Probing the growth of supermassive black holes at z>6 with LOFAR

HII regions surrounding supermassive black holes (BHs) in an otherwise still neutral intergalactic medium (IGM) are likely to be the most easily detectable sources by future 21cm experiments like LOFAR. We have made predictions for the size distribution of such HII regions for several physically motivated models for BH growth at high redshift and compared this to the expected LOFAR sensitivity to these sources. The number of potentially detectable HII regions does not only depend on the ionisation state of the intergalactic medium and the decoupling of the spin temperature of the neutral hydrogen from the cosmic microwave background (CMB) temperature, but is also strongly sensitive to the rate of growth of BHs at high redshift. If the supermassive BHs at redshift 6 were built up via continuous Eddington-limited accretion from low mass seed BHs at high redshift, then LOFAR is not expected to detect isolated QSO HII regions at redshifts much larger than 6, and only if the IGM is still significantly neutral. If the high-redshift growth of BHs starts with massive seed BHs and is driven by short-lived accretion events following the merging of BH hosting galaxies then the detection of HII regions surrounding supermassive BHs may extend to redshifts as large as 8-9 but is still very sensitive to the redshift to which the IGM remains significantly neutral. The most optimistic predictions are for a model where the supermassive BHs at z>6 have grown slowly. HII regions around supermassive BHs may then be detected to significantly larger redshifts.Comment: 11 pages, 6 figures, accepted for publication in MNRA

Personal development planning in the first year

The approach to quality and standards in higher education (HE) in Scotland is enhancement led and learner centred. It was developed through a partnership of the Scottish Funding Council (SFC), Universities Scotland, the National Union of Students in Scotland (NUS Scotland) and the Quality Assurance Agency for Higher Education (QAA) Scotland. The Higher Education Academy has also joined that partnership. The Enhancement Themes are a key element of a five-part framework, which has been designed to provide an integrated approach to quality assurance and enhancement. The Enhancement Themes support learners and staff at all levels in further improving higher education in Scotland; they draw on developing innovative practice within the UK and internationally The five elements of the framework are: z a comprehensive programme of subject-level reviews undertaken by higher education institutions (HEIs) themselves; guidance is published by the SFC (www.sfc.ac.uk) z enhancement-led institutional review (ELIR), run by QAA Scotland (www.qaa.ac.uk/reviews/ELIR) z improved forms of public information about quality; guidance is provided by the SFC (www.sfc.ac.uk) z a greater voice for students in institutional quality systems, supported by a national development service - student participation in quality scotland (sparqs) (www.sparqs.org.uk) z a national programme of Enhancement Themes aimed at developing and sharing good practice to enhance the student learning experience, facilitated by QAA Scotland (www.enhancementthemes.ac.uk). The topics for the Enhancement Themes are identified through consultation with the sector and implemented by steering committees whose members are drawn from the sector and the student body. The steering committees have the task of establishing a programme of development activities, which draw on national and international good practice. Publications emerging from each Theme are intended to provide important reference points for HEIs in the ongoing strategic enhancement of their teaching and learning provision. Full details of each Theme, its steering committee, the range of research and development activities as well as the outcomes are published on the Enhancement Themes website (www.enhancementthemes.ac.uk). To further support the implementation and embedding of a quality enhancement culture within the sector - including taking forward the outcomes of the Enhancement Themes - an overarching committee, the Scottish Higher Education Enhancement Committee (SHEEC), chaired by Professor Kenneth Miller, Vice-Principal, University of Strathclyde, has the important dual role of supporting the overall approach of the Enhancement Themes, including the five-year rolling plan, as well as institutional enhancement strategies and management of quality. SHEEC, working with the individual topic-based Enhancement Themes' steering committees, will continue to provide a powerful vehicle for progressing the enhancement-led approach to quality and standards in Scottish higher education

More than Books: A Study of Women’s Participation in Community Libraries in Rural Nepal

In Nepal there are clear gender roles and accompanying expectations about male and female behavior in social spaces. Based on these expectations and traditions there are key obstacles to local women’s opportunities to be active participants in social life. The creation of two community libraries in village Nepal in 1999 and 2001 has created opportunities for women’s involvement in community-based activities and programs. Through their involvement in library activities, women gain access to education, information and communication and the opportunity to learn about financial matters. This paper explores the impact that women’s involvement in the library has on their overall community participation. It also explores the potential of the library as a vehicle for important ‘grass-roots’ social change

Secretory vesicles are preferentially targeted to areas of low molecular SNARE density

Intercellular communication is commonly mediated by the regulated fusion, or exocytosis, of vesicles with the cell surface. SNARE (soluble N-ethymaleimide sensitive factor attachment protein receptor) proteins are the catalytic core of the secretory machinery, driving vesicle and plasma membrane merger. Plasma membrane SNAREs (tSNAREs) are proposed to reside in dense clusters containing many molecules, thus providing a concentrated reservoir to promote membrane fusion. However, biophysical experiments suggest that a small number of SNAREs are sufficient to drive a single fusion event. Here we show, using molecular imaging, that the majority of tSNARE molecules are spatially separated from secretory vesicles. Furthermore, the motilities of the individual tSNAREs are constrained in membrane micro-domains, maintaining a non-random molecular distribution and limiting the maximum number of molecules encountered by secretory vesicles. Together our results provide a new model for the molecular mechanism of regulated exocytosis and demonstrate the exquisite organization of the plasma membrane at the level of individual molecular machines

Two new methods to fit models for network meta-analysis with random inconsistency effects.

