Role of tumour necrosis factor gene polymorphisms (-308 and -238) in breast cancer susceptibility and severity

Introduction Genetic polymorphisms in the promoter region of the tumour necrosis factor (TNF) gene can regulate gene expression and have been associated with inflammatory and malignant conditions. We have investigated two polymorphisms in the promoter of the TNF gene (-308 G>A and -238 G>A) for their role in breast cancer susceptibility and severity by means of an allelic association study. Methods Using a case–control study design, breast cancer patients (n = 709) and appropriate age-matched and sex-matched controls obtained from the Breast Screening Unit (n = 498) were genotyped for these TNF polymorphisms, using a high-throughput allelic discrimination method. Results Allele frequencies for both polymorphisms were similar in both breast cancer cases and controls. However, the -308 polymorphism was found to be associated with vascular invasion in breast tumours (P = 0.024). Comparison with other standard prognostic indices did not show any association for either genotype. Conclusions We demonstrated no association between the -308G>A polymorphism and the -238G>A polymorphism in the promoter region of TNF and susceptibility to breast cancer, in a large North European population. However, the -308 G>A polymorphism was found to be associated with the presence of vascular invasion in breast tumours

M-theory on `toric' G_2 cones and its type II reduction

We analyze a class of conical G_2 metrics admitting two commuting isometries, together with a certain one-parameter family of G_2 deformations which preserves these symmetries. Upon using recent results of Calderbank and Pedersen, we write down the explicit G_2 metric for the most general member of this family and extract the IIA reduction of M-theory on such backgrounds, as well as its type IIB dual. By studying the asymptotics of type II fields around the relevant loci, we confirm the interpretation of such backgrounds in terms of localized IIA 6-branes and delocalized IIB 5-branes. In particular, we find explicit, general expressions for the string coupling and R-R/NS-NS forms in the vicinity of these objects. Our solutions contain and generalize the field configurations relevant for certain models considered in recent work of Acharya and Witten.Comment: 45 pages, references adde

Representational decisions when learning population dynamics with an instructional simulation

DEMIST is a multi-representational simulation environment that supports understanding of the representations and concepts of population dynamics. We report on a study with 18 subjects with little prior knowledge that explored if DEMIST could support their learning and asked what decisions learners would make about how to use the many representations that DEMIST provides. Analysis revealed that using DEMIST for one hour significantly improved learners' understanding of population dynamics though their knowledge of the relation between representations remained weak. It showed that learners used many of DEMIST's features. For example, they investigated the majority of the representational space, used dynalinking to explore the relation between representations and had preferences for representations with different computational properties. It also revealed that decisions made by designers impacted upon what is intended to be a free discovery environment

The mediating role of parenting in the associations between household chaos and children’s representations of family dysfunction

Children’s drawings are thought to reflect their mental representations of self and their interpersonal relations within families. Household chaos is believed to disrupt key proximal processes related to optimal development. The present study examines the mediating role of parenting behaviors in the relations between two measures of household chaos, instability and disorganization, and how they may be evidenced in children’s representations of family dysfunction as derived from their drawings. The sample (N= 962) is from a longitudinal study of rural poverty exploring the ways in which child, family, and contextual factors shape development over time. Findings reveal that, after controlling for numerous factors including child and primary caregiver covariates, there were significant indirect effects from cumulative family disorganization, but not cumulative family instability, on children’s representation of family dysfunction through parenting behaviors. Results suggest that the proximal effects of daily disorganization outweigh the effects of periodic instability overtime

Can they imagine the future? A qualitative study exploring the skills employers seek in pharmaceutical sciences doctoral graduates

Concerns about the extent to which graduate programs adequately prepare students for the workplace have prompted numerous calls for reform. Understanding what employers look for in doctoral graduates can help schools better align graduate training with workplace needs. Twelve pharmaceutical scientists across diverse specialties and career pathways described the skills considered requisite for success in today’s science economy. Depth and breadth of knowledge, communication, collaboration, adaptability, research productivity, experiential training, and motivation and drive were among the themes identified. These results can be used to inform the development of doctoral curricula in the biomedical sciences

Farm systems assessment of bioenergy feedstock production: Integrating bio-economic models and life cycle analysis approaches

