Outlier SNP markers reveal fine-scale genetic structuring across European hake populations (Merluccius merluccius)

Shallow population structure is generally reported for most marine fish and explained as a consequence of high dispersal, connectivity and large population size. Targeted gene analyses and more recently genome-wide studies have challenged such view, suggesting that adaptive divergence might occur even when neutral markers provide genetic homogeneity across populations. Here, 381 SNPs located in transcribed regions were used to assess large- and fine-scale population structure in the European hake (Merluccius merluccius), a widely distributed demersal species of high priority for the European fishery. Analysis of 850 individuals from 19 locations across the entire distribution range showed evidence for several outlier loci, with significantly higher resolving power. While 299 putatively neutral SNPs confirmed the genetic break between basins (F(CT) = 0.016) and weak differentiation within basins, outlier loci revealed a dramatic divergence between Atlantic and Mediterranean populations (F(CT) range 0.275-0.705) and fine-scale significant population structure. Outlier loci separated North Sea and Northern Portugal populations from all other Atlantic samples and revealed a strong differentiation among Western, Central and Eastern Mediterranean geographical samples. Significant correlation of allele frequencies at outlier loci with seawater surface temperature and salinity supported the hypothesis that populations might be adapted to local conditions. Such evidence highlights the importance of integrating information from neutral and adaptive evolutionary patterns towards a better assessment of genetic diversity. Accordingly, the generated outlier SNP data could be used for tackling illegal practices in hake fishing and commercialization as well as to develop explicit spatial models for defining management units and stock boundaries.

Context-dependent Combination of Sensor Information in Dempster-Shafer Theory for BDI

There has been much interest in the belief–desire–intention (BDI) agent-based model for developing scalable intelligent systems, e.g. using the AgentSpeak framework. However, reasoning from sensor information in these large-scale systems remains a significant challenge. For example, agents may be faced with information from heterogeneous sources which is uncertain and incomplete, while the sources themselves may be unreliable or conflicting. In order to derive meaningful conclusions, it is important that such information be correctly modelled and combined. In this paper, we choose to model uncertain sensor information in Dempster–Shafer (DS) theory. Unfortunately, as in other uncertainty theories, simple combination strategies in DS theory are often too restrictive (losing valuable information) or too permissive (resulting in ignorance). For this reason, we investigate how a context-dependent strategy originally defined for possibility theory can be adapted to DS theory. In particular, we use the notion of largely partially maximal consistent subsets (LPMCSes) to characterise the context for when to use Dempster’s original rule of combination and for when to resort to an alternative. To guide this process, we identify existing measures of similarity and conflict for finding LPMCSes along with quality of information heuristics to ensure that LPMCSes are formed around high-quality information. We then propose an intelligent sensor model for integrating this information into the AgentSpeak framework which is responsible for applying evidence propagation to construct compatible information, for performing context-dependent combination and for deriving beliefs for revising an agent’s belief base. Finally, we present a power grid scenario inspired by a real-world case study to demonstrate our work.

Pet population management and public health:A web service based tool for the improvement of dog traceability

The risks associated with zoonotic infections transmitted by companion animals are a serious public health concern: the control of zoonoses incidence in domestic dogs, both owned and stray, is hence important to protect human health. Integrated dog population management (DPM) programs, based on the availability of information systems providing reliable data on the structure and composition of the existing dog population in a given area, are fundamental for making realistic plans for any disease surveillance and action system. Traceability systems, based on the compulsory electronic identification of dogs and their registration in a computerised database, are one of the most effective ways to ensure the usefulness of DPM programs. Even if this approach provides many advantages, several areas of improvement have emerged in countries where it has been applied. In Italy, every region hosts its own dog register but these are not compatible with one another. This paper shows the advantages of a web-based-application to improve data management of dog regional registers. The approach used for building this system was inspired by farm animal traceability schemes and it relies on a network of services that allows multi-channel access by different devices and data exchange via the web with other existing applications, without changing the pre-existing platforms. Today the system manages a database for over 300,000 dogs registered in three different Italian regions. By integrating multiple Web Services, this approach could be the solution to gather data at national and international levels at reasonable cost and creating a traceability system on a large scale and across borders that can be used for disease surveillance and development of population management plans. © 2012 Elsevier B.V.

