Collagenolytic Activities of the Major Secreted Cathepsin L Peptidases Involved in the Virulence of the Helminth Pathogen, Fasciola hepatica

The temporal expression and secretion of distinct members of a family of virulence-associated cathepsin L cysteine peptidases (FhCL) correlates with the entry and migration of the helminth pathogen Fasciola hepatica in the host. Thus, infective larvae traversing the gut wall secrete cathepsin L3 (FhCL3), liver migrating juvenile parasites secrete both FhCL1 and FhCL2 while the mature bile duct parasites, which are obligate blood feeders, secrete predominantly FhCL1 but also FhCL2.

The Science of Religious Beliefs

Why have humans, throughout history and across cultures, shown a strong tendency to believe in the existence of superhuman intentional agents and attached this belief to notions of morality, misfortune, and the creation of the world? The answer emerging from the cognitive science of religion appears to be that explicit beliefs are informed and constrained by the natural and cross-culturally recurrent operation of implicit cognitive systems. Successful god concepts resonate with the expectations of these implicit systems but also have attention-demanding and inferentially-rich properties that allow their integration into various areas of human concern. Theological concepts may deviate from these natural cognitive moorings but require special cultural scaffolding, such as Whitehouse's two Modes of Religiosity, to do so and constitute additions to, rather than replacements of the religious beliefs supported by implicit cognitive systems.

Proteomics and phylogenetic analysis of the cathepsin L protease family of the helminth pathogen Fasciola hepatica:Expansion of a repertoire of virulence-associated factors

Cathepsin L proteases secreted by the helminth pathogen Fasciola hepatica have functions in parasite virulence including tissue invasion and suppression of host immune responses. Using proteomics methods alongside phylogenetic studies we characterized the profile of cathepsin L proteases secreted by adult F. hepatica and hence identified those involved in host-pathogen interaction. Phylogenetic analyses showed that the Fasciola cathepsin L gene family expanded by a series of gene duplications followed by divergence that gave rise to three clades associated with mature adult worms (Clades 1, 2, and 5) and two clades specific to infective juvenile stages (Clades 3 and 4). Consistent with these observations our proteomics studies identified representatives from Clades 1, 2, and 5 but not from Clades 3 and 4 in adult F. hepatica secretory products. Clades 1 and 2 account for 67.39 and 27.63% of total secreted cathepsin Ls, respectively, suggesting that their expansion was positively driven and that these proteases are most critical for parasite survival and adaptation. Sequence comparison studies revealed that the expansion of cathepsin Ls by gene duplication was followed by residue changes in the S2 pocket of the active site. Our biochemical studies showed that these changes result in alterations in substrate binding and suggested that the divergence of the cathepsin L family produced a repertoire of enzymes with overlapping and complementary substrate specificities that could cleave host macromolecules more efficiently. Although the cathepsin Ls are produced as zymogens containing a prosegment and mature domain, all secreted enzymes identified by MS were processed to mature active enzymes. The prosegment region was highly conserved between the clades except at the boundary of prosegment and mature enzyme. Despite the lack of conservation at this section, sites for exogenous cleavage by asparaginyl endopeptidases and a Leu-Ser[downward arrow]His motif for autocatalytic cleavage by cathepsin Ls were preserved.

Structural and functional relationships in the virulence-associated cathepsin L proteases of the parasitic liver fluke, Fasciola hepatica

The helminth parasite Fasciola hepatica secretes cysteine proteases to facilitate tissue invasion, migration, and development within the mammalian host. The major proteases cathepsin L1 (FheCL1) and cathepsin L2 (FheCL2) were recombinantly produced and biochemically characterized. By using site-directed mutagenesis, we show that residues at position 67 and 205, which lie within the S2 pocket of the active site, are critical in determining the substrate and inhibitor specificity. FheCL1 exhibits a broader specificity and a higher substrate turnover rate compared with FheCL2. However, FheCL2 can efficiently cleave substrates with a Pro in the P2 position and degrade collagen within the triple helices at physiological pH, an activity that among cysteine proteases has only been reported for human cathepsin K. The 1.4-A three-dimensional structure of the FheCL1 was determined by x-ray crystallography, and the three-dimensional structure of FheCL2 was constructed via homology-based modeling. Analysis and comparison of these structures and our biochemical data with those of human cathepsins L and K provided an interpretation of the substrate-recognition mechanisms of these major parasite proteases. Furthermore, our studies suggest that a configuration involving residue 67 and the "gatekeeper" residues 157 and 158 situated at the entrance of the active site pocket create a topology that endows FheCL2 with its unusual collagenolytic activity. The emergence of a specialized collagenolytic function in Fasciola likely contributes to the success of this tissue-invasive parasite.