Climate change and energy security concerns have driven the development of policies that encourage bioenergy production. Meeting EU targets for the consumption of transport fuels from bioenergy by 2020 will require a large increase in the production of bioenergy feedstock. Initially an increase in ‘first generation’ biofuels was observed, however ‘food competition’ concerns have generated interest in second generation biofuels (SGBs). These SGBs can be produced from co-products (e.g. cereal straw) or energy crops (e.g. miscanthus), with the former largely negating food competition concerns. In order to assess the sustainability of feedstock supply for SGBs, the financial, environmental and energy costs and benefits of the farm system must be quantified. Previous research has captured financial costs and benefits through linear programming (LP) approaches, whilst environmental and energy metrics have been largely been undertaken within life cycle analysis (LCA) frameworks. Assessing aspects of the financial, environmental and energy sustainability of supplying co-product second generation biofuel (CPSGB) feedstocks at the farm level requires a framework that permits the trade-offs between these objectives to be quantified and understood. The development of a modelling framework for Managing Energy and Emissions Trade-Offs in Agriculture (MEETA Model) that combines bio-economic process modelling and LCA is presented together with input data parameters obtained from literature and industry sources. The MEETA model quantifies arable farm inputs and outputs in terms of financial, energy and emissions results. The model explicitly captures fertiliser: crop-yield relationships, plus the incorporation of straw or removal for sale, with associated nutrient impacts of incorporation/removal on the following crop in the rotation. Key results of crop-mix, machinery use, greenhouse gas (GHG) emissions per kg of crop product and energy use per hectare are in line with previous research and industry survey findings. Results show that the gross margin – energy trade-off is £36 GJ−1, representing the gross margin forgone by maximising net farm energy cf. maximising farm gross margin. The gross margin–GHG emission trade-off is £0.15 kg−1 CO2 eq, representing the gross margin forgone per kg of CO2 eq reduced when GHG emissions are minimised cf. maximising farm gross margin. The energy–GHG emission trade-off is 0.03 GJ kg−1 CO2 eq quantifying the reduction in net energy from the farm system per kg of CO2 eq reduced when minimising GHG emissions cf. maximising net farm energy. When both farm gross margin and net farm energy are maximised all the cereal straw is baled for sale. Sensitivity analysis of the model in relation to different prices of cereal straw shows that it becomes financially optimal to incorporate wheat straw at price of £11 t−1 for this co-product. Local market conditions for straw and farmer attitudes towards incorporation or sale of straw will impact on the straw price at which farmers will supply this potential bioenergy feedstock and represent important areas for future research

Facilitating implementation of research evidence (FIRE): A randomised controlled trial and process evaluation of two models of facilitation informed by the promoting action on research implementation in health services (PARIHS) framework

Background: The PARIHS framework proposes that successful implementation of research evidence results from the complex interplay between the evidence to be implemented, the context of implementation and the facilitation processes employed. Facilitation is defined as a role (the facilitator) and a process (facilitation strategies/methods). Empirical evidence comparing different facilitation approaches is limited; this paper reports a trial of two different types of facilitation represented in the PARIHS framework. Methods: A pragmatic cluster randomised controlled trial with embedded process evaluation was undertaken in 24 long-term nursing care settings in four European countries. In each country, sites were randomly allocated to standard dissemination of urinary incontinence guideline recommendations and one of two types of external-internal facilitation, labelled Type A and B. Type A facilitation was a less resource intensive approach, underpinned by improvement methodology; Type B was a more intensive, emancipatory model of facilitation, informed by critical social science. The primary outcome was percentage documented compliance with guideline recommendations. Process evaluation was framed by realist methodology and involved quantitative and qualitative data collection from multiple sources. Findings: Quantitative data were obtained from reviews of 2313 records. Qualitative data included over 332 hours of observations of care; 39 hours observation of facilitation activity; 471 staff interviews; 174 resident interviews; 120 next of kin/carer interviews; and 125 stakeholder interviews. There were no significant differences in the primary outcome between study arms and all study arms improved over time. Process data revealed three core mechanisms that influenced the trajectory of the facilitation intervention: alignment of the facilitation approach to the needs and expectations of the internal facilitator and colleagues; engagement of internal facilitators and staff in attitude and action; and learning over time. Data from external facilitators demonstrated that the facilitation interventions did not work as planned, issues were cumulative and maintenance of fidelity was problematic. Implications for D&I Research: Evaluating an intervention - in this case facilitation - that is fluid and dynamic within the methodology of a randomised controlled trial is complex and challenging. For future studies, we suggest a theoretical approach to fidelity, with a focus on mechanisms, as opposed to dose and intensity of the intervention