Behavioural reactivity of ewes and lambs during partial and total social isolation

This work investigated the differences in the reactivity of Sarda (primiparous n= 18, multiparous n= 17) and Dorset (multiparous n= 8) breeds of sheep and their singleton lambs to two challenging test situations involving a mother-lamb partial separation test and an isolation test. Non-parametric analysis used single behavioural variables and fear scores to evaluate the effect of parity, sex of lambs, and the association between mother-lamb behaviour. Amongst ewes, Dorset were characterised by a more calm temperament while Sarda (especially primiparous ewes) were more active in their response to challenge (i.e. more attempts to escape). As with their dams, lambs reflected to a certain extent this divergence and overall during isolation lamb fear score was on average significantly higher than dams. Correlations between measures of behavioural reactivity across tests were carried out to search for predictive measures of fear. A very strong correlation emerged linking vocalisation to locomotor activity. Vocalisation could be a good candidate as predictor factor of an active reaction of sheep to a fearful situation.

Calmodulin disruption impacts growth and motility in juvenile liver fluke

Background: Deficiencies in effective flukicide options and growing issues with drug resistance make current strategies for liver fluke control unsustainable, thereby promoting the need to identify and validate new control targets in Fasciola spp. parasites. Calmodulins (CaMs) are small calcium-sensing proteins with ubiquitous expression in all eukaryotic organisms and generally use fluctuations in intracellular calcium levels to modulate cell signalling events. CaMs are essential for fundamental processes including the phosphorylation of protein kinases, gene transcription, calcium transport and smooth muscle contraction. In the blood fluke Schistosoma mansoni, calmodulins have been implicated in egg hatching, miracidial transformation and larval development. Previously, CaMs have been identified amongst liver fluke excretory-secretory products and three CaM-like proteins have been characterised biochemically from adult Fasciola hepatica, although their functions remain unknown.

Methods: In this study, we set out to investigate the biological function and control target potential of F. hepatica CaMs (FhCaMs) using RNAi methodology alongside novel in vitro bioassays.

Results: Our results reveal that: (i) FhCaMs are widely expressed in parenchymal cells throughout the forebody region of juvenile fluke; (ii) significant transcriptional knockdown of FhCaM1-3 was inducible by exposure to either long (~200 nt) double stranded (ds) RNAs or 27 nt short interfering (si) RNAs, although siRNAs were less effective than long dsRNAs; (iii) transient long dsRNA exposure-induced RNA interference (RNAi) of FhCaMs triggered transcript knockdown that persisted for ≥ 21 days, and led to detectable suppression of FhCaM proteins; (iv) FhCaM RNAi significantly reduced the growth of juvenile flukes maintained in vitro; (v) FhCaM RNAi juveniles also displayed hyperactivity encompassing significantly increased migration; (vi) both the reduced growth and increased motility phenotypes were recapitulated in juvenile fluke using the CaM inhibitor trifluoperazine hydrochloride, supporting phenotype specificity.

Conclusions: These data indicate that the Ca(2+)-modulating functions of FhCaMs are important for juvenile fluke growth and movement and provide the first functional genomics-based example of a growth-defect resulting from gene silencing in liver fluke. Whilst the phenotypic impacts of FhCaM silencing on fluke behaviour do not strongly support their candidature as new flukicide targets, the growth impacts encourage further consideration, especially in light of the speed of juvenile fluke growth in vivo.

GEP analysis validates high risk MDS and acute myeloid leukemia post MDS mice models and highlights novel dysregulated pathways

BACKGROUND: In spite of the recent discovery of genetic mutations in most myelodysplasic (MDS) patients, the pathophysiology of these disorders still remains poorly understood, and only few in vivo models are available to help unravel the disease.

METHODS: We performed global specific gene expression profiling and functional pathway analysis in purified Sca1+ cells of two MDS transgenic mouse models that mimic human high-risk MDS (HR-MDS) and acute myeloid leukemia (AML) post MDS, with NRASD12 and BCL2 transgenes under the control of different promoters MRP8NRASD12/tethBCL-2 or MRP8[NRASD12/hBCL-2], respectively.