The Behavior of compressively loaded stiffener runout specimens - Part I: Experiments

The development of the next generation of civil and military transport aircraft will inevitably see an increased use of advanced carbon fibre composite material in the primary structure if performance targets are to be met. One concern in this development is the vulnerability of co-cured and co-bonded stiffened structures to through-thickness stresses at the skin-stiffener interfaces, particularly in stiffener runout regions. These regions are a consequence of the requirement to terminate stiffeners at cutouts, rib intersections, or other structural features which interrupt the stiffener load path.

This work presents the results of an experimental programme investigating the failure of thick-sectioned stiffener runout specimens loaded in uniaxial compression. For all tests, failure initiated at the edge of the runout and propagated across the skin-stiffener interface. It was found that the failure load of each specimen was greatly influenced by intentional changes in the geometric features of these specimens. High frictional forces at the edge of the runout were also deduced from a fractographic analysis, indicating a predominantly Mode II initial failure mode.

Responding to crisis: When the telephone fails

The world is changing. Advances in telecommunications have meant that the world is shrinking – data can be moved across continents in the time it takes to send an email or access the cloud. Although developments such as these highlight the extent of scientific and technological evolution, in terms of legal liability, questions must be asked as to the capacity of our legal structures to evolve accordingly.

This article looks at how emergency telephone provision and any shift to VoIP systems might fit with existing tort liability and associated duty implications. It does so by analysing the technology through the principles that signpost UK tort law. This article recognises that as an emerging area, the legal liability implications have not yet been discussed in any great detail. The aim of this article therefore is to introduce the area, encourage debate and consider the issues that may become increasingly relevant as these types of technologies become industrial standards.

Development of an objective structured clinical examination (OSCE) to assess formulation and extemporaneous dispensing skills in MPharm undergraduates

Background: The use of Objective Structured Clinical Examination (OSCE) in Pharmacy has been explored; however this is the first attempt in Queen’s University School of Pharmacy, Belfast to assess students via this method in a module where chemistry is the main discipline.

Aims: To devise an OSCE to assess undergraduate ability to check extemporaneously dispensed products for clinical and formulation errors. This activity also aims to consider whether it is a viable method of assessment in such a science-based class, from a staff and student perspective.

Method: Students rotated around a number of stations, performing a check of the product, corresponding prescription and formulation record sheet detailing the theory behind the formulation. They were assessed on their ability to spot intentional mistakes at each one.

Results: Of the 79 students questioned, 95% indicated that OSCE made them aware of the importance of the clinical check carried out by the pharmacist. Nearly all of the undergraduates (72 out of 79) felt that OSCE made them aware of the type of mistakes that students make in class. Most (5 out of 7) of the academic team members strongly agreed that it made students aware of ‘point of dispensing’ checks carried out by pharmacists, in addition to helping them to prepare for their exam.

Conclusion: OSCE assesses both scientific and formulation skills, and has increased the diversity of assessment of this module, bringing with it many additional benefits for the undergraduates since it measures their ability to exercise professional judgement in a time- constrained environment and, in this way, mirrors the conditions many pharmacists work within.

Landmark Cases in Property Law

This book explores the development of basic principles of property law in leading cases. Each paper considers a case on land, personal property or intangibles, discussing what that case contributes to the dominant themes of property jurisprudence - how are property rights acquired? What is the content of property rights? What are the limits or boundaries of property? How are property rights extinguished? Individually and collectively, the papers identify a number of important themes for the doctrinal development of property institutions and their broader justification. These themes include: the obscure and incremental development of seemingly foundational principles, the role of instrumentalism in property reasoning, the influence of the law of tort on the scope of property doctrines, and the impact of Roman legal reasoning on the common law of property. One or more of these themes (and others) is revealed through careful case analysis in each paper and they are collected and critically explored in the editors' introduction. This makes for a coherent and provocative collection.

Sports Law

The term sports law is fourfold in nature and encompasses: (a) traditional areas of law, such as contract, tort, criminal, administrative and EU law, as applied to disputes of a sporting origin; (b) the particular impact that a range of statutory provisions might have on sport; for example, legislation governing discriminatory and unsafe practices in a workplace or monopolistic or fraudulent behaviour in an industry; (c) issues of public and social policy otherwise influencing the legislature and the courts, from the allocation of resources to the allocation of risk; and (d) lex sportiva, where that term is taken to reflect the various internal administrative regulations and awards by dispute-resolving mechanisms in sport. As a matter of practice, sports law tends to be concerned with the application of contract and commercial law principles to professional sport - and namely the application of such branches of law to disputes relating to the following "three pillars" of modern, professional sport i.e., disputes relating to the payment, sponsorship or endorsement of those who play sport for a living; disputes arising from decisions made by sports governing bodies; and disputes arising from the application of law to the holding of sports events.

