Helminth pathogen cathepsin proteases:it's a family affair

Helminth pathogens express papain-like cysteine peptidases, termed cathepsins, which have important roles in virulence, including host entry, tissue migration and the suppression of host immune responses. The liver fluke Fasciola hepatica, an emerging human pathogen, expresses the largest cathepsin L cysteine protease family yet described. Recent phylogenetic, biochemical and structural studies indicate that this family contains five separate clades, which exhibit overlapping but distinct substrate specificities created by a process of gene duplication followed by subtle residue divergence within the protease active site. The developmentally regulated expression of these proteases correlates with the passage of the parasite through host tissues and its encounters with different host macromolecules.

Regulation of TGF-β1-Driven Differentiation of Human Lung Fibroblasts: Emerging Roles of Cathepsin B and Cystatin C

Lung matrix homeostasis partly depends on the fine regulation of proteolytic activities. We examined the expression of human cysteine cathepsins (Cats) and their relative contribution to TGF-β1-induced fibroblast differentiation into myofibroblasts. Assays were conducted using both primary fibroblasts obtained from patients with idiopathic pulmonary fibrosis (IPF) and human lung CCD-19Lu fibroblasts. Pharmacological inhibition and genetic silencing of Cat B diminished α-smooth muscle actin expression, delayed fibroblast differentiation and led to an accumulation of intracellular 50-kDa TGF-β1. Moreover addition of Cat B generated 25-kDa mature form of TGF-β1 in Cat B siRNA-pretreated lysates. Inhibition of Cat B decreased Smad 2/3 phosphorylation, but had no effect on p38 MAPK and JNK phosphorylation indicating that Cat B mostly disturbs TGF-β1-driven canonical Smad signaling pathway. While mRNA expression of cystatin C was stable, its secretion, which was inhibited by brefeldin A, increased during TGF-β1-induced differentiation of IPF and CCD-19Lu fibroblasts. In addition cystatin C participated in the control of extracellular Cats, since its gene silencing restored their proteolytic activities. These data support the notion that Cat B participates in lung myofibrogenesis as suggested for stellate cells during liver fibrosis. Moreover, we propose that TGF-β1 promotes fibrosis by driving the effective cystatin C-dependent inhibition of extracellular matrix-degrading Cats.

Explicit argumentation as a supervisory tool for decision making in child protection cases involving human rights issues

This paper addresses the problems often faced by social workers and their supervisors in decision making where human rights considerations and child protection concerns collide. High profile court cases in the United Kingdom and Europe have consistently called for social workers to convey more clarity when justifying their reasons for interfering with human rights in child protection cases. The themes emerging from these case law decisions imply that social workers need to be better at giving reasons and evidence in more explicit ways to support any actions they propose which cause interference with Convention Rights. Toulmin (1958, 1985) offers a structured approach to argumentation which may have relevance to the supervision of child protection cases when social workers and managers are required to balance these human rights considerations. One of the key challenges in this balancing act is the need for decision makers to feel confident that any interventions resulting in the interference of human rights are both justified and proportionate. Toulmin’s work has already been shown to have relevance for assisting social workers navigate pathways through cases involving competing ethical and moral demands (Osmo and Landau, 2001) and more recently to human rights and decision making in child protection (Duffy et al, 2006). Toulmin’s model takes the practitioner through a series of stages where any argument or proposed recommendation (claim) is subjected to intense critical analysis involving exposition of its strengths and weaknesses. The author therefore proposes that explicit argumentation (Osmo and Landau, 2001) may help supervisors and practitioners towards safer and more confident decision making in child protection cases involving the interference of the human rights of children and parents. In addition to highlighting the broader context of human rights currently permeating child protection decision making, the paper will include case material to practically demonstrate the application of Toulmin’s model of argumentation to the supervision context. In this way the paper adopts a strong practice approach in helping to assist practitioners with the problems and dilemmas they may come up against in decision making in complex cases.

Berries:emerging impact on cardiovascular health

Berries are a good source of polyphenols, especially anthocyanins, micronutrients, and fiber. In epidemiological and clinical studies, these constituents have been associated with improved cardiovascular risk profiles. Human intervention studies using chokeberries, cranberries, blueberries, and strawberries (either fresh, or as juice, or freeze-dried), or purified anthocyanin extracts have demonstrated significant improvements in LDL oxidation, lipid peroxidation, total plasma antioxidant capacity, dyslipidemia, and glucose metabolism. Benefits were seen in healthy subjects and in those with existing metabolic risk factors. Underlying mechanisms for these beneficial effects are believed to include upregulation of endothelial nitric oxide synthase, decreased activities of carbohydrate digestive enzymes, decreased oxidative stress, and inhibition of inflammatory gene expression and foam cell formation. Though limited, these data support the recommendation of berries as an essential fruit group in a heart-healthy diet.