RESULTS: Analysis of dysregulated genes that were unique to the diseased HR-MDS and AML post MDS mice and not their founder mice pointed first to pathways that had previously been reported in MDS patients, including DNA replication/damage/repair, cell cycle, apoptosis, immune responses, and canonical Wnt pathways, further validating these models at the gene expression level. Interestingly, pathways not previously reported in MDS were discovered. These included dysregulated genes of noncanonical Wnt pathways and energy and lipid metabolisms. These dysregulated genes were not only confirmed in a different independent set of BM and spleen Sca1+ cells from the MDS mice but also in MDS CD34+ BM patient samples.

CONCLUSIONS: These two MDS models may thus provide useful preclinical models to target pathways previously identified in MDS patients and to unravel novel pathways highlighted by this study.

After the Critique of Rights: For a Radical Democratic Theory and Practice of Human Rights

The critique of human rights has proliferated in critical legal thinking over recent years, making it clear that we can no longer uncritically approach human rights in their liberal form. In this article I assert that after the critique of rights one way human rights may be productively re-engaged in radical politics is by drawing from the radical democratic tradition. Radical democratic thought provides plausible resources to rework the shortcomings of liberal human rights, and allows human rights to be brought within the purview of a wider political project adopting a critical approach to current relations of power. Building upon previous re-engagements with rights using radical democratic thought, I return to the work of Ernesto Laclau and Chantal Mouffe to explore how human rights may be thought as an antagonistic hegemonic activity within a critical relation to power, a concept which is fundamentally futural, and may emerge as one site for work towards radical and plural democracy. I also assert, via Judith Butler's model of cultural translation, that a radical democratic practice of human rights may be advanced which resonates with and builds upon already existing activism, thereby holding possibilities to persuade those who remain sceptical as to radical re-engagements with rights.

Explaining voting behaviour on free votes: Solely a matter of preference?

While studies examining free votes find MPs’ preferences influence their voting behaviour, most studies also show MPs tend to divide along party lines even after the whips have been withdrawn. Recent work offers a possible alternative explanation for this finding: this sustained party cohesion represents the impact of MPs’ party identification similar to party identification effects in the electorate. This argument is tested using a series of free votes on same-sex relations. Even after controlling for preferences using several direct measures, party continues to shape voting behaviour. Although indirect, this provides evidence in favour of the party-asidentification argument. 

Higher plasma levels of complement C3a, C4a and C5a increase the risk of subretinal fibrosis in neovascular age-related macular degeneration.

Background: The aim of this study was to investigate the plasma levels of complement C3a, C4a, and C5a in different types of neovascular age-related macular degeneration (nAMD) and whether the levels were related to patients’ responsiveness to anti-VEGF therapy.

Results: Ninety-six nAMD patients (including 61 with choroidal neovascularisation (CNV), 17 with retinal angiomatous proliferation (RAP), 14 with polypoidal choroidal vasculopathy (PCV) and 4 unclassified patients) and 43 controls were recruited to this case–control study. Subretinal fibrosis was observed in 45 nAMD patients and was absent in 51 nAMD patients. In addition, the responsiveness to anti-VEGF (Lucentis) therapy was also evaluated in nAMD patients. Forty-four patients were complete responders, 48 were partially responders, and only 4 patients did not respond to the therapy. The plasma levels of C3a, C4a and C5a were significantly higher in nAMD patients compared to
controls. Further analysis of nAMD subgroups showed that the levels of C3a, C4a and C5a were significantly increased in patients with CNV but not RAP and PCV. Significantly increased levels of C3a, C4a and C5a were also observed in nAMD patients with subretinal fibrosis but not in those without subretinal fibrosis. Higher levels of C3a were observed in nAMD patients who responded partially to anti-VEGF therapy.

Conclusions: Our results suggest increased systemic complement activation in nAMD patients with CNV but not RAP and PCV. Our results also suggest that higher levels of systemic complement activation may increase the risk of subretinal fibrosis in nAMD patients

Microneedles: A New Frontier in Nanomedicine Delivery

This review aims to concisely chart the development of two individual research fields, namely nanomedicines, with specific emphasis on nanoparticles (NP) and microparticles (MP), and microneedle (MN) technologies, which have, in the recent past, been exploited in combinatorial approaches for the efficient delivery of a variety of medicinal agents across the skin. This is an emerging and exciting area of pharmaceutical sciences research within the remit of transdermal drug delivery and as such will undoubtedly continue to grow with the emergence of new formulation and fabrication methodologies for particles and MN. Firstly, the fundamental aspects of skin architecture and structure are outlined, with particular reference to their influence on NP and MP penetration. Following on from this, a variety of different particles are described, as are the diverse range of MN modalities currently under development. The review concludes by highlighting some of the novel delivery systems which have been described in the literature exploiting these two approaches and directs the reader towards emerging uses for nanomedicines in combination with MN.

