Antigen-presenting genes and genomic copy number variations in the Tasmanian devil MHC.

RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are.BACKGROUND: The Tasmanian devil (Sarcophilus harrisii) is currently under threat of extinction due to an unusual fatal contagious cancer called Devil Facial Tumour Disease (DFTD). DFTD is caused by a clonal tumour cell line that is transmitted between unrelated individuals as an allograft without triggering immune rejection due to low levels of Major Histocompatibility Complex (MHC) diversity in Tasmanian devils. RESULTS: Here we report the characterization of the genomic regions encompassing MHC Class I and Class II genes in the Tasmanian devil. Four genomic regions approximately 960 kb in length were assembled and annotated using BAC contigs and physically mapped to devil Chromosome 4q. 34 genes and pseudogenes were identified, including five Class I and four Class II loci. Interestingly, when two haplotypes from two individuals were compared, three genomic copy number variants with sizes ranging from 1.6 to 17 kb were observed within the classical Class I gene region. One deletion is particularly important as it turns a Class Ia gene into a pseudogene in one of the haplotypes. This deletion explains the previously observed variation in the Class I allelic number between individuals. The frequency of this deletion is highest in the northwestern devil population and lowest in southeastern areas. CONCLUSIONS: The third sequenced marsupial MHC provides insights into the evolution of this dynamic genomic region among the diverse marsupial species. The two sequenced devil MHC haplotypes revealed three copy number variations that are likely to significantly affect immune response and suggest that future work should focus on the role of copy number variations in disease susceptibility in this species

Antigen-presenting genes and genomic copy number variations in the Tasmanian devil MHC

BACKGROUND The Tasmanian devil (Sarcophilus harrisii) is currently under threat of extinction due to an unusual fatal contagious cancer called Devil Facial Tumour Disease (DFTD). DFTD is caused by a clonal tumour cell line that is transmitted between unrelated individuals as an allograft without triggering immune rejection due to low levels of Major Histocompatibility Complex (MHC) diversity in Tasmanian devils. RESULTS Here we report the characterization of the genomic regions encompassing MHC Class I and Class II genes in the Tasmanian devil. Four genomic regions approximately 960 kb in length were assembled and annotated using BAC contigs and physically mapped to devil Chromosome 4q. 34 genes and pseudogenes were identified, including five Class I and four Class II loci. Interestingly, when two haplotypes from two individuals were compared, three genomic copy number variants with sizes ranging from 1.6 to 17 kb were observed within the classical Class I gene region. One deletion is particularly important as it turns a Class Ia gene into a pseudogene in one of the haplotypes. This deletion explains the previously observed variation in the Class I allelic number between individuals. The frequency of this deletion is highest in the northwestern devil population and lowest in southeastern areas. CONCLUSIONS The third sequenced marsupial MHC provides insights into the evolution of this dynamic genomic region among the diverse marsupial species. The two sequenced devil MHC haplotypes revealed three copy number variations that are likely to significantly affect immune response and suggest that future work should focus on the role of copy number variations in disease susceptibility in this species.This work was funded by an ARC Future Fellowship to KB (FT0992212), the Eric Guiler fund and the Tasmanian Department of Primary Industries, Parks, Water and the Environment. YC was supported by an Endeavour International Postgraduate Research Scholarship, KM by an Australian Postgraduate Award and an ARC Linkage Grant

Emergency Stroke Calls: Obtaining Rapid Telephone Triage (ESCORTT) - a programme of research to facilitate recognition of stroke by emergency medical dispatchers

