Specific rolling circle amplification of low-copy human polyomaviruses BKV, HPyV6, HPyV7, TSPyV, and STLPyV

Eleven new human polyomaviruses have been recently discovered, yet for most of these viruses, little is known of their biology and clinical impact. Rolling circle amplification (RCA) is an ideal method for the amplification of the circular polyomavirus genome due to its high fidelity amplification of circular DNA. In this study, a modified RCA method was developed to selectively amplify a range of polyomavirus genomes. Initial evaluation showed a multiplexed temperature-graded reaction profile gave the best yield and sensitivity in amplifying BK polyomavirus in a background of human DNA, with up to 1 × 10(8)-fold increases in viral genomes from as little as 10 genome copies per reaction. Furthermore, the method proved to be more sensitive and provided a 200-fold greater yield than that of random hexamers based standard RCA. Application of the method to other novel human polyomaviruses showed successful amplification of TSPyV, HPyV6, HPyV7, and STLPyV from low-viral load positive clinical samples, with viral genome enrichment ranging from 1 × 10(8) up to 1 × 10(10). This directed RCA method can be applied to selectively amplify other low-copy polyomaviral genomes from a background of competing non-specific DNA, and is a useful tool in further research into the rapidly expanding Polyomaviridae family.

Effect of age and refractive error on the melanopsin mediated Post-Illumination Pupil Response (PIPR)

Melanopsin containing intrinsically photosensitive Retinal Ganglion cells (ipRGCs) mediate the pupil light reflex (PLR) during light onset and at light offset (the post-illumination pupil response, PIPR). Recent evidence shows that the PLR and PIPR can provide non-invasive, objective markers of age-related retinal and optic nerve disease, however there is no consensus on the effects of healthy ageing or refractive error on the ipRGC mediated pupil function. Here we isolated melanopsin contributions to the pupil control pathway in 59 human participants with no ocular pathology across a range of ages and refractive errors. We show that there is no effect of age or refractive error on ipRGC inputs to the human pupil control pathway. The stability of the ipRGC mediated pupil response across the human lifespan provides a functional correlate of their robustness observed during ageing in rodent models.

Brain-specific epigenetic markers of schizophrenia

Epigenetics plays a crucial role in schizophrenia susceptibility. In a previous study, we identified over 4500 differentially methylated sites in prefrontal cortex (PFC) samples from schizophrenia patients. We believe this was the first genome-wide methylation study performed on human brain tissue using the Illumina Infinium HumanMethylation450 Bead Chip. To understand the biological significance of these results, we sought to identify a smaller number of differentially methylated regions (DMRs) of more functional relevance compared with individual differentially methylated sites. Since our schizophrenia whole genome methylation study was performed, another study analysing two separate data sets of post-mortem tissue in the PFC from schizophrenia patients has been published. We analysed all three data sets using the bumphunter function found in the Bioconductor package minfi to identify regions that are consistently differentially methylated across distinct cohorts. We identified seven regions that are consistently differentially methylated in schizophrenia, despite considerable heterogeneity in the methylation profiles of patients with schizophrenia. The regions were near CERS3, DPPA5, PRDM9, DDX43, REC8, LY6G5C and a region on chromosome 10. Of particular interest is PRDM9 which encodes a histone methyltransferase that is essential for meiotic recombination and is known to tag genes for epigenetic transcriptional activation. These seven DMRs are likely to be key epigenetic factors in the aetiology of schizophrenia and normal brain neurodevelopment.

Overfitting Bayesian mixture models with an unknown number of components

This paper proposes solutions to three issues pertaining to the estimation of finite mixture models with an unknown number of components: the non-identifiability induced by overfitting the number of components, the mixing limitations of standard Markov Chain Monte Carlo (MCMC) sampling techniques, and the related label switching problem. An overfitting approach is used to estimate the number of components in a finite mixture model via a Zmix algorithm. Zmix provides a bridge between multidimensional samplers and test based estimation methods, whereby priors are chosen to encourage extra groups to have weights approaching zero. MCMC sampling is made possible by the implementation of prior parallel tempering, an extension of parallel tempering. Zmix can accurately estimate the number of components, posterior parameter estimates and allocation probabilities given a sufficiently large sample size. The results will reflect uncertainty in the final model and will report the range of possible candidate models and their respective estimated probabilities from a single run. Label switching is resolved with a computationally light-weight method, Zswitch, developed for overfitted mixtures by exploiting the intuitiveness of allocation-based relabelling algorithms and the precision of label-invariant loss functions. Four simulation studies are included to illustrate Zmix and Zswitch, as well as three case studies from the literature. All methods are available as part of the R package Zmix, which can currently be applied to univariate Gaussian mixture models.