Validating the use of intrinsic markers in body feathers to identify inter‑individual differences in non‑breeding areas of northern fulmars

Many wildlife studies use chemical analyses to explore spatio-temporal variation in diet, migratory patterns and contaminant exposure. Intrinsic markers are particularly valuable for studying non-breeding marine predators, when direct methods of investigation are rarely feasible. However, any inferences regarding foraging ecology are dependent upon the time scale over which tissues such as feathers are formed. In this study, we validate the use of body feathers for studying non-breeding foraging patterns in a pelagic seabird, the northern fulmar. Analysis of carcasses of successfully breeding adult fulmars indicated that body feathers moulted between September and March, whereas analyses of carcasses and activity patterns suggested that wing feather and tail feather moult occurred during more restricted periods (September to October and September to January, respectively). By randomly sampling relevant body feathers, average values for individual birds were shown to be consistent. We also integrated chemical analyses of body feather with geolocation tracking data to demonstrate that analyses of δ13C and δ15N values successfully assigned 88 % of birds to one of two broad wintering regions used by breeding adult fulmars from a Scottish study colony. These data provide strong support for the use of body feathers as a tool for exploring non-breeding foraging patterns and diet in wide-ranging, pelagic seabirds.

Peer tutoring in a medical school: perceptions of tutors and tutees

Background: Peer tutoring has been described as “people from similar social groupings who are not professional teachers helping each other to learn and learning themselves by teaching”. Peer tutoring is well accepted as a source of support in many medical curricula, where participation and learning involve a process of socialisation.
Peer tutoring can ease the transition of the junior students from the university class environment to the hospital workplace. In this paper, we apply the Experienced Based Learning (ExBL) model to explore medical students’ perceptions of their experience of taking part in a newly established peer tutoring program at a hospital based
clinical school.
Methods: In 2014, all students at Sydney Medical School – Central, located at Royal Prince Alfred Hospital were invited to voluntarily participate in the peer tutoring program. Year 3 students (n = 46) were invited to act as tutors for Year 1 students (n = 50), and Year 4 students (n = 60) were invited to act as tutors for Year 2 students (n = 51). Similarly, the ‘tutees’ were invited to take part on a voluntary basis. Students were invited to attend focus groups, which were held at the end of the program. Framework analysis was used to code and categorise data into themes.
Results: In total, 108/207 (52 %) students participated in the program. A total of 42/106 (40 %) of Year 3 and 4 students took part as tutors; and of 66/101 (65 %) of Year 1 and 2 students took part as tutees. Five focus groups were held, with 50/108 (46 %) of students voluntarily participating. Senior students (tutors) valued the opportunity to practice and improve their medical knowledge and teaching skills. Junior students (tutees) valued the opportunity for additional practice and patient interaction, within a relaxed, small group learning environment.
Conclusion: Students perceived the peer tutoring program as affording opportunities not otherwise available within the curriculum. The peer teaching program provided a framework within the medical curriculum for senior students to practice and improve their medical knowledge and teaching skills. Concurrently, junior students were provided with a valuable learning experience that they reported as being qualitatively different to traditional teaching by faculty.

Impact of non-pharmacological interventions on prevention and treatment of delirium in critically ill patients: protocol for a systematic review of quantitative and qualitative research

Background: Critically ill patients have an increased risk of developing delirium during their intensive care stay.To date, pharmacological interventions have not been shown to be effective for delirium management but non-pharmacological interventions have shown some promise. The aim of this systematic review is to identify effective non-pharmacological interventions for reducing the incidence or the duration of delirium in critically ill patients.

