Investigation of Frizzled-5 during embryonic neural development in mouse

Journal ArticleCellular and tissue--tissue interactions regulate development of the central nervous system (CNS) and a paramount question is what is the nature of the signals involved in these interactions. The vertebrate eye represents an excellent and challenging CNS model because it contains multiple cell and tissue types that must coordinate their development to form a functional unit. Eye development becomes apparent when the ventral diencephalic neuroepithelium evaginates to form the optic vesicles. The neural retina and retinal pigment epithelium become patterned in the distal and proximal domains of the optic vesicle, respectively. Adjacent extraocular tissues such as the surrounding mesenchyme, the overlying surface ectoderm and the ventral diencephalon regulate these patterning events. Interaction between the distal optic vesicle and surface (lens) ectoderm leads to invagination, formation of the optic cup, and subsequent development of the lens. Several genes have been shown to control optic cup morphogenesis and differentiation of ocular tissues

Standardisation of data from real-time quantitative PCR methods – evaluation of outliers and comparison of calibration curves

BACKGROUND: As real-time quantitative PCR (RT-QPCR) is increasingly being relied upon for the enforcement of legislation and regulations dependent upon the trace detection of DNA, focus has increased on the quality issues related to the technique. Recent work has focused on the identification of factors that contribute towards significant measurement uncertainty in the real-time quantitative PCR technique, through investigation of the experimental design and operating procedure. However, measurement uncertainty contributions made during the data analysis procedure have not been studied in detail. This paper presents two additional approaches for standardising data analysis through the novel application of statistical methods to RT-QPCR, in order to minimise potential uncertainty in results. RESULTS: Experimental data was generated in order to develop the two aspects of data handling and analysis that can contribute towards measurement uncertainty in results. This paper describes preliminary aspects in standardising data through the application of statistical techniques to the area of RT-QPCR. The first aspect concerns the statistical identification and subsequent handling of outlying values arising from RT-QPCR, and discusses the implementation of ISO guidelines in relation to acceptance or rejection of outlying values. The second aspect relates to the development of an objective statistical test for the comparison of calibration curves. CONCLUSION: The preliminary statistical tests for outlying values and comparisons between calibration curves can be applied using basic functions found in standard spreadsheet software. These two aspects emphasise that the comparability of results arising from RT-QPCR needs further refinement and development at the data-handling phase. The implementation of standardised approaches to data analysis should further help minimise variation due to subjective judgements. The aspects described in this paper will help contribute towards the development of a set of best practice guidelines regarding standardising handling and interpretation of data arising from RT-QPCR experiments

The Atacama Cosmology Telescope: Cosmology from Galaxy Clusters Detected via the Sunyaev-Zel'dovich Effect

We present constraints on cosmological parameters based on a sample of Sunyaev-Zel'dovich-selected galaxy clusters detected in a millimeter-wave survey by the Atacama Cosmology Telescope. The cluster sample used in this analysis consists of 9 optically-confirmed high-mass clusters comprising the high-significance end of the total cluster sample identified in 455 square degrees of sky surveyed during 2008 at 148 GHz. We focus on the most massive systems to reduce the degeneracy between unknown cluster astrophysics and cosmology derived from SZ surveys. We describe the scaling relation between cluster mass and SZ signal with a 4-parameter fit. Marginalizing over the values of the parameters in this fit with conservative priors gives sigma_8 = 0.851 +/- 0.115 and w = -1.14 +/- 0.35 for a spatially-flat wCDM cosmological model with WMAP 7-year priors on cosmological parameters. This gives a modest improvement in statistical uncertainty over WMAP 7-year constraints alone. Fixing the scaling relation between cluster mass and SZ signal to a fiducial relation obtained from numerical simulations and calibrated by X-ray observations, we find sigma_8 = 0.821 +/- 0.044 and w = -1.05 +/- 0.20. These results are consistent with constraints from WMAP 7 plus baryon acoustic oscillations plus type Ia supernoava which give sigma_8 = 0.802 +/- 0.038 and w = -0.98 +/- 0.053. A stacking analysis of the clusters in this sample compared to clusters simulated assuming the fiducial model also shows good agreement. These results suggest that, given the sample of clusters used here, both the astrophysics of massive clusters and the cosmological parameters derived from them are broadly consistent with current models.Comment: 12 pages, 7 figures. Submitted to Ap