Intersex onscreen: An overview of recent fictional characters with intersex variations on television

Throughout history, people with intersex variations have been positioned somewhere between ‘prodigy literature and pornography, mythology and medical discourse’ (Gilbert 2000, 145). Indubitably, contemporary representations have changed in step with societal values, yet it could be argued there is still slippage, and, moreover, very little is seen or heard about intersex at all. Where once there was the awe and horror of the highly visible carnival sideshow or medical treatise, the intersex body is now rendered absent by medical intervention, which is invoked to fix the intersexed in both mind and body. This paper explores the fictional representation of people with intersex variations on screen – television and film in predominantly the genres of drama and comedy – arriving finally at characters originating from program-makers willing to work closely with the intersex community. Such texts disrupt unwarranted categorization and erasure by “owning” discursive practices, defying current medical interference and promoting ethical debates around the will-to-normalise what is considered to be aberrant, deviant and abject.

Seasonal variations in the body composition of lightweight rowers

OBJECTIVE To monitor the seasonal body composition alterations in 18 lightweight rowers (six females, 12 males) across a rowing season incorporating preseason, early competition, competition, and postseason. METHODS Subject age was 23.1 (SD 4.5) years, height 170.8 (5.6) cm (female, 23.5 (3.5) years, 180.5 (2.7) cm (male). Body weight, fat mass, and fat-free mass (FFM) were assessed using dual energy x ray absorptiometry (DXA-L Lunar) and skinfold techniques. Weight control techniques were documented before major regattas by a questionnaire. RESULTS Female body weight was reduced from 61.3 (2.9) to 57.0 (1.1) kg (5.9%), while male body weight was reduced from 75.6 (3.1) to 69.8 (1.6) kg (7.8%) preseason to competition season respectively. These body weight reductions were mirrored by a significant reduction in fat mass as indicated by the sum of skinfolds [female seven sites: 80.9 (8.1) to 68.2 (11.8) mm; male eight sites: 54.2 (8.7) to 41.8 (4.8) mm], percentage body fat [female 22.1 (1.0) to 19.7 (2.4)%; male 10.0 (0.9) to 7.8 (0.8)%], and total fat [female 12.5 (5.2) to 10.9 (1.4) kg; male 7.3 (1.9) to 5.6 (1.8) kg] (DXA). In contrast, no changes were observed in FFM despite a season of intensive rowing training. Seasonal body weight control was achieved through reduced total energy and dietary fat intakes. Acute body weight reductions were achieved by exercise in 73.3% of participants, food restriction in 71.4%, and fluid restrictions in 62.9%. CONCLUSIONS Seasonal body weight alterations in lightweight rowers are in response to a significant reduction in fat mass. However, the weight restrictions appear to be limiting an increase in FFM which could be beneficial to rowing performance.

Single layer bismuth iodide: Computational exploration of structural, electrical, mechanical and optical properties

Layered graphitic materials exhibit new intriguing electronic structure and the search for new types of two-dimensional (2D) monolayer is of importance for the fabrication of next generation miniature electronic and optoelectronic devices. By means of density functional theory (DFT) computations, we investigated in detail the structural, electronic, mechanical and optical properties of the single-layer bismuth iodide (BiI3) nanosheet. Monolayer BiI3 is dynamically stable as confirmed by the computed phonon spectrum. The cleavage energy (Ecl) and interlayer coupling strength of bulk BiI3 are comparable to the experimental values of graphite, which indicates that the exfoliation of BiI3 is highly feasible. The obtained stress-strain curve shows that the BiI3 nanosheet is a brittle material with a breaking strain of 13%. The BiI3 monolayer has an indirect band gap of 1.57 eV with spin orbit coupling (SOC), indicating its potential application for solar cells. Furthermore, the band gap of BiI3 monolayer can be modulated by biaxial strain. Most interestingly, interfacing electrically active graphene with monolayer BiI3 nanosheet leads to enhanced light absorption compared to that in pure monolayer BiI3 nanosheet, highlighting its great potential applications in photonics and photovoltaic solar cells.

Can we safely deform a plate to fit every bone? Population-based fit assessment and finite element deformation of a distal tibial plate

Anatomically precontoured plates are commonly used to treat periarticular fractures. A well-fitting plate can be used as a tool for anatomical reduction of the fractured bone. Recent studies highlighted that some plates fit poorly for many patients due to considerable shape variations between bones of the same anatomical site. While it is impossible to design one shape that fits all, it is also burdensome for the manufacturers and hospitals to produce, store and manage multiple plate shapes without the certainty of utilization by a patient population. In this study, we investigated the number of shapes required for maximum fit within a given dataset, and if they could be obtained by manually deforming the original plate. A distal medial tibial plate was automatically positioned on 45 individual tibiae, and the optimal deformation was determined iteratively using finite element analysis simulation. Within the studied dataset, we found that: (i) 89% fit could be achieved with four shapes, (ii) 100% fit was impossible through mechanical deformation, and (iii) the deformations required to obtain the four plate shapes were safe for the stainless steel plate for further clinical use. The proposed framework is easily transferable to other orthopaedic plates.