Background: Rapid access to emergency stroke care can reduce death and disability by enabling immediate provision of interventions such as thrombolysis, physiological monitoring and stabilisation. One of the ways that access to services can be facilitated is through emergency medical service (EMS)dispatchers. The sensitivity of EMS dispatchers for identifying stroke is < 50%. Studies have shown that activation of the EMSs is the single most important factor in the rapid triage and treatment of acute stroke patients. Objectives: To facilitate recognition of stroke by emergency medical dispatchers (EMDs). Design: An eight-phase mixed-methods study. Phase 1: a retrospective cohort study exploring stroke diagnosis. Phase 2: semi-structured interviews exploring public and EMS interactions. Phases 3 and 4: a content analysis of 999 calls exploring the interaction between the public and EMDs. Phases 5–7: development and implementation of stroke-specific online training (based on phases 1–4). Phase 8: an interrupted time series exploring the impact of the online training. Setting: One ambulance service and four hospitals. Participants: Patients arriving at hospital by ambulance with stroke suspected somewhere on the stroke pathway (phases 1 and 8). Patients arriving at hospital by ambulance with a final diagnosis of stroke (phase 2). Calls to the EMSs relating to phase 1 patients (phases 3 and 4). EMDs (phase 7). Interventions: Stroke-specific online training package, designed to improve recognition of stroke for EMDs. Main outcome measures: Phase 1: symptoms indicative of a final and dispatch diagnosis of stroke. Phase 2: factors involved in the decision to call the EMSs when stroke is suspected. Phases 3 and 4: keywords used by the public when describing stroke and non-stroke symptoms to EMDs. Phase 8: proportion of patients with a final diagnosis of stroke correctly dispatched as stroke by EMDs. Results: Phase 1: for patients with a final diagnosis of stroke, facial weakness and speech problems were significantly associated with an EMD code of stroke. Phase 2: four factors were identified – perceived seriousness; seeking and receiving lay or professional advice; caller’s description of symptoms and emotional response to symptoms. Phases 3 and 4: mention of ‘stroke’ or one or more Face Arm Speech Test (FAST) items is much more common in stroke compared with non-stroke calls. Consciousness level was often difficult for callers to determine and/or communicate. Phase 8: there was a significant difference (p = 0.003) in proportions correctly dispatched as stroke – before the training was implemented 58 out of 92 (63%); during implementation of training 42 out of 48 (88%); and after training implemented 47 out of 59 (80%). Conclusions: EMDs should be aware that callers are likely to describe loss of function (e.g. unable to grip) rather than symptoms (e.g. weakness) and that callers using the word ‘stroke’ or describing facial weakness, limb weakness or speech problems are likely to be calling about a stroke. Ambiguities and contradictions in dialogue about consciousness level arise during ambulance calls for suspected and confirmed stroke. The online training package improved recognition of stroke by EMDs. Recommendations for future research include testing the effectiveness of the Emergency Stroke Calls: Obtaining Rapid Telephone Triage (ESCORTT) training package on the recognition of stroke across other EMSs in England; and exploring the impact of the early identification of stroke by call handlers on patient and process outcomes. Funding: The National Institute for Health Research Programme Grants for Applied Research programme

Defining and assessing spiritual health : a comparative study among 13- to 15-year-old pupils attending secular schools, Anglican schools, and private Christian schools in England and Wales

This article argues that the nation's commitment to young people involves proper concern for their physical health, their psychological health, and their spiritual health. In this context the notion of spiritual health is clarified by a critique of John Fisher's model of spiritual health. Fisher developed a relational model of spiritual health, which defines good spiritual health in terms of an individual's relationship to four domains: the personal, the communal, the environmental, and the transcendental. In the present analysis, we make comparisons between pupils educated in three types of schools: publicly funded schools without religious foundation, publicly funded schools with an Anglican foundation, and new independent Christian schools (not publicly funded). Our findings draw attention to significant differences in the levels of spiritual health experienced by pupils within these three types of schools

Beyond the ‘Tomlinson Trap’: analysing the effectiveness of section 1 of the Compensation Act 2006

One of the intentions underpinning section 1 of the Compensation Act 2006 was to provide reassurance to individual volunteers, and voluntary organisations, involved in what the provision called ‘desirable activities’ and including sport. The perception was that such volunteers, motivated by an apprehension about their increased vulnerability to negligence liability, and as driven by a fear of a wider societal compensation culture, were engaging excessively in risk-averse behaviour to the detriment of such socially desirable activities. Academic commentary on section 1 of the Compensation Act 2006 has largely regarded the provision as unnecessary and doing little more than restating existing common law practice. This article argues otherwise and, on critically reviewing the emerging jurisprudence, posits the alternative view that section 1, in practice, affords an enhanced level of protection and safeguarding for individuals undertaking functions in connection with a desirable activity. Nonetheless, the occasionally idiosyncratic judicial interpretation given to term ‘desirable activity’, potentially compounded by recent enactment of the Social Action, Responsibility and Heroism Act 2015, remains problematic. Two points of interest will be used to inform this debate. First, an analysis of the then House of Lords’ decision in Tomlinson and its celebrated ‘balancing exercise’ when assessing reasonableness in the context of negligence liability. Second, a fuller analysis of the application of section 1 in the specific context of negligence actions relating to the coaching of sport where it is argued that the, albeit limited, jurisprudence might support the practical utility of a heightened evidential threshold of gross negligence

Identification, characterisation and expression analysis of natural killer receptor genes in Chlamydia pecorum infected koalas (Phascolarctos cinereus)