Recent Advances in Modeling Stellar Interiors

Advances in stellar interior modeling are being driven by new data from large-scale surveys and high-precision photometric and spectroscopic observations. Here we focus on single stars in normal evolutionary phases; we will not discuss the many advances in modeling star formation, interacting binaries, supernovae, or neutron stars. We review briefly: 1) updates to input physics of stellar models; 2) progress in two and three-dimensional evolution and hydrodynamic models; 3) insights from oscillation data used to infer stellar interior structure and validate model predictions (asteroseismology). We close by highlighting a few outstanding problems, e.g., the driving mechanisms for hybrid gamma Dor/delta Sct star pulsations, the cause of giant eruptions seen in luminous blue variables such as eta Car and P Cyg, and the solar abundance problem.Comment: Proceedings for invited talk at conference High Energy Density Laboratory Astrophysics 2010, Caltech, March 2010, submitted for special issue of Astrophysics and Space Science; 7 pages; 5 figure

A role for XRCC2 gene polymorphisms in breast cancer risk and survival

Background The XRCC2 gene is a key mediator in the homologous recombination repair of DNA double strand breaks. It is hypothesised that inherited variants in the XRCC2 gene might also affect susceptibility to, and survival from, breast cancer. Methods The study genotyped 12 XRCC2 tagging single nucleotide polymorphisms (SNPs) in 1131 breast cancer cases and 1148 controls from the Sheffield Breast Cancer Study (SBCS), and examined their associations with breast cancer risk and survival by estimating ORs and HRs, and their corresponding 95% CIs. Positive findings were further investigated in 860 cases and 869 controls from the Utah Breast Cancer Study (UBCS) and jointly analysed together with available published data for breast cancer risk. The survival findings were further confirmed in studies (8074 cases) from the Breast Cancer Association Consortium (BCAC). Results The most significant association with breast cancer risk in the SBCS dataset was the XRCC2 rs3218408 SNP (recessive model p=2.3×10−4, minor allele frequency (MAF)=0.23). This SNP yielded an ORrec of 1.64 (95% CI 1.25 to 2.16) in a two-site analysis of SBCS and UBCS, and a meta-ORrec of 1.33 (95% CI 1.12 to 1.57) when all published data were included. This SNP may mark a rare risk haplotype carried by two in 1000 of the control population. Furthermore, the XRCC2 coding R188H SNP (rs3218536, MAF=0.08) was significantly associated with poor survival, with an increased per-allele HR of 1.58 (95% CI 1.01 to 2.49) in a multivariate analysis. This effect was still evident in a pooled meta-analysis of 8781 breast cancer patients from the BCAC (HR 1.19, 95% CI 1.05 to 1.36; p=0.01). Conclusions These findings suggest that XRCC2 SNPs may influence breast cancer risk and survival

The Science of Sungrazers, Sunskirters, and Other Near-Sun Comets

This review addresses our current understanding of comets that venture close to the Sun, and are hence exposed to much more extreme conditions than comets that are typically studied from Earth. The extreme solar heating and plasma environments that these objects encounter change many aspects of their behaviour, thus yielding valuable information on both the comets themselves that complements other data we have on primitive solar system bodies, as well as on the near-solar environment which they traverse. We propose clear definitions for these comets: We use the term near-Sun comets to encompass all objects that pass sunward of the perihelion distance of planet Mercury (0.307 AU). Sunskirters are defined as objects that pass within 33 solar radii of the Sun’s centre, equal to half of Mercury’s perihelion distance, and the commonly-used phrase sungrazers to be objects that reach perihelion within 3.45 solar radii, i.e. the fluid Roche limit. Finally, comets with orbits that intersect the solar photosphere are termed sundivers. We summarize past studies of these objects, as well as the instruments and facilities used to study them, including space-based platforms that have led to a recent revolution in the quantity and quality of relevant observations. Relevant comet populations are described, including the Kreutz, Marsden, Kracht, and Meyer groups, near-Sun asteroids, and a brief discussion of their origins. The importance of light curves and the clues they provide on cometary composition are emphasized, together with what information has been gleaned about nucleus parameters, including the sizes and masses of objects and their families, and their tensile strengths. The physical processes occurring at these objects are considered in some detail, including the disruption of nuclei, sublimation, and ionisation, and we consider the mass, momentum, and energy loss of comets in the corona and those that venture to lower altitudes. The different components of comae and tails are described, including dust, neutral and ionised gases, their chemical reactions, and their contributions to the near-Sun environment. Comet-solar wind interactions are discussed, including the use of comets as probes of solar wind and coronal conditions in their vicinities. We address the relevance of work on comets near the Sun to similar objects orbiting other stars, and conclude with a discussion of future directions for the field and the planned ground- and space-based facilities that will allow us to address those science topics