Analysis of the distribution of the number of bidders in construction contract auctions

The number of bidders, N, involved in a construction procurement auction is known to have an important effect on the value of the lowest bid and the mark up applied by bidders. In practice, for example, it is important for a bidder to have a good estimate of N when bidding for a current contract. One approach, instigated by Friedman in 1956, is to make such an estimate by statistical analysis and modelling. Since then, however, finding a suitable model for N has been an enduring problem for researchers and, despite intensive research activity in the subsequent thirty years little progress has been made - due principally to the absence of new ideas and perspectives. This paper resumes the debate by checking old assumptions, providing new evidence relating to concomitant variables and proposing a new model. In doing this and in order to assure universality, a novel approach is developed and tested by using a unique set of twelve construction tender databases from four continents. This shows the new model provides a significant advancement on previous versions. Several new research questions are also posed and other approaches identified for future study.

Common genetic influences underlie comorbidity of migraine and endometriosis

We examined the co-occurrence of migraine and endometriosis within the largest known collection of families containing multiple women with surgically confirmed endometriosis and in an independent sample of 815 monozygotic and 457 dizygotic female twin pairs. Within the endometriosis families, a significantly increased risk of migrainous headache was observed in women with endometriosis compared to women without endometriosis (odds ratio [OR] 1.57, 95% confidence interval [CI]: 1.12-2.21, P=0.009). Bivariate heritability analyses indicated no evidence for common environmental factors influencing either migraine or endometriosis but significant genetic components for both traits, with heritability estimates of 69 and 49%, respectively. Importantly, a significant additive genetic correlation (r(G) = 0.27, 95% CI: 0.06-0.47) and bivariate heritability (h(2)=0.17, 95% CI: 0.08-0.27) was observed between migraine and endometriosis. Controlling for the personality trait neuroticism made little impact on this association. These results confirm the previously reported comorbidity between migraine and endometriosis and indicate common genetic influences completely explain their co-occurrence within individuals. Given pharmacological treatments for endometriosis typically target hormonal pathways and a number of findings provide support for a relationship between hormonal variations and migraine, hormone-related genes and pathways are highly plausible candidates for both migraine and endometriosis. Therefore, taking into account the status of both migraine and endometriosis may provide a novel opportunity to identify the genes underlying them. Finally, we propose that the analysis of such genetically correlated comorbid traits can increase power to detect genetic risk loci through the use of more specific, homogenous and heritable phenotypes.

Cord blood 25-hydroxyvitamin D and fetal growth in the China-Anhui birth cohort study

We determined the association of cord blood 25-hydroxyvitamin D [25(OH)D] with birth weight and the risk of small for gestational age (SGA). As part of the China-Anhui Birth Cohort (C-ABC) study, we measured cord blood levels of 25(OH)D in 1491 neonates in Hefei, China. The data on maternal sociodemographic characteristics, health status, lifestyle, birth outcomes were prospectively collected. Multiple regression models were used to estimate the association of 25(OH)D levels with birth weight and the risk of SGA. Compared with neonates in the lowest decile of cord blood 25(OH)D levels, neonates in four deciles (the fourth, fifth, sixth and seventh deciles) had significantly increased birth weight and decreased risk of SGA. Multiple linear regression models showed that per 10 nmol/L increase in cord blood 25(OH)D, birth weight increased by 61.0 g (95% CI: 31.9, 89.9) at concentrations less than 40 nmol/L, and then decreased by 68.5 g (95% CI: −110.5, −26.6) at concentrations from 40 to 70 nmol/L. This study provides the first epidemiological evidence that there was an inverted U shaped relationship between neonatal vitamin D status and fetal growth, and the risk of SGA reduced at moderate concentration.