Human cytomegalovirus UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112

Human cytomegalovirus (HCMV) UL141 induces protection against natural killer cell-mediated cytolysis by downregulating cell surface expression of CD155 (nectin-like molecule 5; poliovirus receptor), a ligand for the activating receptor DNAM-1 (CD226). However, DNAM-1 is also recognized to bind a second ligand, CD112 (nectin-2). We now show that HCMV targets CD112 for proteasome-mediated degradation by 48 h post-infection, thus removing both activating ligands for DNAM-1 from the cell surface during productive infection. Significantly, cell surface expression of both CD112 and CD155 was restored when UL141 was deleted from the HCMV genome. While gpUL141 alone is sufficient to mediate retention of CD155 in the endoplasmic reticulum, UL141 requires assistance from additional HCMV-encoded functions to suppress expression of CD112

Estimates of probable dementia prevalence from population-based surveys compared with dementia prevalence estimates based on meta-analyses

<p>Abstract</p> <p>Background</p> <p>National data on dementia prevalence are not always available, yet it may be possible to obtain estimates from large surveys that include dementia screening instruments. In Australia, many of the dementia prevalence estimates are based on European data collected between 15 and 50 years ago. We derived population-based estimates of probable dementia and possible cognitive impairment in Australian studies using the Mini-Mental State Examination (MMSE), and compared these to estimates of dementia prevalence from meta-analyses of European studies.</p> <p>Methods</p> <p>Data sources included a pooled dataset of Australian longitudinal studies (DYNOPTA), and two Australian Bureau of Statistics National Surveys of Mental Health and Wellbeing. National rates of probable dementia (MMSE < 24) and possible cognitive impairment (24-26) were estimated using combined sample weights.</p> <p>Results</p> <p>Estimates of probable dementia were higher in surveys than in meta-analyses for ages 65-84, but were similar at ages 85 and older. Surveys used weights to account for sample bias, but no adjustments were made in meta-analyses. Results from DYNOPTA and meta-analyses had a very similar pattern of increase with age. Contrary to trends from some meta-analyses, rates of probable dementia were not higher among women in the Australian surveys. Lower education was associated with higher prevalence of probable dementia. Data from investigator-led longitudinal studies designed to assess cognitive decline appeared more reliable than government health surveys.</p> <p>Conclusions</p> <p>This study shows that estimates of probable dementia based on MMSE in studies where cognitive decline and dementia are a focus, are a useful adjunct to clinical studies of dementia prevalence. Such information and may be used to inform projections of dementia prevalence and the concomitant burden of disease.</p

Toward interoperable bioscience data

© The Author(s), 2012. This article is distributed under the terms of the Creative Commons Attribution License. The definitive version was published in Nature Genetics 44 (2012): 121-126, doi:10.1038/ng.1054.To make full use of research data, the bioscience community needs to adopt technologies and reward mechanisms that support interoperability and promote the growth of an open 'data commoning' culture. Here we describe the prerequisites for data commoning and present an established and growing ecosystem of solutions using the shared 'Investigation-Study-Assay' framework to support that vision.The authors also acknowledge the following funding sources in particular: UK Biotechnology and Biological Sciences Research Council (BBSRC) BB/I000771/1 to S.-A.S. and A.T.; UK BBSRC BB/I025840/1 to S.-A.S.; UK BBSRC BB/I000917/1 to D.F.; EU CarcinoGENOMICS (PL037712) to J.K.; US National Institutes of Health (NIH) 1RC2CA148222-01 to W.H. and the HSCI; US MIRADA LTERS DEB-0717390 and Alfred P. Sloan Foundation (ICoMM) to L.A.-Z.; Swiss Federal Government through the Federal Office of Education and Science (FOES) to L.B. and I.X.; EU Innovative Medicines Initiative (IMI) Open PHACTS 115191 to C.T.E.; US Department of Energy (DOE) DE-AC02- 06CH11357 and Arthur P. Sloan Foundation (2011- 6-05) to J.G.; UK BBSRC SysMO-DB2 BB/I004637/1 and BBG0102181 to C.G.; UK BBSRC BB/I000933/1 to C.S. and J.L.G.; UK MRC UD99999906 to J.L.G.; US NIH R21 MH087336 (National Institute of Mental Health) and R00 GM079953 (National Institute of General Medical Science) to A.L.; NIH U54 HG006097 to J.C. and C.E.S.; Australian government through the National Collaborative Research Infrastructure Strategy (NCRIS); BIRN U24-RR025736 and BioScholar RO1-GM083871 to G.B. and the 2009 Super Science initiative to C.A.S

