Distinct roles for the IIId2 sub-domain in pestivirus and picornavirus internal ribosome entry sites.

Viral internal ribosomes entry site (IRES) elements coordinate the recruitment of the host translation machinery to direct the initiation of viral protein synthesis. Within hepatitis C virus (HCV)-like IRES elements, the sub-domain IIId(1) is crucial for recruiting the 40S ribosomal subunit. However, some HCV-like IRES elements possess an additional sub-domain, termed IIId2, whose function remains unclear. Herein, we show that IIId2 sub-domains from divergent viruses have different functions. The IIId2 sub-domain present in Seneca valley virus (SVV), a picornavirus, is dispensable for IRES activity, while the IIId2 sub-domains of two pestiviruses, classical swine fever virus (CSFV) and border disease virus (BDV), are required for 80S ribosomes assembly and IRES activity. Unlike in SVV, the deletion of IIId2 from the CSFV and BDV IRES elements impairs initiation of translation by inhibiting the assembly of 80S ribosomes. Consequently, this negatively affects the replication of CSFV and BDV. Finally, we show that the SVV IIId2 sub-domain is required for efficient viral RNA synthesis and growth of SVV, but not for IRES function. This study sheds light on the molecular evolution of viruses by clearly demonstrating that conserved RNA structures, within distantly related RNA viruses, have acquired different roles in the virus life cycles

Design and evaluation of the immunogenicity and efficacy of a biomimetic particulate formulation of viral antigens

Subunit viral vaccines are typically not as efficient as live attenuated or inactivated vaccines at inducing protective immune responses. This paper describes an alternative 'biomimetic' technology; whereby viral antigens were formulated around a polymeric shell in a rationally arranged fashion with a surface glycoprotein coated on to the surface and non-structural antigen and adjuvant encapsulated. We evaluated this model using BVDV E2 and NS3 proteins formulated in poly-(D, L-lactic-co-glycolic acid) (PLGA) nanoparticles adjuvanted with polyinosinic:polycytidylic acid (poly(I:C) as an adjuvant (Vaccine-NP). This Vaccine-NP was compared to ovalbumin and poly(I:C) formulated in a similar manner (Control-NP) and a commercial adjuvanted inactivated BVDV vaccine (IAV), all inoculated subcutaneously and boosted prior to BVDV-1 challenge. Significant virus-neutralizing activity, and E2 and NS3 specific antibodies were observed in both Vaccine-NP and IAV groups following the booster immunisation. IFN-γ responses were observed in ex vivo PBMC stimulated with E2 and NS3 proteins in both vaccinated groups. We observed that the protection afforded by the particulate vaccine was comparable to the licenced IAV formulation. In conclusion, the biomimetic particulates showed a promising immunogenicity and efficacy profile that may be improved by virtue of being a customisable mode of delivery

HCV IRES manipulates the ribosome to promote the switch from translation initiation to elongation.

The internal ribosome entry site (IRES) of the hepatitis C virus (HCV) drives noncanonical initiation of protein synthesis necessary for viral replication. Functional studies of the HCV IRES have focused on 80S ribosome formation but have not explored its role after the 80S ribosome is poised at the start codon. Here, we report that mutations of an IRES domain that docks in the 40S subunit's decoding groove cause only a local perturbation in IRES structure and result in conformational changes in the IRES-rabbit 40S subunit complex. Functionally, the mutations decrease IRES activity by inhibiting the first ribosomal translocation event, and modeling results suggest that this effect occurs through an interaction with a single ribosomal protein. The ability of the HCV IRES to manipulate the ribosome provides insight into how the ribosome's structure and function can be altered by bound RNAs, including those derived from cellular invaders

Modal Analysis and Coupling in Metal-Insulator-Metal Waveguides

This paper shows how to analyze plasmonic metal-insulator-metal waveguides using the full modal structure of these guides. The analysis applies to all frequencies, particularly including the near infrared and visible spectrum, and to a wide range of sizes, including nanometallic structures. We use the approach here specifically to analyze waveguide junctions. We show that the full modal structure of the metal-insulator-metal (MIM) waveguides--which consists of real and complex discrete eigenvalue spectra, as well as the continuous spectrum--forms a complete basis set. We provide the derivation of these modes using the techniques developed for Sturm-Liouville and generalized eigenvalue equations. We demonstrate the need to include all parts of the spectrum to have a complete set of basis vectors to describe scattering within MIM waveguides with the mode-matching technique. We numerically compare the mode-matching formulation with finite-difference frequency-domain analysis and find very good agreement between the two for modal scattering at symmetric MIM waveguide junctions. We touch upon the similarities between the underlying mathematical structure of the MIM waveguide and the PT symmetric quantum mechanical pseudo-Hermitian Hamiltonians. The rich set of modes that the MIM waveguide supports forms a canonical example against which other more complicated geometries can be compared. Our work here encompasses the microwave results, but extends also to waveguides with real metals even at infrared and optical frequencies.Comment: 17 pages, 13 figures, 2 tables, references expanded, typos fixed, figures slightly modifie