The identification of teaching interactions used in one-to-one teaching of number in the early years of schooling

This research paper reports on phase one of an investigation of video recorded intensive one-to-one teaching interactions with 6–7-year-old students who were in their second year of schooling in Australia and identified by the their teacher as low attaining in early number. The two-phased study from which this paper emerges was originally conducted in 1998 as part of my Bachelor of Teaching Honours (Research) program at Southern Cross University Lismore, New South Wales. That study identified teaching interactions particularly suited to one-to-one teaching in the Maths Recovery Program, a program designed for these students who were at risk of failure in early number. Since that time a great deal has not changed with limited literature available that comprehensively reports on teaching interactions in intensive one-to-one settings. Revisiting the original study is considered timely given the increasing number of withdrawal and intensive programs now funded and adopted by schools and yet, rarely reported on in terms of the effectiveness of the teaching interactions that occur in such settings. This paper then presents a discussion of a preliminary series of teaching interactions that either positively and or negatively influence an intensive one-to-one teaching and learning setting

The clinical effectiveness and cost-effectiveness of exercise referral schemes: A systematic review and economic evaluation

- Background Exercise referral schemes (ERS) aim to identify inactive adults in the primary-care setting. The GP or health-care professional then refers the patient to a third-party service, with this service taking responsibility for prescribing and monitoring an exercise programme tailored to the needs of the individual. - Objective To assess the clinical effectiveness and cost-effectiveness of ERS for people with a diagnosed medical condition known to benefit from physical activity (PA). The scope of this report was broadened to consider individuals without a diagnosed condition who are sedentary. - Data sources MEDLINE; EMBASE; PsycINFO; The Cochrane Library, ISI Web of Science; SPORTDiscus and ongoing trial registries were searched (from 1990 to October 2009) and included study references were checked. - Methods Systematic reviews: the effectiveness of ERS, predictors of ERS uptake and adherence, and the cost-effectiveness of ERS; and the development of a decision-analytic economic model to assess cost-effectiveness of ERS. - Results Seven randomised controlled trials (UK, n = 5; non-UK, n = 2) met the effectiveness inclusion criteria, five comparing ERS with usual care, two compared ERS with an alternative PA intervention, and one to an ERS plus a self-determination theory (SDT) intervention. In intention-to-treat analysis, compared with usual care, there was weak evidence of an increase in the number of ERS participants who achieved a self-reported 90-150 minutes of at least moderate-intensity PA per week at 6-12 months' follow-up [pooled relative risk (RR) 1.11, 95% confidence interval 0.99 to 1.25]. There was no consistent evidence of a difference between ERS and usual care in the duration of moderate/vigorous intensity and total PA or other outcomes, for example physical fitness, serum lipids, health-related quality of life (HRQoL). There was no between-group difference in outcomes between ERS and alternative PA interventions or ERS plus a SDT intervention. None of the included trials separately reported outcomes in individuals with medical diagnoses. Fourteen observational studies and five randomised controlled trials provided a numerical assessment of ERS uptake and adherence (UK, n = 16; non-UK, n = 3). Women and older people were more likely to take up ERS but women, when compared with men, were less likely to adhere. The four previous economic evaluations identified suggest ERS to be a cost-effective intervention. Indicative incremental cost per quality-adjusted life-year (QALY) estimates for ERS for various scenarios were based on a de novo model-based economic evaluation. Compared with usual care, the mean incremental cost for ERS was £169 and the mean incremental QALY was 0.008, with the base-case incremental cost-effectiveness ratio at £20,876 per QALY in sedentary people without a medical condition and a cost per QALY of £14,618 in sedentary obese individuals, £12,834 in sedentary hypertensive patients, and £8414 for sedentary individuals with depression. Estimates of cost-effectiveness were highly sensitive to plausible variations in the RR for change in PA and cost of ERS. - Limitations We found very limited evidence of the effectiveness of ERS. The estimates of the cost-effectiveness of ERS are based on a simple analytical framework. The economic evaluation reports small differences in costs and effects, and findings highlight the wide range of uncertainty associated with the estimates of effectiveness and the impact of effectiveness on HRQoL. No data were identified as part of the effectiveness review to allow for adjustment of the effect of ERS in different populations. - Conclusions There remains considerable uncertainty as to the effectiveness of ERS for increasing activity, fitness or health indicators or whether they are an efficient use of resources in sedentary people without a medical diagnosis. We failed to identify any trial-based evidence of the effectiveness of ERS in those with a medical diagnosis. Future work should include randomised controlled trials assessing the cinical effectiveness and cost-effectivenesss of ERS in disease groups that may benefit from PA. - Funding The National Institute for Health Research Health Technology Assessment programme.

Editorial of "International Journal of Critical Indigenous Studies Volume 1, Number 1, 2008"

We perceive the epistemological boundaries of Critical Indigenous Studies as marked by analyses of contemporary colonising power in its multiple forms in different contexts. This first issue brings together a diverse group of international Indigenous scholars who are politically and intellectually engaged in theorising from their respective standpoints as well as spatial and geographic locations. As such these essays enable dialogue across and within different colonial power contexts addressing epistemological ethical and methodological concerns within the broad field of Indigenous studies. In each essay a connecting theme is the need for intercultural and comparative work and to import Indigenous agency in the writing of history...