Pan-genome analysis of the emerging foodborne pathogen Cronobacter spp. suggests a species-level bidirectional divergence driven by niche adaptation

Background: Members of the genus Cronobacter are causes of rare but severe illness in neonates and preterm infants following the ingestion of contaminated infant formula. Seven species have been described and two of the species genomes were subsequently published. In this study, we performed comparative genomics on eight strains of Cronobacter, including six that we sequenced (representing six of the seven species) and two previously published, closed genomes.

Results: We identified and characterized the features associated with the core and pan genome of the genus Cronobacter in an attempt to understand the evolution of these bacteria and the genetic content of each species. We identified 84 genomic regions that are present in two or more Cronobacter genomes, along with 45 unique genomic regions. Many potentially horizontally transferred genes, such as lysogenic prophages, were also identified. Most notable among these were several type six secretion system gene clusters, transposons that carried tellurium, copper and/or silver resistance genes, and a novel integrative conjugative element.

Conclusions: Cronobacter have diverged into two clusters, one consisting of C. dublinensis and C. muytjensii (Cdub-Cmuy) and the other comprised of C. sakazakii, C. malonaticus, C. universalis, and C. turicensis, (Csak-Cmal-Cuni-Ctur) from the most recent common ancestral species. While several genetic determinants for plant-association and human virulence could be found in the core genome of Cronobacter, the four Cdub-Cmuy clade genomes contained several accessory genomic regions important for survival in a plant-associated environmental niche, while the Csak-Cmal-Cuni-Ctur clade genomes harbored numerous virulence-related genetic traits.

Development and single laboratory validation of an optical biosensor assay for tetrodotoxin detection as a tool to combat emerging risks in European seafood

Tetrodotoxin (TTX) is a potent neurotoxin emerging in European waters due to increasing ocean temperatures. Its detection in seafood is currently performed as a consequence of using the Association of Analytical Communities (AOAC) mouse bioassay (MBA) for paralytic shellfish poisoning (PSP) toxins, but TTX is not monitored routinely in Europe. Due to ethical and performance-related issues associated with this bioassay, the European Commission has recently published directives extending procedures that may be used for official PSP control. An AOAC-accredited high-performance liquid chromatography (HPLC) method has now been accepted by the European Union as a first action screening method for PSP toxins to replace the MBA. However, this AOAC HPLC method is not capable of detecting TTX, so this potent toxin would be undetected; thereby, a separate method of analysis is required. Surface plasmon resonance (SPR) optical biosensor technology has been proven as a potential alternative screening method to detect PSP toxins in seafood. The addition of a similar SPR inhibition assay for TTX would complement the PSP assay in removing the MBA. The present report describes the development and single laboratory validation in accordance with AOAC and IUPAC guidelines of an SPR method to be used as a rapid screening tool to detect TTX in the sea snail Charonia lampas lampas, a species which has been implicated in 2008 in the first case of human TTX poisoning in Europe. As no current regulatory limits are set for TTX in Europe, single laboratory validation was undertaken using those for PSP toxins at 800 µg/kg. The decision limit (CCa) was 100 µg/kg, with the detection capability (CCß) found to be =200 µg/kg. Repeatability and reproducibility were assessed at 200, 400, and 800 µg/kg and showed relative standard deviations of 8.3, 3.8, and 5.4 % and 7.8, 8.3, and 3.7 % for both parameters at each level, respectively. At these three respective levels, the recovery of the assay was 112, 98, and 99 %.

Mutations in the H, F, or M proteins can facilitate resistance of measles virus to neutralizing human anti-MV sera

Although there is currently no evidence of emerging strains of measles virus (MV) that can resist neutralization by the anti-MV antibodies present in vaccinees, certain mutations in circulating wt MV strains appear to reduce the efficacy of these antibodies. Moreover, it has been hypothesized that resistance to neutralization by such antibodies could allow MV to persist. In this study, we use a novel in vitro system to determine the molecular basis of MV's resistance to neutralization. We find that both wild-type and laboratory strain MV variants that escape neutralization by anti-MV polyclonal sera possess multiple mutations in their H, F, and M proteins. Cytometric analysis of cells expressing viral escape mutants possessing minimal mutations and their plasmid-expressed H, F, and M proteins indicates that immune resistance is due to particular mutations that can occur in any of these three proteins that affect at distance, rather than directly, the native conformation of the MV-H globular head and hence its epitopes. A high percentage of the escape mutants contain mutations found in cases of Subacute Sclerosing Panencephalitis (SSPE) and our results could potentially shed light on the pathogenesis of this rare fatal disease.