Spectral theory of some non-selfadjoint linear differential operators

We give a characterisation of the spectral properties of linear differential operators with constant coefficients, acting on functions defined on a bounded interval, and determined by general linear boundary conditions. The boundary conditions may be such that the resulting operator is not selfadjoint. We associate the spectral properties of such an operator $S$ with the properties of the solution of a corresponding boundary value problem for the partial differential equation $\partial_t q \pm iSq=0$. Namely, we are able to establish an explicit correspondence between the properties of the family of eigenfunctions of the operator, and in particular whether this family is a basis, and the existence and properties of the unique solution of the associated boundary value problem. When such a unique solution exists, we consider its representation as a complex contour integral that is obtained using a transform method recently proposed by Fokas and one of the authors. The analyticity properties of the integrand in this representation are crucial for studying the spectral theory of the associated operator.Comment: 1 figur

Differentiation and displacement: Unpicking the relationship between accounts of illness and social structure

This article seeks to unpack the relationship between social structure and accounts of illness. Taking dentine hypersensitivity as an example, this article explores the perspective that accounts of illness are sense-making processes that draw on a readily available pool of meaning. This pool of meaning is composed of a series of distinctions that make available a range of different lines of communication and action about such conditions. Such lines of communication are condensed and preserved over time and are often formed around a concept and its counter concept. The study of such processes is referred to as semantic analysis and involves drawing on the tools and techniques of conceptual history. This article goes on to explore how the semantics of dentine hypersensitivity developed. It illustrates how processes of social differentiation led to the concept being separated from the more dominant concept of dentine sensitivity and how it was medicalised, scientised and economised. In short, this study seeks to present the story of how society has developed a specific language for communicating about sensitivity and hypersensitivity in teeth. In doing so, it proposes that accounts of dentine hypersensitivity draw on lines of communication that society has preserved over time

Ezrin interacts with the SARS coronavirus spike protein and restrains infection at the entry stage

© 2012 Millet et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.Background: Entry of Severe Acute Respiratory Syndrome coronavirus (SARS-CoV) and its envelope fusion with host cell membrane are controlled by a series of complex molecular mechanisms, largely dependent on the viral envelope glycoprotein Spike (S). There are still many unknowns on the implication of cellular factors that regulate the entry process. Methodology/Principal Findings: We performed a yeast two-hybrid screen using as bait the carboxy-terminal endodomain of S, which faces the cytosol during and after opening of the fusion pore at early stages of the virus life cycle. Here we show that the ezrin membrane-actin linker interacts with S endodomain through the F1 lobe of its FERM domain and that both the eight carboxy-terminal amino-acids and a membrane-proximal cysteine cluster of S endodomain are important for this interaction in vitro. Interestingly, we found that ezrin is present at the site of entry of S-pseudotyped lentiviral particles in Vero E6 cells. Targeting ezrin function by small interfering RNA increased S-mediated entry of pseudotyped particles in epithelial cells. Furthermore, deletion of the eight carboxy-terminal amino acids of S enhanced S-pseudotyped particles infection. Expression of the ezrin dominant negative FERM domain enhanced cell susceptibility to infection by SARS-CoV and S pseudotyped particles and potentiated S-dependent membrane fusion. Conclusions/Significance: Ezrin interacts with SARS-CoV S endodomain and limits virus entry and fusion. Our data present a novel mechanism involving a cellular factor in the regulation of S-dependent early events of infection.This work was supported by the Research Grant Council of Hong Kong (RGC#760208)and the RESPARI project of the International Network of Pasteur Institutes

Success in periodontology: An evolutive concept

AimThe purpose of this editorial was to discuss a definition of success after periodontal therapy based on the retention of natural dentition.Materials and MethodsBased on topic and relevance, references were collected and then divided into four categories: (a) the influence of available therapeutic techniques on the definition of hopeless teeth, (b) the longâ term rate of tooth loss during supportive periodontal therapy, (c) the duration of time that the treatment outcomes may be considered stable and (d) patientsâ perception and satisfaction of periodontal therapy.ResultsPeriodontal therapy can change the prognosis of hopeless teeth, making them maintainable in the long term. The rate of tooth loss can be minimized in a way that a period of 10 years or more is needed to evaluate further periodontal breakdown. In addition, patientsâ perception and satisfaction of the treatment should be considered as the main therapeutic endpoints of the provided periodontal therapy.ConclusionsDefinition of success is linked to the available therapeutic tools. Due to the recent advancement of treatment modalities, periodontally hopeless teeth can now be treated and maintained for a long period of time with health, function and patient satisfaction.Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/150541/1/jcpe13150.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/150541/2/jcpe13150_am.pd