Dynamic changes in the epigenomic landscape regulate human organogenesis and link to developmental disorders

How the genome activates or silences transcriptional programmes governs organ formation. Little is known in human embryos undermining our ability to benchmark the fidelity of stem cell differentiation or cell programming, or interpret the pathogenicity of noncoding variation. Here, we study histone modifications across thirteen tissues during human organogenesis. We integrate the data with transcription to build an overview of how the human genome differentially regulates alternative organ fates including by repression. Promoters from nearly 20,000 genes partition into discrete states. Key developmental gene sets are actively repressed outside of the appropriate organ without obvious bivalency. Candidate enhancers, functional in zebrafish, allow imputation of tissue-specific and shared patterns of transcription factor binding. Overlaying more than 700 noncoding mutations from patients with developmental disorders allows correlation to unanticipated target genes. Taken together, the data provide a comprehensive genomic framework for investigating normal and abnormal human development

Folding Circular Permutants of IL-1β: Route Selection Driven by Functional Frustration

Interleukin-1β (IL-1β) is the cytokine crucial to inflammatory and immune response. Two dominant routes are populated in the folding to native structure. These distinct routes are a result of the competition between early packing of the functional loops versus closure of the β-barrel to achieve efficient folding and have been observed both experimentally and computationally. Kinetic experiments on the WT protein established that the dominant route is characterized by early packing of geometrically frustrated functional loops. However, deletion of one of the functional loops, the β-bulge, switches the dominant route to an alternative, yet, as accessible, route, where the termini necessary for barrel closure form first. Here, we explore the effect of circular permutation of the WT sequence on the observed folding landscape with a combination of kinetic and thermodynamic experiments. Our experiments show that while the rate of formation of permutant protein is always slower than that observed for the WT sequence, the region of initial nucleation for all permutants is similar to that observed for the WT protein and occurs within a similar timescale. That is, even permutants with significant sequence rearrangement in which the functional-nucleus is placed at opposing ends of the polypeptide chain, fold by the dominant WT “functional loop-packing route”, despite the entropic cost of having to fold the N- and C- termini early. Taken together, our results indicate that the early packing of the functional loops dominates the folding landscape in active proteins, and, despite the entropic penalty of coalescing the termini early, these proteins will populate an entropically unfavorable route in order to conserve function. More generally, circular permutation can elucidate the influence of local energetic stabilization of functional regions within a protein, where topological complexity creates a mismatch between energetics and topology in active proteins

Systematic Bias in Genomic Classification Due to Contaminating Non-neoplastic Tissue in Breast Tumor Samples

Abstract Background Genomic tests are available to predict breast cancer recurrence and to guide clinical decision making. These predictors provide recurrence risk scores along with a measure of uncertainty, usually a confidence interval. The confidence interval conveys random error and not systematic bias. Standard tumor sampling methods make this problematic, as it is common to have a substantial proportion (typically 30-50%) of a tumor sample comprised of histologically benign tissue. This "normal" tissue could represent a source of non-random error or systematic bias in genomic classification. Methods To assess the performance characteristics of genomic classification to systematic error from normal contamination, we collected 55 tumor samples and paired tumor-adjacent normal tissue. Using genomic signatures from the tumor and paired normal, we evaluated how increasing normal contamination altered recurrence risk scores for various genomic predictors. Results Simulations of normal tissue contamination caused misclassification of tumors in all predictors evaluated, but different breast cancer predictors showed different types of vulnerability to normal tissue bias. While two predictors had unpredictable direction of bias (either higher or lower risk of relapse resulted from normal contamination), one signature showed predictable direction of normal tissue effects. Due to this predictable direction of effect, this signature (the PAM50) was adjusted for normal tissue contamination and these corrections improved sensitivity and negative predictive value. For all three assays quality control standards and/or appropriate bias adjustment strategies can be used to improve assay reliability. Conclusions Normal tissue sampled concurrently with tumor is an important source of bias in breast genomic predictors. All genomic predictors show some sensitivity to normal tissue contamination and ideal strategies for mitigating this bias vary depending upon the particular genes and computational methods used in the predictor

BRCA1 mutations and other sequence variants in a population-based sample of Australian women with breast cancer

