Zein-Based Nanoparticles Improve the Oral Bioavailability of Resveratrol and Its Anti-inflammatory Effects in a Mouse Model of Endotoxic Shock

Resveratrol offers pleiotropic health benefits including a reported ability to inhibit lipopolysaccharide (LPS)-induced cytokine production. The aim of this work was to prepare, characterize and evaluate a resveratrol nanoparticulate formulation based on zein. For this purpose, the oral bioavailability of the encapsulated polyphenol as well as its anti-inflammatory effects in a mouse model of endotoxic shock was studied. The resveratrol-loaded nanoparticles displayed a mean size of 307±3 nm, with a negative zeta potential (-51.1±1.55 mV), and a polyphenol loading of 80.2±3.26 μg/mg. In vitro, the release of resveratrol from the nanoparticles was found to be pH independent and adjusted well to the Peppas-Sahlin kinetic model, suggesting a mechanism based on the combination of diffusion and erosion of the nanoparticle matrix. Pharmacokinetic studies demonstrated that zein-based nanoparticles provided high and prolonged plasma levels of the polyphenol for at least 48 h. The oral bioavailability of resveratrol when administered in these nanoparticles increased up to 50% (19.2-fold higher than for the control solution of the polyphenol). Furthermore, nanoparticles administered daily for 7 days at 15 mg/kg, were able to diminish the endotoxic symptoms induced in mice by the intraperitoneal administration of LPS (i.e., hypothermia, piloerection and stillness). In addition, serum TNF-α levels were slightly lower (approximately 15%) than those observed in the control.

An unbiased genetic screen reveals the polygenic nature of the influenza virus anti-interferon response

UNLABELLED: Influenza A viruses counteract the cellular innate immune response at several steps, including blocking RIG I-dependent activation of interferon (IFN) transcription, interferon (IFN)-dependent upregulation of IFN-stimulated genes (ISGs), and the activity of various ISG products; the multifunctional NS1 protein is responsible for most of these activities. To determine the importance of other viral genes in the interplay between the virus and the host IFN response, we characterized populations and selected mutants of wild-type viruses selected by passage through non-IFN-responsive cells. We reasoned that, by allowing replication to occur in the absence of the selection pressure exerted by IFN, the virus could mutate at positions that would normally be restricted and could thus find new optimal sequence solutions. Deep sequencing of selected virus populations and individual virus mutants indicated that nonsynonymous mutations occurred at many phylogenetically conserved positions in nearly all virus genes. Most individual mutants selected for further characterization induced IFN and ISGs and were unable to counteract the effects of exogenous IFN, yet only one contained a mutation in NS1. The relevance of these mutations for the virus phenotype was verified by reverse genetics. Of note, several virus mutants expressing intact NS1 proteins exhibited alterations in the M1/M2 proteins and accumulated large amounts of deleted genomic RNAs but nonetheless replicated to high titers. This suggests that the overproduction of IFN inducers by these viruses can override NS1-mediated IFN modulation. Altogether, the results suggest that influenza viruses replicating in IFN-competent cells have tuned their complete genomes to evade the cellular innate immune system and that serial replication in non-IFN-responsive cells allows the virus to relax from these constraints and find a new genome consensus within its sequence space.

IMPORTANCE: In natural virus infections, the production of interferons leads to an antiviral state in cells that effectively limits virus replication. The interferon response places considerable selection pressure on viruses, and they have evolved a variety of ways to evade it. Although the influenza virus NS1 protein is a powerful interferon antagonist, the contributions of other viral genes to interferon evasion have not been well characterized. Here, we examined the effects of alleviating the selection pressure exerted by interferon by serially passaging influenza viruses in cells unable to respond to interferon. Viruses that grew to high titers had mutations at many normally conserved positions in nearly all genes and were not restricted to the NS1 gene. Our results demonstrate that influenza viruses have fine-tuned their entire genomes to evade the interferon response, and by removing interferon-mediated constraints, viruses can mutate at genome positions normally restricted by the interferon response.

