A coherent middle Pliocene magnetostratigraphy, Wanganui Basin, New Zealand

We document magnetostratigraphies for three river sections (Turakina, Rangitikei, Wanganui) in Wanganui Basin and interpret them as corresponding to the Upper Gilbert, the Gauss and lower Matuyama Chrons of the Geomagnetic Polarity Timescale, in agreement with foraminiferal biostratigraphic datums. The Gauss-Gilbert transition (3.58 Ma) is located in both the Turakina and Wanganui River sections, while the Gauss-Matuyama transition (2.58 Ma) is located in all three sections, as are the lower and upper boundaries of the Mammoth (3.33–3.22 Ma) and Kaena (3.11–3.04 Ma) Subchrons. Our interpretations are based in part on the re-analysis of existing datasets and in part on the acquisition and analysis of new data, particularly for the Wanganui River section. The palaeomagnetic dates of these six horizons provide the only numerical age control for a thick (up to 2000 m) mudstone succession (Tangahoe Mudstone) that accumulated chiefly in upper bathyal and outer neritic palaeoenvironments. In the Wanganui River section the mean sediment accumulation rate is estimated to have been about 1.8 m/k.y., in the Turakina section it was about 1.5 m/k.y., and in the Rangitikei section, the mean rate from the beginning of the Mammoth Subchron to the Hautawa Shellbed was about 1.1 m/k.y. The high rates may be associated with the progradation of slope clinoforms northward through the basin. This new palaeomagnetic timescale allows revised correlations to be made between cyclothems in the Rangitikei River section and the global Oxygen Isotope Stages (OIS) as represented in Ocean Drilling Program (ODP) Site 846. The 16 depositional sequences between the end of the Mammoth Subchron and the Gauss-Matuyama Boundary are correlated with OIS MG2 to 100. The cyclothems average 39 k.y. in duration in our age model, which is close to the 41 k.y. duration of the orbital obliquity cycles. We support the arguments advanced recently in defence of the need for local New Zealand stages as a means of classifying New Zealand sedimentary successions, and strongly oppose the proposal to move stage boundaries to selected geomagnetic polarity transitions. The primary magnetisation of New Zealand mudstone is frequently overprinted with secondary components of diagenetic origin, and hence it is often difficult to obtain reliable magnetostratigraphic records. We suggest specific approaches, analytical methods, and criteria to help ensure robustness and coherency in the palaeomagnetic identification of chron boundaries in typical New Zealand Cenozoic mudstone successions

Development of a scale to measure stigma related to podoconiosis in Southern Ethiopia

Background: Health-related stigma adds to the physical and economic burdens experienced by people suffering from neglected tropical diseases (NTDs). Previous research into the NTD podoconiosis showed significant stigma towards those with the disease, yet no formal instrument exists by which to assess stigma or interventions to reduce stigma. We aimed to develop, pilot and validate scales to measure the extent of stigma towards podoconiosis among patients and in podoconiosis-endemic communities. Methods: Indicators of stigma were drawn from existing qualitative podoconiosis research and a literature review on measuring leprosy stigma. These were then formulated into items for questioning and evaluated through a Delphi process in which irrelevant items were discounted. The final items formed four scales measuring two distinct forms of stigma (felt stigma and enacted stigma) for those with podoconiosis and those without the disease. The scales were formatted as two questionnaires, one for podoconiosis patients and one for unaffected community members. 150 podoconiosis patients and 500 unaffected community members from Wolaita zone, Southern Ethiopia were selected through multistage random sampling to complete the questionnaires which were interview-administered. The scales were evaluated through reliability assessment, content and construct validity analysis of the items, factor analysis and internal consistency analysis. Results: All scales had Cronbach’s alpha over 0.7, indicating good consistency. The content and construct validity of the scales were satisfactory with modest correlation between items. There was significant correlation between the felt and enacted stigma scales among patients (Spearman’s r = 0.892; p < 0.001) and within the community (Spearman’s r = 0.794; p < 0.001). Conclusion: We report the development and testing of the first standardised measures of podoconiosis stigma. Although further research is needed to validate the scales in other contexts, we anticipate they will be useful in situational analysis and in designing, monitoring and evaluating interventions. The scales will enable an evidencebased approach to mitigating stigma which will enable implementation of more effective disease control and help break the cycle of poverty and NTDs

α-Synuclein Aggregation Inhibitory Prunolides and a Dibrominated β-Carboline Sulfamate from the Ascidian Synoicum prunum