The frequency, in women with breast cancer, of mutations and other variants in the susceptibility gene, BRCA1, was investigated using a population-based case–control-family study. Cases were women living in Melbourne or Sydney, Australia, with histologically confirmed, first primary, invasive breast cancer, diagnosed before the age of 40 years, recorded on the state Cancer Registries. Controls were women without breast cancer, frequency-matched for age, randomly selected from electoral rolls. Full manual sequencing of the coding region of BRCA1 was conducted in a randomly stratified sample of 91 cases; 47 with, and 44 without, a family history of breast cancer in a first- or second-degree relative. All detected variants were tested in a random sample of 67 controls. Three cases with a (protein-truncating) mutation were detected. Only one case had a family history; her mother had breast cancer, but did not carry the mutation. The proportion of Australian women with breast cancer before age 40 who carry a germline mutation in BRCA1 was estimated to be 3.8% (95% Cl 0.3–12.6%). Seven rare variants were also detected, but for none was there evidence of a strong effect on breast cancer susceptibility. Therefore, on a population basis, rare variants are likely to contribute little to breast cancer incidence. © 1999 Cancer Research Campaig

Case management used to optimize cancer care pathways: A systematic review

<p>Abstract</p> <p>Background</p> <p>Reports of inadequate cancer patient care have given rise to various interventions to support cancer care pathways which, overall, seem poorly studied. Case management (CM) is one method that may support a cost-effective, high-quality patient-centred treatment and care.</p> <p>The purpose of this article was to summarise intervention characteristics, outcomes of interest, results, and validity components of the published randomized controlled trials (RCTs) examining CM as a method for optimizing cancer care pathways.</p> <p>Methods</p> <p>PubMed, Embase, Web of Science, CINAHL and The Cochrane Central Register of Controlled Trials were systematically searched for RCTs published all years up to August 2008. Identified papers were included if they passed the following standards. Inclusion criteria: 1) The intervention should meet the criteria for CM which includes multidisciplinary collaboration, care co-ordination, and it should include in-person meetings between patient and the case manager aimed at supporting, informing and educating the patient. 2) The intervention should focus on cancer patient care. 3) The intervention should aim to improve subjective or objective quality outcomes, and effects should be reported in the paper.</p> <p>Exclusion criteria: Studies centred on cancer screening or palliative cancer care.</p> <p>Data extraction was conducted in order to obtain a descriptive overview of intervention characteristics, outcomes of interest and findings. Elements of CONSORT guidelines and checklists were used to assess aspects of study validity.</p> <p>Results</p> <p>The searches identified 654 unique papers, of which 25 were retrieved for scrutiny. Seven papers were finally included. Intervention characteristics, outcomes studied, findings and methodological aspects were all very diverse.</p> <p>Conclusion</p> <p>Due to the scarcity of papers included (seven), significant heterogeneity in target group, intervention setting, outcomes measured and methodologies applied, no conclusions can be drawn about the effect of CM on cancer patient care.</p> <p>It is a major challenge that CM shrouds in a "black box", which means that it is difficult to determine which aspect(s) of interventions contribute to overall effects. More trials on rigorously developed CM interventions (opening up the "black box") are needed as is the re-testing of interventions and outcomes studied in various settings.</p

Utilizing Spatial Demographic and Life History Variation to Optimize Sustainable Yield of a Temperate Sex-Changing Fish

Fish populations vary geographically in demography and life history due to environmental and ecological processes and in response to exploitation. However, population dynamic models and stock assessments, used to manage fisheries, rarely explicitly incorporate spatial variation to inform management decisions. Here, we describe extensive geographic variation in several demographic and life history characteristics (e.g., size structure, growth, survivorship, maturation, and sex change) of California sheephead (Semicossyphus pulcher), a temperate rocky reef fish targeted by recreational and commercial fisheries. Fish were sampled from nine locations throughout southern California in 2007–2008. We developed a dynamic size and age-structured model, parameterized separately for each location, to assess the potential cost or benefit in terms of fisheries yield and conservation objectives of changing minimum size limits and/or fishing mortality rates (compared to the status quo). Results indicate that managing populations individually, with location-specific regulations, could increase yield by over 26% while maintaining conservative levels of spawning biomass. While this local management approach would be challenging to implement in practice, we found statistically similar increases in yield could be achieved by dividing southern California into two separate management regions, reflecting geographic similarities in demography. To maximize yield, size limits should be increased by 90 mm in the northern region and held at current levels in the south. We also found that managing the fishery as one single stock (the status quo), but with a size limit 50 mm greater than the current regulations, could increase overall fishery yield by 15%. Increases in size limits are predicted to enhance fishery yield and may also have important ecological consequences for the predatory role of sheephead in kelp forests. This framework for incorporating demographic variation into fisheries models can be exported generally to other species and may aid in identifying the appropriate spatial scales for fisheries management