Development and evaluation of a novel integrated anti-icing/de-icing technology for carbon fibre composite aerostructures using an electro-conductive textile

The preliminary evaluation is described of a new electro-thermal anti-icing/de-icing device for carbon fibre composite aerostructures. The heating element is an electro-conductive carbon-based textile (ECT) by Gorix. Electrical shorting between the structural carbon fibres and the ECT was mitigated by incorporating an insulating layer formed of glass fibre plies or a polymer film. A laboratory-based anti-icing and de-icing test program demonstrated that the film-insulated devices yielded better performance than the glssass fibre insulated ones. The heating capability after impact damage was maintained as long as the ECT fabric was not breached to the extent of causing electrical shorting. A modified structural scarf repair was shown to restore the heating capacity of a damaged specimen.

Anti-biofilm activity of ultrashort cinnamic acid peptide derivatives against medical device-related pathogens

The threat of antimicrobial resistance has placed increasing emphasis on the development of innovative approaches to eradicate multidrug-resistant pathogens. Biofilm-forming microorganisms, for example, Staphylococcus epidermidis and Staphylococcus aureus, are responsible for increased incidence of biomaterial infection, extended hospital stays and patient morbidity and mortality. This paper highlights the potential of ultrashort tetra-peptide conjugated to hydrophobic cinnamic acid derivatives. These peptidomimetic molecules demonstrate selective and highly potent activity against resistant biofilm forms of Gram-positive medical device-related pathogens. 3-(4-Hydroxyphenyl)propionic)-Orn-Orn-Trp-Trp-NH2 displays particular promise with minimum biofilm eradication concentration (MBEC) values of 125 µg/ml against methicillin sensitive (ATCC 29213) and resistant (ATCC 43300) S. aureus and activity shown against biofilm forms of Escherichia coli (MBEC: 1000 µg/ml). Kill kinetics confirms complete eradication of established 24-h biofilms at MBEC with 6-h exposure. Reduced cell cytotoxicity, relative to Gram-positive pathogens, was proven via tissue culture (HaCaT) and haemolysis assays (equine erythrocytes).

Existing in nature as part of the immune response, antimicrobial peptides display great promise for exploitation by the pharmaceutical industry in order to increase the library of available therapeutic molecules. Ultrashort variants are particularly promising for translation as clinical therapeutics as they are more cost-effective, easier to synthesise and can be tailored to specific functional requirements based on the primary sequence allowing factors such as spectrum of activity to be varied.

This is Abuse… Or is it? Domestic abuse perpetrators’ responses to anti-domestic violence publicity

Social marketing has become a key component of policy initiatives aimed at reducing the incidence of domestic abuse. However, its efficacy remains debated, with most measures of effectiveness being somewhat crude. More subtle effects of social marketing, such as the boomerang effect whereby the message engenders the opposite effect to that intended, have been detected, suggesting a need for modes of analysis sensitive to the multiple ways in which viewers react to social opprobrium. This article attempts to deliver just this. It begins with a short history and critique of the concept of social marketing. It then proceeds to explore the utility of the more complex notion that viewers often identify with the subject positions thrown open by social marketing on a quite temporary basis, before reconfiguring them. Using the responses of domestic abuse perpetrators exposed to the UK Government’s This is Abuse campaign film, the article shows how contradictory identifications with both anti-violence messages and victim-blaming discourses are negotiated by those young men prone to perpetrating domestic abuse. The article concludes by exploring how effectiveness might be better conceptualised and assessed with regard to the impact of anti-violence social marketing that speaks to domestic abuse perpetrators.

Robust bimodal person identification using face and speech with limited training data and corruption of both modalities

This paper presents a novel method of audio-visual fusion for person identification where both the speech and facial modalities may be corrupted, and there is a lack of prior knowledge about the corruption. Furthermore, we assume there is a limited amount of training data for each modality (e.g., a short training speech segment and a single training facial image for each person). A new representation and a modified cosine similarity are introduced for combining and comparing bimodal features with limited training data as well as vastly differing data rates and feature sizes. Optimal feature selection and multicondition training are used to reduce the mismatch between training and testing, thereby making the system robust to unknown bimodal corruption. Experiments have been carried out on a bimodal data set created from the SPIDRE and AR databases with variable noise corruption of speech and occlusion in the face images. The new method has demonstrated improved recognition accuracy.