Recent Developments in the Law of Torts in Northern Ireland Annual Conference of the Irish Association of Law Teachers

This paper reviews decisions from the Northern Ireland and England and Wales High Courts and Courts of Appeal as well as the UK Supreme Court relating to tort and principally to the tort of negligence in the past 12 months or so.

In structure, the paper will be presented in four parts. First, three preliminary points relating to contemporary features of the NI civil courts: personal litigants – Devine v McAteer [2012] NICA 30 (7 September 2012); pre-action protocols – Monaghan v Graham [2013] NIQB 53 (3 May 2013); and the rise of alternative dispute resolution. On the last named issue, the recent decision of PGF II SA v OMFS Company 1 Ltd [2013] EWCA Civ 1288 (23 October 2013) on unreasonable refusal to mediate, will be discussed.

Second, the paper moves to consider the law of negligence generally and case law from the NI High Court reiterating Lord Hoffmann’s view in Tomlinson v Congleton Borough Council [2004] 1 AC 46 that no duty of care arises from obvious risks of injury. In this, reference will be made to the application of the above “Hoffmann principle” in West Sussex County Council v Pierce [2013] EWCA Civ 1230 (16 October 2013), which concerned an accident sustained by a child at school. A similar set of facts was presented recently to the UK Supreme Court in Woodland v Essex County Council [2013] UKSC 66 (23 October 2013). The decision there, on non-delegable duties of care, will have a significant impact for schools in the provision of extracurricular activities.

Third, I will review a NI case of note on the duty of care of solicitors in the context of professional negligence in the context of conflicting advice by counsel.

Fourth, I will examine a series of cases on employer liability and including issues such as the duty of care towards the volunteer worker; tort and safety at work principles generally; and, more specifically, the duty of care of the employer towards an employee who suffers psychiatric illness as a result of stress and/or harassment at work. On the issue of workplace stress, the NI courts have made extensive reference to the Hale LJ principles found in the Court of Appeal decision of Hatton v Sutherland [2002] 1 All ER 1 and applied to those who have suffered trauma in reporting on or policing “the troubles” in Northern Ireland. On the issue of statutory harassment at work, the paper will also mention the UK Supreme Court’s decision in Hayes v Willoughby [2013] UKSC 17 (20 March 2013).

The significance of bruising in the pre-mobile infant

The majority of children in our society are loved andcherished. The occasional cases of intentional injury to a childresulting in death or significant harm evoke powerful anduncomfortable feelings (Devaney et al, 2013), and the publicoutcry may result in health and social workers facing criticism.Identifying whether an infant is at risk of abuse is a challengefor practitioners, and can be a source of stress and anxiety(Brandon et al, 2011). Bruising is a strong indicator of childabuse involving intentional injury (Kemp et al, 2014). Theincidence of bruising correlates to developmental stage, withnon-mobile infants least likely to incur bruising. Therefore, itspresence in pre-mobile infants requires immediate assessment.A search of the literature around bruising in pre-mobile infantsrevealed themes of missed opportunities for early intervention,the role of the father in the family and the significance of childdevelopment. Sharing of knowledge and expertise within themultidisciplinary team is key to safeguarding infants.

The extracellular vesicles of the helminth pathogen, Fasciola hepatica: biogenesis pathways and cargo molecules involved in parasite pathogenesis.

Extracellular vesicles (EVs) released by parasites have important roles in establishing and maintaining infection. Analysis of the soluble and vesicular secretions of adult Fasciola hepatica has established a definitive characterisation of the total secretome of this zoonotic parasite. Fasciola secretes at least two sub-populations of EVs that differ according to size, cargo molecules and site of release from the parasite. The larger EVs are released from the specialised cells that line the parasite gastrodermus and contain the zymogen of the 37 kDa cathepsin L peptidase that performs a digestive function. The smaller exosome-like vesicle population originate from multivesicular bodies within the tegumental syncytium and carry many previously described immunomodulatory molecules that could be delivered into host cells. By integrating our proteomics data with recently available transcriptomic datasets we have detailed the pathways involved with EV biogenesis in F. hepatica and propose that the small exosome biogenesis occurs via ESCRT-dependent MVB formation in the tegumental syncytium before being shed from the apical plasma membrane. Furthermore, we found that the molecular machinery required for EV biogenesis is constitutively expressed across the intra-mammalian development stages of the parasite. By contrast, the cargo molecules packaged within the EVs are developmentally regulated, most likely to facilitate the parasites migration through host tissue and to counteract host immune attack.