Protection Induced by Plasmodium falciparum MSP142 Is Strain-Specific, Antigen and Adjuvant Dependent, and Correlates with Antibody Responses

Vaccination with Plasmodium falciparum MSP142/complete Freund's adjuvant (FA) followed by MSP142/incomplete FA is the only known regimen that protects Aotus nancymaae monkeys against infection by erythrocytic stage malaria parasites. The role of adjuvant is not defined; however complete FA cannot be used in humans. In rodent models, immunity is strain-specific. We vaccinated Aotus monkeys with the FVO or 3D7 alleles of MSP142 expressed in Escherichia coli or with the FVO allele expressed in baculovirus (bv) combined with complete and incomplete FA, Montanide ISA-720 (ISA-720) or AS02A. Challenge with FVO strain P. falciparum showed that suppression of cumulative day 11 parasitemia was strain-specific and could be induced by E. coli expressed MSP142 in combination with FA or ISA-720 but not with AS02A. The coli42-FVO antigen induced a stronger protective effect than the bv42-FVO antigen, and FA induced a stronger protective effect than ISA-720. ELISA antibody (Ab) responses at day of challenge (DOC) were strain-specific and correlated inversely with c-day 11 parasitemia (r = −0.843). ELISA Ab levels at DOC meeting a titer of at least 115,000 ELISA Ab units identified the vaccinees not requiring treatment (noTx) with a true positive rate of 83.3% and false positive rate of 14.3 %. Correlation between functional growth inhibitory Ab levels (GIA) and cumulative day 11 parasitemia was weaker (r = −0.511), and was not as predictive for a response of noTx. The lowest false positive rate for GIA was 30% when requiring a true positive rate of 83.3%. These inhibition results along with those showing that antigen/FA combinations induced a stronger protective immunity than antigen/ISA-720 or antigen/AS02 combinations are consistent with protection as ascribed to MSP1-specific cytophilic antibodies. Development of an effective MSP142 vaccine against erythrocytic stage P. falciparum infection will depend not only on antigen quality, but also upon the selection of an optimal adjuvant component

A randomised controlled feasibility trial for an educational school-based mental health intervention: study protocol

Background: With the burden of mental illness estimated to be costing the English economy alone around £22.5 billion a year [1], coupled with growing evidence that many mental disorders have their origins in adolescence, there is increasing pressure for schools to address the emotional well-being of their students, alongside the stigma and discrimination of mental illness. A number of prior educational interventions have been developed and evaluated for this purpose, but inconsistency of findings, reporting standards, and methodologies have led the majority of reviewers to conclude that the evidence for the efficacy of these programmes remains inconclusive. Methods/Design: A cluster randomised controlled trial design has been employed to enable a feasibility study of 'SchoolSpace', an intervention in 7 UK secondary schools addressing stigma of mental illness, mental health literacy, and promotion of mental health. A central aspect of the intervention involves students in the experimental condition interacting with a young person with lived experience of mental illness, a stigma reducing technique designed to facilitate students' engagement in the project. The primary outcome is the level of stigma related to mental illness. Secondary outcomes include mental health literacy, resilience to mental illness, and emotional well-being. Outcomes will be measured pre and post intervention, as well as at 6 month follow-up. Discussion: The proposed intervention presents the potential for increased engagement due to its combination of education and contact with a young person with lived experience of mental illness. Contact as a technique to reduce discrimination has been evaluated previously in research with adults, but has been employed in only a minority of research trials investigating the impact on youth. Prior to this study, the effect of contact on mental health literacy, resilience, and emotional well-being has not been evaluated to the authors' knowledge. If efficacious the intervention could provide a reliable and cost-effective method to reduce stigma in young people, whilst increasing mental health literacy, and emotional well-being. Trial registration: ISRCTN: ISRCTN0740602