Using Comparative Constitutionalism in Human Rights Discourse:Ireland’s Past and Scotland’s Future

The article considers the use of comparisons in constitutional development, specifically the use of comparative reasoning in the context of debates about human rights in newly emerging independent states, using the examples of Ireland and Scotland.

Empowering Human Services Organizations to Embrace Evidence-informed Practice: International Best Practices

Human service organizations are increasingly using knowledge as a mechanism for implementing change. Knowledge emerging from many sources that may include academic publications, grey literature, and service user and practitioner wisdom contributes toward informing best practice. The question is: how do we harness this knowledge to make practice more effective? This paper synthesizes the lessons learned from eight international organizations that have made a commitment to knowledge mobilization as an important priority in their mission and operation. The paper provides a conceptual model, tools and resources to help human services organizations create strategies for building, enhancing or sustaining their knowledge mobilization efforts. The paper describes a flexible blueprint for human service organizations to leverage knowledge mobilization efforts at all levels of service delivery.

Awareness and attitudes towards the emerging use of nanotechnology in the agri-food sector

Nanotechnology has relevance to applications in all areas of agri-food including agriculture, aquaculture, production, processing, packaging, safety and nutrition. Scientific literature indicates uncertainties in food safety aspects about using nanomaterials due to potential health risks. To date the agri-food industry's awareness and attitude towards nanotechnology have not been addressed. We surveyed the awareness and attitudes of agri-food organisations on the island of Ireland (IoI) with regards to nanotechnology. A total of 14 agri-food stakeholders were interviewed and 88 agri-food stakeholders responded to an on-line questionnaire. The findings indicate that the current awareness of nanotechnology applications in the agri-food sector on the IoI is low and respondents are neither positive nor negative towards agri-food applications of nanotechnology. Safer food, reduced waste and increased product shelf life were considered to be the most important benefits to the agri-food industry. Knowledge of practical examples of agri-food applications is limited however opportunities were identified in precision farming techniques, innovative packaging, functional ingredients and nutrition of foods, processing equipment, and safety testing. Perceived impediments to nanotechnology adoption were potential unknown human health and environmental impacts, consumer acceptance and media framing. The need for a risk assessment framework, research into long term health and environmental effects, and better engagement between scientists, government bodies, the agri-food industry and the public were identified as important.

Human melioidosis, Malawi, 2011

A case of human melioidosis caused by a novel sequence type of Burkholderia pseudomallei occurred in a child in Malawi, southern Africa. A literature review showed that human cases reported from the continent have been increasing.

Bouyid v Belgium: The “minimum level of severity” and Human Dignity's Role in Article 3 ECHR

The Grand Chamber of the European Court of Human Rights recently delivered an important judgment on Article 3 ECHR in the case of Bouyid v Belgium. In Bouyid, the Grand Chamber was called upon to consider whether slaps inflicted on a minor and an adult in police custody were in breach of Article 3 ECHR, which provides that ‘No one shall be subjected to torture or to inhuman or degrading treatment or punishment’. Overruling the Chamber judgment in the case, the Grand Chamber ruled by 14 votes to 3 that there had been a substantive violation of Article 3 in that the applicants had been subjected to degrading treatment by members of the Belgian police; it found that there had been a breach of the investigative duty under Article 3 also. In this comment, I focus on the fundamental basis of disagreement between the majority of the Grand Chamber and those who found themselves in dissent, on the question of whether there had been a substantive breach of Article 3. The crux of the disagreement lay in the understanding and application of the test of ‘minimum level of severity’, which the ECtHR has established as decisive of whether a particular form of ill-treatment crosses the Article 3 threshold, seen also in light of Article 3’s absolute character, which makes it non-displaceable – that is, immune to trade-offs of the type applicable in relation to qualified rights such as privacy and freedom of expression. I consider the way the majority of the Grand Chamber unpacked and applied the concept of dignity – or ‘human dignity’ – towards finding a substantive breach of Article 3, and briefly distil some of the principles underpinning the understanding of human dignity emerging in the Court’s analysis.