Seven new polyaromatic bis-spiroketal-containing butenolides, the prunolides D–I (4–9) and cis-prunolide C (10), a new dibrominated β-carboline sulfamate named pityriacitrin C (11), alongside the known prunolides A–C (1–3) were isolated from the Australian colonial ascidian Synoicum prunum. The prunolides D–G (4–7) represent the first asymmetrically brominated prunolides, while cis-prunolide C (10) is the first reported with a cis-configuration about the prunolide’s bis-spiroketal core. The prunolides displayed binding activities with the Parkinson’s disease-implicated amyloid protein α-synuclein in a mass spectrometry binding assay, while the prunolides (1–5 and 10) were found to significantly inhibit the aggregation (>89.0%) of α-synuclein in a ThT amyloid dye assay. The prunolides A–C (1–3) were also tested for inhibition of pSyn aggregate formation in a primary embryonic mouse midbrain dopamine neuron model with prunolide B (2) displaying statistically significant inhibitory activity at 0.5 μM. The antiplasmodial and antibacterial activities of the isolates were also examined with prunolide C (3) displaying only weak activity against the 3D7 parasite strain of Plasmodium falciparum. Our findings reported herein suggest that the prunolides could provide a novel scaffold for the exploration of future therapeutics aimed at inhibiting amyloid protein aggregation and the treatment of numerous neurodegenerative diseases.Peer reviewe

The UK Independence Party and the Politics of Englishness

The rise of the UK Independence Party has been one of the most dramatic and widely discussed features of British politics in recent years. This article argues that one vital but largely overlooked facet of this phenomenon has been the politics of national identity. It argues that despite the UK Independence Party’s ostensibly unionist stance, Englishness is an important pivot around which key elements of the party’s appeal revolve, notably in terms of its Euroscepticism, its opposition to immigration and its anti-establishment narrative. It argues that the Anglo-Britishness promulgated by the UK Independence Party allows space for the celebration of English identity rather more easily than of other sub-state national identities, as it does not challenge the legitimacy of the UK state, which is itself seen as the expression of Anglo-British identity and sovereignty. Scottish nationalism, on the other hand, is seen as a threat to the union and therefore anti-English

Disease progression in Plasmodium knowlesi malaria is linked to variation in invasion gene family members.

Emerging pathogens undermine initiatives to control the global health impact of infectious diseases. Zoonotic malaria is no exception. Plasmodium knowlesi, a malaria parasite of Southeast Asian macaques, has entered the human population. P. knowlesi, like Plasmodium falciparum, can reach high parasitaemia in human infections, and the World Health Organization guidelines for severe malaria list hyperparasitaemia among the measures of severe malaria in both infections. Not all patients with P. knowlesi infections develop hyperparasitaemia, and it is important to determine why. Between isolate variability in erythrocyte invasion, efficiency seems key. Here we investigate the idea that particular alleles of two P. knowlesi erythrocyte invasion genes, P. knowlesi normocyte binding protein Pknbpxa and Pknbpxb, influence parasitaemia and human disease progression. Pknbpxa and Pknbpxb reference DNA sequences were generated from five geographically and temporally distinct P. knowlesi patient isolates. Polymorphic regions of each gene (approximately 800 bp) were identified by haplotyping 147 patient isolates at each locus. Parasitaemia in the study cohort was associated with markers of disease severity including liver and renal dysfunction, haemoglobin, platelets and lactate, (r = ≥ 0.34, p =  <0.0001 for all). Seventy-five and 51 Pknbpxa and Pknbpxb haplotypes were resolved in 138 (94%) and 134 (92%) patient isolates respectively. The haplotypes formed twelve Pknbpxa and two Pknbpxb allelic groups. Patients infected with parasites with particular Pknbpxa and Pknbpxb alleles within the groups had significantly higher parasitaemia and other markers of disease severity. Our study strongly suggests that P. knowlesi invasion gene variants contribute to parasite virulence. We focused on two invasion genes, and we anticipate that additional virulent loci will be identified in pathogen genome-wide studies. The multiple sustained entries of this diverse pathogen into the human population must give cause for concern to malaria elimination strategists in the Southeast Asian region

A major genetic locus in <i>Trypanosoma brucei</i> is a determinant of host pathology

The progression and variation of pathology during infections can be due to components from both host or pathogen, and/or the interaction between them. The influence of host genetic variation on disease pathology during infections with trypanosomes has been well studied in recent years, but the role of parasite genetic variation has not been extensively studied. We have shown that there is parasite strain-specific variation in the level of splenomegaly and hepatomegaly in infected mice and used a forward genetic approach to identify the parasite loci that determine this variation. This approach allowed us to dissect and identify the parasite loci that determine the complex phenotypes induced by infection. Using the available trypanosome genetic map, a major quantitative trait locus (QTL) was identified on T. brucei chromosome 3 (LOD = 7.2) that accounted for approximately two thirds of the variance observed in each of two correlated phenotypes, splenomegaly and hepatomegaly, in the infected mice (named &lt;i&gt;TbOrg1&lt;/i&gt;). In addition, a second locus was identified that contributed to splenomegaly, hepatomegaly and reticulocytosis (&lt;i&gt;TbOrg2&lt;/i&gt;). This is the first use of quantitative trait locus mapping in a diploid protozoan and shows that there are trypanosome genes that directly contribute to the progression of pathology during infections and, therefore, that parasite genetic variation can be a critical factor in disease outcome. The identification of parasite loci is a first step towards identifying the genes that are responsible for these important traits and shows the power of genetic analysis as a tool for dissecting complex quantitative phenotypic traits