Methods: We will search MEDLINE, EMBASE, CINAHL, Web of Science, AMED, psycINFO and the Cochrane Library.We will include studies of critically ill adults and children. We will include randomised trials and controlled trials which measure the effectiveness of one or more non-pharmacological interventions in reducing incidence or duration ofdelirium in critically ill patients. We will also include qualitative studies that provide an insight into patients and their families’ experiences of delirium and non-pharmacological interventions. Two independent reviewers will assess studies for eligibility, extract data and appraise quality. We will conduct meta-analyses if possible or present results narratively.Qualitative studies will also be reviewed by two independent reviewers, and a specially designed quality assessment tool incorporating the CASP framework and the POPAY framework will be used to assess quality.

Discussion: Although non-pharmacological interventions have been studied in populations outside of intensive care units and multicomponent interventions have successfully reduced incidence and duration of delirium, no systematic review of non-pharmacological interventions specifically targeting delirium in critically ill patients have been undertaken to date. This systematic review will provide evidence for the development of a multicomponent intervention for delirium management of critically ill patients that can be tested in a subsequent multicentre randomised trial.

Systematic review of interventions to improve the psychological well-being of general practitioners

BACKGROUND: The health of doctors who work in primary care is threatened by workforce and workload issues. There is a need to find and appraise ways in which to protect their mental health, including how to achieve the broader, positive outcome of well-being. Our primary outcome was to evaluate systematically the research evidence regarding the effectiveness of interventions designed to improve General Practitioner (GP) well-being across two continua; psychopathology (mental ill-health focus) and 'languishing to flourishing' (positive mental health focus). In addition we explored the extent to which developments in well-being research may be integrated within existing approaches to design an intervention that will promote mental health and prevent mental illness among these doctors.

METHODS: Medline, Embase, Cinahl, PsychINFO, Cochrane Register of Trials and Web of Science were searched from inception to January 2015 for studies where General Practitioners and synonyms were the primary participants. Eligible interventions included mental ill-health prevention strategies (e.g. promotion of early help-seeking) and mental health promotion programmes (e.g. targeting the development of protective factors at individual and organizational levels). A control group was the minimum design requirement for study inclusion and primary outcomes had to be assessed by validated measures of well-being or mental ill-health. Titles and abstracts were assessed independently by two reviewers with 99 % agreement and full papers were appraised critically using validated tools.

RESULTS: Only four studies (with a total of 997 GPs) from 5392 titles met inclusion criteria. The studies reported statistically significant improvement in self-reported mental ill-health. Two interventions used cognitive-behavioural techniques, one was mindfulness-based and one fed-back GHQ scores and self-help information.

CONCLUSION: There is an urgent need for high quality, controlled studies in GP well-being. Research on improving GP well-being is limited by focusing mainly on stressors and not giving systematic attention to the development of positive mental health.

Impaired orthostatic blood pressure recovery and cognitive performance at two-year follow up in older adults: The Irish Longitudinal Study on Ageing

Background: Prospective investigations of the association between impaired orthostatic blood pressure (BP) regulation and cognitive decline in older adults are limited, and findings to-date have been mixed. The aim of this study was to determine whether impaired recovery of orthostatic BP was associated with change in cognitive function over a 2-year period, in a population based sample of community dwelling older adults. 

Methods: Data from the first two waves of the Irish Longitudinal Study on Ageing were analysed. Orthostatic BP was measured during a lying to standing orthostatic stress protocol at wave 1 using beat-to-beat digital plethysmography, and impaired recovery of BP at 40 s post stand was investigated. Cognitive function was assessed at wave 1 and wave 2 (2 years later) using the Mini-Mental State Exam (MMSE), verbal fluency and word recall tasks. 

Results: After adjustment for measured, potential confounders, and multiple imputation for missing data, the change in the number of errors between waves on the MMSE was 10 % higher [IRR (95 % CI) = 1.10 (0.96, 1.26)] in those with impaired recovery at 40 s. However, this was not statistically significant (p = 0.17). Impaired BP recovery was not associated with change in performance on any of the other cognitive measures. 

Conclusions: There was no clear evidence for an association between impaired recovery of orthostatic BP and change in cognition over a 2-year period in this nationally representative cohort of older adults. Longer follow-up and more detailed cognitive testing would be advantageous to further investigate the relationship between orthostatic BP and cognitive decline.