BACKGROUND: Koalas (Phascolarctos cinereus), an iconic Australian marsupial, are being heavily impacted by the spread of Chlamydia pecorum, an obligate intracellular bacterial pathogen. Koalas vary in their response to this pathogen, with some showing no symptoms, while others suffer severe symptoms leading to infertility, blindness or death. Little is known about the pathology of this disease and the immune response against it in this host. Studies have demonstrated that natural killer (NK) cells, key components of the innate immune system, are involved in the immune response to chlamydial infections in humans. These cells can directly lyse cells infected by intracellular pathogens and their ability to recognise these infected cells is mediated through NK receptors on their surface. These are encoded in two regions of the genome, the leukocyte receptor complex (LRC) and the natural killer complex (NKC). These two families evolve rapidly and different repertoires of genes, which have evolved by gene duplication, are seen in different species. METHODS: In this study we aimed to characterise genes belonging to the NK receptor clusters in the koala by searching available koala transcriptomes using a combination of search methods. We developed a qPCR assay to quantify relative expression of four genes, two encoded within the NK receptor cluster (CLEC1B, CLEC4E) and two known to play a role in NK response to Chalmydia in humans (NCR3, PRF1). RESULTS: We found that the NK receptor repertoire of the koala closely resembles that of the Tasmanian devil, with minimal genes in the NKC, but with lineage specific expansions in the LRC. Additional genes important for NK cell activity, NCR3 and PRF1, were also identified and characterised. In a preliminary study to investigate whether these genes are involved in the koala immune response to infection by its chlamydial pathogen, C. pecorum, we investigated the expression of four genes in koalas with active chlamydia infection, those with past infection and those without infection using qPCR. This analysis revealed that one of these four, CLEC4E, may be upregulated in response to chlamydia infection. CONCLUSION: We have characterised genes of the NKC and LRC in koalas and have discovered evidence that one of these genes may be upregulated in koalas with chlamydia, suggesting that these receptors may play a role in the immune response of koalas to chlamydia infection

Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe

Probing Clostridium difficile Infection in Complex Human Gut Cellular Models

Interactions of anaerobic gut bacteria, such as Clostridium difficile, with the intestinal mucosa have been poorly studied due to challenges in culturing anaerobes with the oxygen-requiring gut epithelium. Although gut colonization by C. difficile is a key determinant of disease outcome, precise mechanisms of mucosal attachment and spread remain unclear. Here, using human gut epithelial monolayers co-cultured within dual environment chambers, we demonstrate that C. difficile adhesion to gut epithelial cells is accompanied by a gradual increase in bacterial numbers. Prolonged infection causes redistribution of actin and loss of epithelial integrity, accompanied by production of C. difficile spores, toxins, and bacterial filaments. This system was used to examine C. difficile interactions with the commensal Bacteroides dorei, and interestingly, C. difficile growth is significantly reduced in the presence of B. dorei. Subsequently, we have developed novel models containing a myofibroblast layer, in addition to the epithelium, grown on polycarbonate or three-dimensional (3D) electrospun scaffolds. In these more complex models, C. difficile adheres more efficiently to epithelial cells, as compared to the single epithelial monolayers, leading to a quicker destruction of the epithelium. Our study describes new controlled environment human gut models that enable host–anaerobe and pathogen–commensal interaction studies in vitro

Transgenic Overexpression of the Type I Isoform of Neuregulin 1 Affects Working Memory and Hippocampal Oscillations but not Long-term Potentiation

Neuregulin 1 (NRG1) is a growth factor involved in neurodevelopment and plasticity. It is a schizophrenia candidate gene, and hippocampal expression of the NRG1 type I isoform is increased in the disorder. We have studied transgenic mice overexpressing NRG1 type I (NRG1tg-type I) and their wild-type littermates and measured hippocampal electrophysiological and behavioral phenotypes. Young NRG1tg-type I mice showed normal memory performance, but in older NRG1tg-type I mice, hippocampus-dependent spatial working memory was selectively impaired. Hippocampal slice preparations from NRG1tg-type I mice exhibited a reduced frequency of carbachol-induced gamma oscillations and an increased tendency to epileptiform activity. Long-term potentiation in NRG1tg-type I mice was normal. The results provide evidence that NRG1 type I impacts on hippocampal function and circuitry. The effects are likely mediated via inhibitory interneurons and may be relevant to the involvement of NRG1 in schizophrenia. However, the findings, in concert with those from other genetic and pharmacological manipulations of NRG1, emphasize the complex and pleiotropic nature of the gene, even with regard to a single isoform