Rationales, rhetoric and realities:FIFA’s World Cup in South Africa 2010 and Brazil 2014

The 2010 FIFA World Cup was heralded by mainstream media outlets, the local organisers, the South African government and FIFA as an unequivocal success. The month-long spectacle saw South Africa take centre stage and host the world’s largest single sporting event. This occurred against a backdrop of rationales and promises made that the event would leave lasting legacies for all, in particular marginalised South Africans. The reality is quite different. In this article we consider the South African World Cup in the build up to Brazil 2014. We argue that the rationales and rhetoric are similar in both countries and suggest the reality for Brazil 2014 will be the same as South Africa 2010 in that the mega-event will be primarily funded by significant public investment, while the primary beneficiaries will be private capital and FIFA

A glycoconjugate of Haemophilus influenzae Type b capsular polysaccharide with tetanus toxoid protein: hydrodynamic properties mainly influenced by the carbohydrate

Three important physical properties which may affect the performance of glycoconjugate vaccines against serious disease are molar mass (molecular weight), heterogeneity (polydispersity), and conformational flexibility in solution. The dilute solution behaviour of native and activated capsular polyribosylribitol (PRP) polysaccharides extracted from Haemophilus influenzae type b (Hib), and the corresponding glycoconjugate made by conjugating this with the tetanus toxoid (TT) protein have been characterized and compared using a combination of sedimentation equilibrium and sedimentation velocity in the analytical ultracentrifuge with viscometry. The weight average molar mass of the activated material was considerably reduced (Mw ~ 0.24 × 106 g.mol−1) compared to the native (Mw ~ 1.2 × 106 g.mol−1). Conjugation with the TT protein yielded large polydisperse structures (of Mw ~ 7.4 × 106 g.mol−1), but which retained the high degree of flexibility of the native and activated polysaccharide, with frictional ratio, intrinsic viscosity, sedimentation conformation zoning behaviour and persistence length all commensurate with highly flexible coil behaviour and unlike the previously characterised tetanus toxoid protein (slightly extended and hydrodynamically compact structure with an aspect ratio of ~3). This non-protein like behaviour clearly indicates that it is the carbohydrate component which mainly influences the physical behaviour of the glycoconjugate in solution

The Relationship between Regular Sports Participation and Vigilance in Male and Female Adolescents

The present study investigated the relationship between regular sport participation (soccer) and vigilance performance. Two groups of male and female adolescents differentiated in terms of their sport participation (athletes, n = 39, and non-athletes, n = 36) took part in the study. In one session, participants performed the Leger Multi-stage fitness test to estimate their aerobic fitness level. In the other session, participants completed the Psychomotor Vigilance Task (PVT) to evaluate their vigilance performance. Perceived arousal prior to the task and motivation toward the task were also measured in the PVT session. The results revealed that athletes had better cardiovascular fitness and showed better performance in the PVT. However, correlation analyses did not show any significant relationship between cardiovascular fitness and performance in the PVT. Athletes showed larger scores in motivation and perceived arousal measures with respect to non-athletes, although, once again, these variables were not correlated with PVT performance. Gender differences were observed only in the Leger test, with males showing greater fitness level than females. The major outcome of this research points to a positive relationship between regular sport participation and vigilance during adolescence. This relationship did not seem to be influenced by gender, perceived arousal, motivation toward the task or cardiovascular fitness. We discuss our results in terms of the different hypotheses put forward in the literature to explain the relationship between physical activity and cognitive functioning.This research was supported by a Spanish Ministerio de Educación y Cultura (https://sede. educacion.gob.es) predoctoral grant (FPU13-05605) to the first author, and project research grants: Junta de Andalucia Proyecto de Excelencia SEJ-6414 (http://www.juntadeandalucia.es) and Ministerio de Economía y Competitividad PSI2013-46385 (http://www.mineco.gob.es) to DS and FH