BACKGROUND: Meta-analysis is a valuable tool for combining evidence from multiple studies. Network meta-analysis is becoming more widely used as a means to compare multiple treatments in the same analysis. However, a network meta-analysis may exhibit inconsistency, whereby the treatment effect estimates do not agree across all trial designs, even after taking between-study heterogeneity into account. We propose two new estimation methods for network meta-analysis models with random inconsistency effects. METHODS: The model we consider is an extension of the conventional random-effects model for meta-analysis to the network meta-analysis setting and allows for potential inconsistency using random inconsistency effects. Our first new estimation method uses a Bayesian framework with empirically-based prior distributions for both the heterogeneity and the inconsistency variances. We fit the model using importance sampling and thereby avoid some of the difficulties that might be associated with using Markov Chain Monte Carlo (MCMC). However, we confirm the accuracy of our importance sampling method by comparing the results to those obtained using MCMC as the gold standard. The second new estimation method we describe uses a likelihood-based approach, implemented in the metafor package, which can be used to obtain (restricted) maximum-likelihood estimates of the model parameters and profile likelihood confidence intervals of the variance components. RESULTS: We illustrate the application of the methods using two contrasting examples. The first uses all-cause mortality as an outcome, and shows little evidence of between-study heterogeneity or inconsistency. The second uses "ear discharge" as an outcome, and exhibits substantial between-study heterogeneity and inconsistency. Both new estimation methods give results similar to those obtained using MCMC. CONCLUSIONS: The extent of heterogeneity and inconsistency should be assessed and reported in any network meta-analysis. Our two new methods can be used to fit models for network meta-analysis with random inconsistency effects. They are easily implemented using the accompanying R code in the Additional file 1. Using these estimation methods, the extent of inconsistency can be assessed and reported

Loneliness, social isolation and social relationships: what are we measuring? A novel framework for classifying and comparing tools

OBJECTIVES: We present a novel way of classifying and comparing measures of social relationships to help readers interpret the growing literature on loneliness and social isolation and to provide researchers with a starting point to guide their choice of measuring tool. METHODS: Measures of social relationships used in epidemiological studies were identified from two systematic reviews—one review on the association between social relationships and health and social care service use, and a second review on the association between social relationships and health. Questions from each measure were retrieved and tabulated to derive a classification of social relationship measures. RESULTS: We present a classification of measures according to two dimensions: (1) whether instruments cover structural or functional aspects of social relationships and (2) the degree of subjectivity asked of respondents. We explain how this classification can be used to clarify the remit of the many questionnaires used in the literature and to compare them. CONCLUSIONS: Different dimensions of social relationships are likely to have different implications for health. Our classification of social relationship measures transcends disciplinary and conceptual boundaries, allowing researchers to compare tools that developed from different theoretical perspectives. Careful choice of measures is essential to further our understanding of the links between social relationships and health, to identify people in need of help and to design appropriate prevention and intervention strategies

Sex-dependent influence of endogenous estrogen in pulmonary hypertension

Rationale: The incidence of pulmonary arterial hypertension (PAH) is greater in women suggesting estrogens may play a role in the disease pathogenesis. Experimentally, in males exogenously administered estrogen can protect against PH; however in models that display female susceptibility estrogens may play a causative role. Objectives: To clarify the influence of endogenous estrogen and gender in PH and assess the therapeutic potential of a clinically available aromatase inhibitor. Methods: We interrogated the effect of reduced endogenous estrogen in males and females using the aromatase inhibitor, anastrozole, in two models of PH; the hypoxic mouse and Sugen 5416/hypoxic rat. We also determined the effects of gender on pulmonary expression of aromatase in these models and in lungs from PAH patients. Results: Anastrozole attenuated PH in both models studied, but only in females. To verify this effect was due to reduced estrogenic activity we confirmed that in hypoxic mice inhibition of estrogen receptor alpha also has a therapeutic effect specifically in females. Female rodent lung displays increased aromatase and decreased BMPR2 and Id1 expression compared to male. Anastrozole treatment reversed the impaired BMPR2 pathway in females. Increased aromatase expression was also detected in female human pulmonary artery smooth muscle cells compared to male. Conclusions: The unique phenotype of female pulmonary arteries facilitates the therapeutic effects of anastrozole in experimental PH confirming a role for endogenous estrogen in the disease pathogenesis in females and suggests aromatase inhibitors may have therapeutic potential

MSK1 regulates transcriptional induction of Arc/Arg3.1 in response to neurotrophins

The immediate early gene activity-regulated cytoskeletal protein (Arc)/Arg3.1 and the neurotrophin brain-derived neurotrophic factor (BDNF) play important roles in synaptic plasticity and learning and memory in the mammalian brain. However, the mechanisms by which BDNF regulates the expression of Arc/Arg3.1 are unclear. In this study, we show that BDNF acts via the ERK1/2 pathway to activate the nuclear kinase mitogen- and stress-activated protein kinase 1 (MSK1). MSK1 then induces Arc/Arg3.1 expression via the phosphorylation of histone H3 at the Arc/Arg3.1 promoter. MSK1 can also phosphorylate the transcription factor cyclic-AMP response element-binding protein (CREB) on Ser133. However, this is not required for BDNF-induced Arc.Arg3.1 transcription as a Ser133Ala knockin mutation had no effect on Arc/Arg3.1 induction. In parallel, ERK1/2 directly activates Arc/Arg3.1 mRNA transcription via at least one serum response element on the promoter, which bind a complex of the Serum Response Factor (SRF) and a Ternary Complex Factor (TCF)