristics most amenable for small-scale, inland aquaculture. The four top-ranked candidates are all mountain mullets Cestraeus spp., followed by Nile tilapia (Oreochromis niloticus). Lower ranked candidates include three other mullets (Planiliza melinoptera, P. subviridis and Mugil cephalus) and rock flagtail Kuhlia rupestris. Importantly, many species remain data deficient in aspects of their reproductive biology or culture performance. Species profiles and ranked priority species by country are provided with logistical, technological and environmental assessments of country capacities to culture each species

Microscopic calculations of medium effects for 200-MeV (p,p') reactions

We examine the quality of a G-matrix calculation of the effective nucleon-nucleon (NN) interaction for the prediction of the cross section and analyzing power for 200-MeV (p,p') reactions that populate natural parity states in $^{16}$O, $^{28}$Si, and $^{40}$Ca. This calculation is based on a one-boson-exchange model of the free NN force that reproduces NN observables well. The G-matrix includes the effects of Pauli blocking, nuclear binding, and strong relativistic mean-field potentials. The implications of adjustments to the effective mass ansatz to improve the quality of the approximation at momenta above the Fermi level will be discussed, along with the general quality of agreement to a variety of (p,p') transitions.Comment: 36 pages, TeX, 18 figure

Microarray analysis of the in vivo sequence preferences of a minor groove binding drug

<p>Abstract</p> <p>Background</p> <p>Minor groove binding drugs (MGBDs) interact with DNA in a sequence-specific manner and can cause changes in gene expression at the level of transcription. They serve as valuable models for protein interactions with DNA and form an important class of antitumor, antiviral, antitrypanosomal and antibacterial drugs. There is a need to extend knowledge of the sequence requirements for MGBDs from <it>in vitro </it>DNA binding studies to living cells.</p> <p>Results</p> <p>Here we describe the use of microarray analysis to discover yeast genes that are affected by treatment with the MGBD berenil, thereby allowing the investigation of its sequence requirements for binding <it>in vivo</it>. A novel approach to sequence analysis allowed us to address hypotheses about genes that were directly or indirectly affected by drug binding. The results show that the sequence features of A/T richness and heteropolymeric character discovered by <it>in vitro </it>berenil binding studies are found upstream of genes hypothesized to be directly affected by berenil but not upstream of those hypothesized to be indirectly affected or those shown to be unaffected.</p> <p>Conclusion</p> <p>The data support the conclusion that effects of berenil on gene expression in yeast cells can be explained by sequence patterns discovered by <it>in vitro </it>binding experiments. The results shed light on the sequence and structural rules by which berenil binds to DNA and affects the transcriptional regulation of genes and contribute generally to the development of MGBDs as tools for basic and applied research.</p