Terrorism Laws and Legal Accountability

This chapter explores the extent to which courts can contribute to the countering of terrorism. It suggests that the contribution will depend on the type of actor the courts are attempting to hold to account as well as on the powers that are conferred on courts by national and international legal regimes. It concludes that courts are most legitimate and effective in relation to terrorist suspects and law enforcers, but less so in relation to counter-terrorism operatives and law-makers.

Sporting Justice: An Arbitrator's Perspective

Drawing on my experience of a number of sports dispute resolution tribunals in the UK and Ireland (such as Sports Resolutions UK; Just Sport Ireland; the Football Association of Ireland’s Disciplinary Panel and the Gaelic Athletic Association’s Dispute Resolution Authority) I intend to use this paper to review the legal arguments typically made in sports-related arbitrations. These points of interest can be summarised as a series of three questions: the fairness question; the liability question; the penalty question.

In answer to the fairness question, the aim is to give a brief outline on best practice in establishing a "fair" sports disciplinary tribunal. The answer, I believe, is always twofold in nature: first, and to paraphrase Lord Steyn in R v Secretary of State For The Home Department, Ex Parte Daly [2001] UKHL 26 at [28] "in law, context is everything" – translated into the present matter, this means that in sports disciplinary cases, the more serious the charges against the individual (in terms of reputational damage, economic impact and/or length of sanction); the more tightly wrapped the procedural safeguards surrounding any subsequent disciplinary hearing must be. A fair disciplinary system will be discussed in the context of the principles laid down in Article 8 of the World Anti-Doping Code which, in effect, acts as sport’s Article 6 of the ECHR on a right to a fair trial.

Following on from the above, in the 60 or so sports arbitrations that I have heard, there are two further points of interest. First, the claim before the arbitral panel will often be framed in an argument that, for various reasons of substantive and procedural irregularity, the sanction imposed on the appellant should be quashed ("the liability"). Second, and in alternative, that the sanction imposed was wholly disproportionate ("the penalty").

The liability issue usually breaks down into two further questions. First, what is the nature of the legal duty upon a sports body in exercising its disciplinary remit? Second, to what extent does a de novo hearing on appeal cure any apparent defects in a hearing of first instance? The first issue often results in an arbitral panel debating the contra preferentum approach to the interpretation of a contested rule i.e., the sports body’s rules in question are so ambiguous that they should be interpreted in a manner to the detriment of the rule maker and in favour of the appellant. On the second matter, it now appears to be a general principle of sports law, administrative law and even human rights law that even if a violation of the principles of natural justice takes place at the first instance stage of a disciplinary process, they may be cured on de novo appeal. Authority for this approach can be found at the Court of Arbitration for Sport and in particular in CAS 2009/A/1920 FK Pobeda, Aleksandar Zabrcanec, Nikolce Zdraveski v UEFA at para 87.

The question on proportionality asks what, aside from precedent found within the decisions of the sports body in question, are the general legal principles against which a sanction by a sports disciplinary body can be benchmarked in order to ascertain whether it is disproportionate in length or even irrational in nature?

On the matter of (dis)proportionality of sanction, the debate is usually guided by the authority in Bradley v the Jockey Club [2004] EWHC 2164 (QB) and affirmed at [2005] EWCA Civ 1056. The Bradley principles on proportionality of sports-specific sanctions, recently cited with approval at the Court of Arbitration for Sport, will be examined in this presentation.

Finally, an interesting application of many of the above principles (and others such as the appropriate standard of proof in sports disciplinary procedures) can be made to recent match-fixing or corruption related hearings held by the British Horse Racing Authority, the integrity units of snooker and tennis, and at the Court of Arbitration for Sport.