Allele Frequency–Based and Polymorphism-Versus-Divergence Indices of Balancing Selection in a New Filtered Set of Polymorphic Genes in Plasmodium falciparum

Signatures of balancing selection operating on specific gene loci in endemic pathogens can identify candidate targets of naturally acquired immunity. In malaria parasites, several leading vaccine candidates convincingly show such signatures when subjected to several tests of neutrality, but the discovery of new targets affected by selection to a similar extent has been slow. A small minority of all genes are under such selection, as indicated by a recent study of 26 Plasmodium falciparum merozoite-stage genes that were not previously prioritized as vaccine candidates, of which only one (locus PF10_0348) showed a strong signature. Therefore, to focus discovery efforts on genes that are polymorphic, we scanned all available shotgun genome sequence data from laboratory lines of P. falciparum and chose six loci with more than five single nucleotide polymorphisms per kilobase (including PF10_0348) for in-depth frequency–based analyses in a Kenyan population (allele sample sizes >50 for each locus) and comparison of Hudson–Kreitman–Aguade (HKA) ratios of population diversity (π) to interspecific divergence (K) from the chimpanzee parasite Plasmodium reichenowi. Three of these (the msp3/6-like genes PF10_0348 and PF10_0355 and the surf4.1 gene PFD1160w) showed exceptionally high positive values of Tajima's D and Fu and Li's F indices and have the highest HKA ratios, indicating that they are under balancing selection and should be prioritized for studies of their protein products as candidate targets of immunity. Combined with earlier results, there is now strong evidence that high HKA ratio (as well as the frequency-independent ratio of Watterson's θ/K) is predictive of high values of Tajima's D. Thus, the former offers value for use in genome-wide screening when numbers of genome sequences within a species are low or in combination with Tajima's D as a 2D test on large population genomic samples

Understanding the power of the prime minister : structure and agency in models of prime ministerial power

Understanding the power of the prime minister is important because of the centrality of the prime minister within the core executive of British government, but existing models of prime ministerial power are unsatisfactory for various reasons. This article makes an original contribution by providing an overview and critique of the dominant models of prime ministerial power, highlighting their largely positivist bent and the related problem of the prevalence of overly parsimonious conceptions of the structural contexts prime ministers face. The central argument the paper makes is that much of the existing literature on prime ministerial power is premised on flawed understandings of the relationship between structure and agency, that this leads to misunderstandings of the real scope of prime ministerial agency, as well as its determinants, and that this can be rectified by adopting a strategic-relational view of structure and agency

The role of measuring exhaled breath biomarkers in sarcoidosis: A systematic review

Introduction: Sarcoidosis is a chronic granulomatous disease of unknown aetiology with a variable clinical course and prognosis. There is a growing need to identify non-invasive biomarkers to differentiate between clinical phenotypes, identify those at risk of disease progression and monitor response to treatment. Objectives: We undertook a systematic review and meta-analysis, to evaluate the utility of breath-based biomarkers in discriminating sarcoidosis from healthy controls, alongside correlation with existing non-breath based biomarkers used in clinical practice, radiological stage, markers of disease activity and response to treatment. Methods: Electronic searches were undertaken during November 2017 using PubMed, Ebsco, Embase and Web of Science to capture relevant studies evaluating breath-based biomarkers in adult patients with sarcoidosis. Results: 353 papers were screened; 21 met the inclusion criteria and assessed 25 different biomarkers alongside VOCs in exhaled breath gas or condensate. Considerable heterogeneity existed amongst the studies in terms of participant characteristics, sampling and analytical methods. Elevated biomarkers in sarcoidosis included 8-isoprostane, carbon monoxide, neopterin, TGF-β1, TNFα, CysLT and several metallic elements including chromium, silicon and nickel. Three studies exploring VOCs were able to distinguish sarcoidosis from controls. Meta-analysis of four studies assessing alveolar nitric oxide showed no significant difference between sarcoidosis and healthy controls (2.22ppb; 95% CI -0.83, 5.27) however, a high degree of heterogeneity was observed with an I2 of 93.4% (p<0.001). Inconsistent or statistically insignificant results were observed for correlations between several biomarkers and radiological stage, markers of disease activity or treatment. Conclusions: The evidence for using breath biomarkers to diagnose and monitor sarcoidosis remains inconclusive with many studies limited by small sample sizes and lack of standardisation. VOCs have shown promising potential but further research is required to evaluate their prognostic role