Moral asymmetries in judgments of agency withstand ludicrous causal deviance

Americans have been shown to attribute greater intentionality to immoral than to amoral actions in cases of causal deviance, that is, cases where a goal is satisfied in a way that deviates from initially planned means (e.g., a gunman wants to hit a target and his hand slips, but the bullet ricochets off a rock into the target). However, past research has yet to assess whether this asymmetry persists in cases of extreme causal deviance. Here, we manipulated the level of mild to extreme causal deviance of an immoral versus amoral act. The asymmetry in attributions of intentionality was observed at all but the
most extreme level of causal deviance, and, as we hypothesized, was mediated by attributions of Blame/credit and judgments of action performance. These findings are discussed as they support a multiple-concepts interpretation of the asymmetry, wherein blame renders a naïve concept of intentional action (the outcome matches the intention) more salient than a composite concept (the outcome matches the intention and was brought about by planned means), and in terms of their implications for cross-cultural research on judgments of agency.

Intentionality, morality, and the incest taboo in Madagascar

In a recent article (Astuti & Bloch, 2015), cognitive anthropologists Rita Astuti and Maurice Bloch claim that the Malagasy are ambivalent as to whether considerations of intentionality are relevant to moral judgments concerning incest and its presumed catastrophic consequences: when making moral judgments about those who commit incest, the Malagasy take into account whether the incest is intentional or not, but, when making moral judgments relating to incest’s catastrophic consequences, they do not take intentionality into account. Astuti & Bloch explain the irrelevance of intentionality in terms of incest entailing such a fundamental attack on the transcendental social order that the Malagasy become dumbfounded and leave aside considerations of intentionality. Finally, they claim that a similar dumbfound reaction is what is involved in the moral dumbfounding concerning incest that social psychologist Jonathan Haidt has found in the US. In this article, we argue that (i) Astuti & Bloch are unclear about many aspects of their claims (in particular, about the moral judgments at stake), (ii) they do not provide sufficient evidence that considerations of intentionality are deemed irrelevant to moral judgments relating to incest’s presumed catastrophic consequences (and hence for the claim that the Malagasy are ambivalent), (iii) their hypothesis that conceiving of incest as an attack on the transcendental social renders considerations of intentionality irrelevant lacks coherence, and (iv) the extension of their explanatory account to the moral dumfounding of American students in Haidt’s well-known scenario of intentional incest is unwarranted.

Actividade física e autonomia instrumental das pessoas idosas

Pretende-se perceber se existe uma relação entre o nível regular de actividade física praticado pelas pessoas idosas e a sua autonomia instrumental. Desenvolveu-se um estudo descritivo, correlacional e transversal, no ano 2010, com amostra intencional constituída por 100 indivíduos com idade igual ou superior a 60 anos, de ambos sexos. A colheita de dados foi efectuada em dois ginásios e dois centros de dia localizados na cidade de Lisboa, e foram utilizados como instrumentos a Escala de Actividades Instrumentais de Vida Diária de Lawton e Brody e o International Physical Activity Questionnaire. Obteve-se uma média de idades de 76 anos, sendo 78% dos inquiridos do sexo feminino. Inseriram-se 30% na categoria de actividade física “ligeira”, 45% na “moderada” e 25% na “vigorosa”. Relativamente à autonomia instrumental, a maioria era moderadamente dependente. Verificou-se que o grau de autonomia instrumental dos idosos aumenta com o incremento da actividade física praticada (ρS=0.815; p-value<0.001); Abstract: This work seeks to realize if there is a relationship between the level of regular physical activity practiced by elderly persons and its instrumental autonomy. A descriptive, related and transversal study was developed in the year 2010, with an intentional sample consisting of 100 individuals, aged 60 years or above, of both genders. The data collection was carried out in two gymnasiums and two day care centers located in the city of Lisbon, and were used the Lawton and Brody’s Instrumental Activities of Daily Living Scale and the International Physical Activity Questionnaire. A mean age of 76 years was obtained and 78% of the respondents were female. 30% were classified as having a "low" physical activity level, 45% as "moderate" and 25% as "high". Regarding instrumental autonomy, most were moderately dependent. It was verified that the degree of instrumental autonomy of the elderly increases with increased physical activity (ρS=0.815; p-value<0.001).